Clinical trial NCT02756364
Conditions: Breast Neoplasms
Keywords: Drug Therapy
Sponsor: Calithera Biosciences, Inc
Start date: 2016-07-28; Completion date: 2019-11-25
Enrollment: 141 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to compare the progression free survival (PFS) of participants treated with the combination of fulvestrant plus daily sapanisertib and fulvestrant plus weekly sapanisertib versus participants treated with single-agent fulvestrant.

Detailed description:
The drug being tested in this study is called sapanisertib. Sapanisertib is being tested to treat postmenopausal women with advanced or metastatic estrogen receptor (ER) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer that has progressed during or after aromatase inhibitor (AI) therapy. This study will evaluate the efficacy and safety of combination of fulvestrant + daily sapanisertib and fulvestrant + weekly sapanisertib compared with fulvestrant alone.

The study will enroll approximately 153 patients. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

* Fulvestrant 500 mg
* Fulvestrant 500 mg + Sapanisertib 4 mg
* Fulvestrant 500 mg + Sapanisertib 30 mg

All participants will receive either fulvestrant 500 mg intramuscularly (IM), fulvestrant 500 mg + sapanisertib 4 mg daily or fulvestrant 500 mg + sapanisertib 30 mg weekly.

This multicenter trial will be conducted Spain and the USA. Participants will make multiple visits to the clinic, and end of treatment (EOT) visit which will occur 30 to 40 days after receiving their last dose of study drug or before the start of any subsequent anticancer therapy. After EOT, participants will be followed for progression free survival (PFS) and overall survival (OS).

Arms: arm 1: Fulvestrant 500 mg, intramuscularly (IM), once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 16.0 weeks). arm 2: Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with the sapanisertib 4 mg, capsules, orally, once daily in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 20.1 and 20.3 weeks for fulvestrant and sapanisertib respectively). arm 3: Fulvestrant 500 mg, IM, once on Days 1 and 15 in Cycle 1, and then on Day 1 of each subsequent 28-day cycle along with sapanisertib 30 mg, capsule, orally, once weekly in each 28-day treatment cycle until progressive disease, unacceptable toxicity, or withdrawal of consent (Median duration of treatment was 17.0 weeks for fulvestrant and sapanisertib, each).
Interventions: intervention 1: Fulvestrant intervention 2: Sapanisertib
Intervention descriptions: intervention 1: Fulvestrant IM injection. intervention 2: Sapanisertib capsule.

Protocol documents:
Prot_000.pdf: 



Title: An Open-Label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With 
Fulvestrant in Women With ER-Positive/HER2-Negative Advanced or Metastatic Breast Cancer That 
Has Progressed During or After Aromatase Inhibitor Therapy
MLN0128 in Combination With Fulvestrant in Women With Advanced or Metastatic Breast Cancer 
After Aromatase Inhibitor Therapy
NCT Number: NCT02756364
Protocol Approve Date: 02 October 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from view 
with a black/blue bar) to protect either personally identifiable information (PPD) or company confidential 
information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


PROTOCOL
An Open-Label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With 
Fulvestrant in Women With ER-Positive/HER2-Negative Advanced or Metastatic Breast 
Cancer That Has Progressed During or After Aromatase Inhibitor Therapy
MLN0128 in Combination With Fulvestrant in Women With Advanced or Metastatic 
Breast Cancer After Aromatase Inhibitor Therapy
Sponsor:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as 
“Millennium”, “sponsor”, or “Takeda”.
Study Number:
C31006
IND Number:
126,346
EudraCT Number:
2015-003612-20
Compound:
MLN0128 (TAK-228)
Date:
02 October 2017
Amendment Number:
3
Amendment History:
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
10 February 2016
Initial Protocol
Not applicable
Global
30 March 2016
1
Nonsubstantial
Global
07 March 2017
2
Substantial
Global
02 October 2017
3
Substantial
Global
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1.0
ADMINISTRATIVE
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event (SAE) reporting information is presented in Section 11.0, as is information 
on reporting product complaints.
Takeda Development Center, Inc. (TDC) sponsored investigators, per individual country 
requirements, will be provided with emergency medical contact information cards to be carried by 
each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
Europe
SAE reporting
See Section 11.2
See Section 11.2
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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 medical officer (and other signatories, as applicable) can be found 
on the signature page.
Electronic Signatures may be found on the last page of this document.
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
dance
ance
wing:
wing:
olidated
lidate
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priva
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thihis doc
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Protocol Incorporating Amendment No. 3
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
fulvestrant 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 SAEs defined in Section 11.0 of this protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B–Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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Protocol Incorporating Amendment No. 3
02 October 2017
1.3
Protocol Amendment 3 Summary of Changes
Rationale for Amendment 3
This document describes the changes in reference to the protocol incorporating 
Amendment No. 03. The primary reason for this amendment is to update those sections affected 
by new nonclinical data for MLN0128 metabolism by specific cytochrome P450 (CYP) isoforms. 
The study’s exclusion criteria, list of prohibited concomitant medications, list of relevant CYP
inhibitors and inducers, and dietary restrictions related to CYP inhibitors and inducers have been 
updated accordingly. The number of study sites, recommendations for initiation of crossover 
treatment, and guidance for fasting serum glucose post-dose collection have also been updated. 
Minor grammatical, editorial, and formatting changes are included for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix J.
Changes in Amendment 03
1. Remove the exclusion criterion relating to treatment with strong CYP inhibitors or inducers.
2. Update the list of concomitant medications prohibited during the study.
3. Update the list of relevant CYP inhibitors and inducers.
4. Remove dietary restrictions related to CYP inhibitors and inducers.
5. Update the number of study sites.
6. Update the recommendations for initiation of crossover treatment.
7. Update guidance for fasting serum glucose post-dose collection on non-dosing days.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 3 Summary of Changes............................................................5
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................15
3.1
Study-Related Responsibilities.................................................................................15
3.2
Principal Investigator/Coordinating Investigator ......................................................15
3.3
List of Abbreviations ...............................................................................................16
3.4
Corporate Identification...........................................................................................18
4.0
INTRODUCTION.........................................................................................................19
4.1
Background .............................................................................................................19
4.1.1
Disease Under Treatment: Breast Cancer.......................................................19
4.1.2
Study Drug: MLN0128..................................................................................20
4.1.3
Nonclinical Experience..................................................................................20
4.1.3.1 Clinical Experience with MLN0128 .............................................................20
4.1.3.2 Preliminary Data in Women With ER-Positive/HER2-Negative Breast 
Cancer With MLN0128 in Combination With Exemestane or Fulvestrant ....21
4.1.3.3 Risk-Benefit Assessment for the Use of MLN0128 in 
ER-Positive/HER2-Negative Breast Cancer..................................................22
4.2
Rationale for the Proposed Study.............................................................................22
5.0
STUDY OBJECTIVES .................................................................................................26
5.1
Primary Objectives ..................................................................................................26
5.2
Secondary Objectives...............................................................................................26
5.3
Health-Related Quality of Life Objective.................................................................26
5.4
Exploratory Objectives ............................................................................................26
6.0
STUDY ENDPOINTS...................................................................................................28
6.1
Primary Endpoint.....................................................................................................28
6.2
Secondary Endpoints ...............................................................................................28
6.3
Health-Related Quality of Life Endpoints ................................................................28
6.4
Exploratory Endpoints .............................................................................................28
7.0
STUDY DESIGN..........................................................................................................29
7.1
Overview of Study Design.......................................................................................29
7.1.1
Enrollment and Randomization .....................................................................29
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7.1.2
Weekly MLN0128 Dose Confirmation (Arm C)............................................30
7.1.3
Study Evaluations (All Treatment Arms).......................................................31
7.1.4
Potential for Crossover Treatment .................................................................31
7.1.5
Potential for Single-Agent MLN0128 Dosing................................................32
7.2
Number of Patients ..................................................................................................32
7.3
Duration of Study ....................................................................................................32
8.0
STUDY POPULATION................................................................................................34
8.1
Inclusion Criteria .....................................................................................................34
8.2
Exclusion Criteria ....................................................................................................35
9.0
STUDY DRUG .............................................................................................................38
9.1
Study Drug Administration: Fulvestrant Plus MLN0128..........................................38
9.2
Reference/Control Therapy: Single-Agent Fulvestrant .............................................39
9.3
Definitions of DLT (Weekly MLN0128 Dose Confirmation)...................................39
9.4
Dose Modification Guidelines..................................................................................40
9.4.1
MLN0128 Dose Interruption .........................................................................40
9.4.2
MLN0128 Dose Reduction............................................................................41
9.4.3
Discontinuation of MLN0128........................................................................41
9.5
Excluded Concomitant Medications and Procedures ................................................41
9.5.1
Excluded Concomitant Medications and Procedures for Single-Agent 
Fulvestrant Treatment Arm (Arm A) .............................................................41
9.5.2
Excluded Concomitant Medications and Procedures for Combination 
MLN0128 Plus Fulvestrant Treatment Arms (Arm B and Arm C) .................42
9.6
Permitted Concomitant Medications and Procedures (All Treatment Arms) .............42
9.7
Precautions and Restrictions ....................................................................................43
9.8
Management of Clinical Events ...............................................................................43
9.8.1
Management of Hyperglycemia.....................................................................43
9.8.2
Management of Hyperlipidemia ....................................................................45
9.8.3
Management of Oral Mucositis......................................................................46
9.8.4
Management of Rash.....................................................................................47
9.8.5
Management of Nausea and/or Vomiting.......................................................48
9.8.6
Management of Noninfectious Pneumonitis...................................................49
9.8.7
Management of Other Nonhematologic Toxicities.........................................50
9.9
Blinding and Unblinding..........................................................................................50
9.10
Description of Investigational Agents ......................................................................50
9.11
Preparation, Reconstitution, and Dispensation..........................................................50
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9.12
Packaging and Labeling...........................................................................................51
9.13
Storage, Handling, and Accountability.....................................................................51
10.0
STUDY CONDUCT......................................................................................................53
10.1
Study Personnel and Organizations..........................................................................53
10.2
Arrangements for Recruitment of Patients................................................................53
10.3
Treatment Group Assignments.................................................................................53
10.4
Study Procedures.....................................................................................................54
10.4.1
Informed Consent..........................................................................................54
10.4.2
Patient Demographics....................................................................................54
10.4.3
Medical History.............................................................................................54
10.4.4
Enrollment ....................................................................................................54
10.4.5
Patient Height and Weight.............................................................................55
10.4.6
Physical Examination ....................................................................................55
10.4.7
Vital Signs.....................................................................................................55
10.4.8
ECOG Performance Status ............................................................................55
10.4.9
ECG..............................................................................................................55
10.4.10
Disease Assessment.......................................................................................55
10.4.10.1 CT Scan or MRI.....................................................................................55
10.4.10.2 Bone Scan ..............................................................................................56
10.4.10.3 Health-related Quality of Life Assessments ............................................56
10.4.11
Concomitant Medications and Procedures .....................................................56
10.4.12
AEs ...............................................................................................................56
10.4.13
Patient Diary Instruction and Review.............................................................57
10.4.14
Clinical Laboratory Evaluations ....................................................................57
10.4.15
In-Home Daily FBG Monitoring (Combination Arms Only)..........................58
10.4.16
Biomarker Measurements in Blood................................................................59
10.4.17
Circulating Tumor Cells ................................................................................59
10.4.18
Banked Tumor Specimen Measurements.......................................................59
10.4.19
PK Measurements (Combination Arms Only)................................................60
10.5
Completion of Study Treatment ...............................................................................60
10.6
Completion of Study................................................................................................60
10.7
Discontinuation of Treatment With Study Drug .......................................................60
10.8
Withdrawal of Patients From Study .........................................................................61
10.9
Study Compliance....................................................................................................61
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10.10 Post-Treatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)..................................................................................................................61
11.0
ADVERSE EVENTS ....................................................................................................63
11.1
Definitions...............................................................................................................63
11.1.1
PTE Definition ..............................................................................................63
11.1.2
AE Definition................................................................................................63
11.1.3
SAE Definition..............................................................................................63
11.2
Procedures for Recording and Reporting AEs and SAEs..........................................64
11.3
Monitoring of AEs and Period of Observation .........................................................65
11.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........66
11.5
Procedures for Reporting Product Complaints..........................................................66
11.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........66
12.0
STUDY-SPECIFIC COMMITTEES .............................................................................67
13.0
DATA HANDLING AND RECORDKEEPING............................................................68
13.1
Electronic Case Report Forms..................................................................................68
13.2
Record Retention .....................................................................................................68
14.0
STATISTICAL METHODS..........................................................................................70
14.1
Statistical and Analytical Plans ................................................................................70
14.1.1
Analysis Sets.................................................................................................70
14.1.2
Analysis of Demographics and Other Baseline Characteristics ......................70
14.1.3
Efficacy Analysis ..........................................................................................70
14.1.3.1
Primary Efficacy Endpoint .....................................................................70
14.1.3.2
Secondary Efficacy Endpoints................................................................70
14.1.4
PK Analysis ..................................................................................................71
14.1.5
Pharmacodynamic Analyses/Biomarker Analyses..........................................71
14.1.6
Patient-Reported Outcomes ...........................................................................71
14.1.7
Safety Analysis..............................................................................................72
14.2
Interim Analysis and Criteria for Early Termination ................................................73
14.3
Determination of Sample Size..................................................................................73
15.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................74
15.1
Study-Site Monitoring Visits ...................................................................................74
15.2
Protocol Deviations..................................................................................................74
15.3
Quality Assurance Audits and Regulatory Agency Inspections ................................74
16.0
ETHICAL ASPECTS OF THE STUDY........................................................................75
16.1
IRB and/or IEC Approval ........................................................................................75
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16.2
Subject Information, Informed Consent, and Subject Authorization .........................76
16.3
Subject Confidentiality ............................................................................................77
16.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................77
16.4.1
Publication and Disclosure ............................................................................77
16.4.2
Clinical Trial Registration .............................................................................78
16.4.3
Clinical Trial Results Disclosure ...................................................................78
16.5
Insurance and Compensation for Injury....................................................................78
17.0
REFERENCES..............................................................................................................79
LIST OF IN-TEXT TABLES
Table 4.a
DLT Observed With Weekly MLN0128 in Study MLN0128-1004 ....................24
Table 9.a
Examples of a Light Meal ..................................................................................38
Table 9.b
Dose Reductions for MLN0128..........................................................................41
Table 9.c
Management of Hyperglycemia .........................................................................45
Table 9.d
Management of Hyperlipidemia .........................................................................46
Table 9.e
Management of Oral Mucositis ..........................................................................47
Table 9.f
Management of Rash .........................................................................................48
Table 9.g
Management of Nausea and/or Vomiting ...........................................................49
Table 9.h
Management of Noninfectious Pneumonitis .......................................................49
Table 9.i
Management of Asthenia, Weakness, and Fatigue..............................................50
Table 10.a
Clinical Chemistry, Hematology, and Coagulation Tests....................................57
Table 10.b
Clinical Urinalysis Tests ....................................................................................57
Table 10.c
Fasting Lipid Profile ..........................................................................................58
LIST OF IN-TEXT FIGURES
Figure 7.a
C31006 Study Design ........................................................................................30
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................83
Appendix B
Responsibilities of the Investigator.....................................................................91
Appendix C
Investigator Consent to Use of Personal Information..........................................93
Appendix D
ECOG Scale for Performance Status ..................................................................94
Appendix E
Cockcroft-Gault Equation ..................................................................................95
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Appendix F
New York Heart Association Classification of Cardiac Disease..........................96
Appendix G
List of Relevant Cytochrome P450 Inhibitors and Inducers ................................97
Appendix H
EORTC QLQ-C30 Version 3 .............................................................................98
Appendix I
EORTC QLQ-BR23.........................................................................................100
Appendix J
Detailed Description of Amendments to Text...................................................102
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2.0
STUDY SUMMARY 
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc.
Compound:
MLN0128 (TAK-228)
Title of Protocol: An Open-Label Phase 2 Study of 
MLN0128 (A TORC1/2 Inhibitor) in Combination With 
Fulvestrant in Women With ER-Positive/HER2-Negative 
Advanced or Metastatic Breast Cancer That Has Progressed 
During or After Aromatase Inhibitor Therapy.
IND No.: 126,346
EudraCT No.: 
2015-003612-20
Study Number: C31006
Phase: 2
Study Design:
This phase 2, open-label, randomized, 3-arm study is designed to evaluate the efficacy and safety of the combination 
of fulvestrant+daily MLN0128 compared with single-agent fulvestrant, and the combination of fulvestrant+weekly 
(QW) MLN0128 compared with single-agent fulvestrant in the treatment of postmenopausal women with advanced or 
metastatic estrogen receptor (ER) positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer 
that has progressed during or after aromatase inhibitor (AI) therapy. Patients who meet all eligibility criteria will be 
stratified according to the presence or absence of visceral metastasis (defined as all lesions not included in the 
following list: breast, skin, subcutaneous tissue, lymph node or bone), previous sensitivity to hormonal therapy, and 
previous exposure to cyclin-dependent kinase (CDK) 4/6 inhibitors and will be randomized 1:1:1 to 1 of 3 treatment 
arms: 
!
Arm A: Single-agent fulvestrant.
!
Arm B: Combination of fulvestrant+daily MLN0128.
!
Arm C: Combination of fulvestrant+weekly MLN0128.
A safety and tolerability assessment will be performed for the first 6 evaluable patients in Arm C treated with 
fulvestrant+30 mg weekly MLN0128. After the sixth evaluable patient completes Cycle 1, a review will be 
performed: if ≤1 dose-limiting toxicity (DLT; see Section 9.3) occurs, the MLN0128 dose for this treatment arm will 
remain the same (ie, 30 mg weekly MLN0128, in combination with fulvestrant); if ≥2 DLTs occur, all patients 
subsequently randomized to this treatment arm will receive a starting dose of 20 mg weekly MLN0128 in combination 
with fulvestrant. For any patients initially assigned to the 30 mg weekly starting dose, the MLN0128 dose may be 
decreased if necessary per the dose modification criteria in Section 9.4.
Safety assessments (including adverse events [AEs], serious adverse events, laboratory assessments, vital signs, 
electrocardiograms, Eastern Cooperative Oncology Group [ECOG] performance status, and weight) will be 
performed throughout the treatment period, including the End-of-Treatment (EOT) visit, to evaluate the safety and 
tolerability of MLN0128. Radiological tumor evaluations will be used to evaluate disease response according to 
Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (Version 1.1) [1].
 
 
 
 
 
Patients will receive study medication(s) until disease progression (progressive disease [PD]), unacceptable toxicity, 
or withdrawal of consent. Patients who discontinue study treatment for reasons other than PD will continue to have 
progression-free survival (PFS) follow-up visits every 2 months for the first 6 months after the EOT Visit and then 
every 3 months, until PD or start of another anticancer therapy, whichever occurs first. After PD or start of another 
anticancer therapy, patients will be followed for survival every 6 months.
Patients in the single-agent fulvestrant arm who have confirmed PD may be allowed to receive crossover treatment 
with fulvestrant+MLN0128. 
CCI
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MLN0128 (TAK-228)
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Protocol Incorporating Amendment No. 3
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Primary Objectives:

To compare the PFS of patients treated with the combination of fulvestrant+daily MLN0128 versus patients 
treated with single-agent fulvestrant.

To compare the PFS of patients treated with the combination of fulvestrant+weekly MLN0128 versus patients 
treated with single-agent fulvestrant.
Secondary Objectives:

To compare secondary efficacy endpoints in patients treated with the combination of fulvestrant+daily MLN0128 
versus patients treated with single-agent fulvestrant.

To compare secondary efficacy endpoints in patients treated with the combination of fulvestrant+weekly 
MLN0128 versus patients treated with single-agent fulvestrant.

To assess the safety and tolerability of the combination of fulvestrant+MLN0128.

To collect plasma concentration-time data with sparse pharmacokinetic (PK) sampling (combination 
fulvestrant+MLN0128 treatment arms [Arm B and Arm C] only) to contribute to future population PK analysis.
Subject Population: Postmenopausal women with advanced or metastatic ER-positive/HER2-negative breast cancer 
that has progressed during or after AI therapy. Enrollment will be managed to ensure that approximately 40% of 
enrolled patients have previously received a CDK4/6 inhibitor in combination with an AI.
Number of Subjects: Approximately 153 patients (51 per 
treatment arm).
Number of Sites: Approximately 65 study centers in 
the United States and Europe.
Dose Level(s):

Arm A, single-agent fulvestrant: fulvestrant, 500 mg 
intramuscularly (IM), on Cycle 1 Days 1 and 15 
(loading regimen), and then on Day 1 of each 
subsequent 28-day treatment cycle.

Arm B, combination of fulvestrant+daily MLN0128: 
fulvestrant as above plus MLN0128, 4 mg orally (PO) 
every day (QD) of a 28-day treatment cycle.

Arm C, combination of fulvestrant+weekly MLN0128: 
fulvestrant as above plus MLN0128, 30 mg PO QW of 
a 28-day treatment cycle.
Route of Administration:

Fulvestrant: IM.

MLN0128: PO.
Duration of Treatment:
Patients will receive study medication(s) until PD, 
unacceptable toxicity, or withdrawal of consent.
Period of Evaluation:
Patients who discontinue study treatment for reasons 
other than PD will continue to have PFS follow-up 
visits every 2 months for the first 6 months after the 
EOT Visit, and then every 3 months until PD or start of 
another anticancer therapy (whichever occurs first). 
After PD or start of another anticancer therapy, patients 
will be followed for survival every 6 months. 
Main Criteria for Inclusion:
Postmenopausal women with local histological confirmation of ER-positive/HER2-negative metastatic or advanced 
breast cancer; measurable extra-osseous lesion, or measurable bone lesion (lytic or mixed); ECOG status of 0 or 1; PD 
during or after prior AI therapy, defined as recurrence during or within 12 months after discontinuation of adjuvant 
therapy or defined as PD during or within 1 month after discontinuation in the metastatic setting; adequate bone 
marrow, coagulation, hepatic, cardiac, renal, and metabolic function.
Main Criteria for Exclusion:
Prior therapy with mechanistic target of rapamycin (mTOR) inhibitors, phosphoinositide-3-kinase (PI3K) inhibitors, 
dual PI3K-mTOR inhibitors, serine/threonine-specific protein kinase (AKT; also known as protein kinase B) 
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inhibitors, or fulvestrant; prior treatment with >1 line of chemotherapy for metastatic breast cancer; experienced PD 
on >2 endocrine therapies for metastatic breast cancer; significant previous or existing cardiac conditions; other 
comorbidities of interest (including poorly controlled diabetes mellitus, significant pulmonary disease).
Main Criteria for Evaluation and Analyses:
The primary endpoint for this study is PFS. Secondary endpoints for this study are overall survival (OS), time to 
progression (TTP), objective response rate (ORR), clinical benefit rate (CBR) with stable disease (SD) of any 
duration, CBR with SD duration of at least 6 months, and the number and percentage of patients with 
treatment-emergent AEs.
Statistical Considerations:
The primary endpoint, PFS, is defined as the time from the date of randomization to the date of first documentation of 
progression or death due to any cause, whichever occurs first. For a patient whose disease has not progressed and is 
last known to be alive, or started alternate therapy prior to PD, PFS will be censored at the last response assessment 
that is SD or better. The Kaplan-Meier method will be used to analyze the distribution of PFS for each treatment arm. 
The primary hypothesis is to be tested at the 0.10 significance level (2-sided). The p-values from a stratified log-rank 
test and hazard ratios (HRs) will be presented for each pair-wise comparison.
Secondary efficacy endpoints include OS, ORR, TTP, CBR with SD of any duration, and CBR with SD duration of at 
least 6 months. OS is defined as the time from the date of randomization to the date of death. Patients without 
documentation of death at the time of analysis will be censored at the date last known to be alive. OS will be analyzed 
using similar methods as the primary endpoint of PFS.
ORR is defined as the proportion of patients who achieve a best response of complete response (CR) or partial 
response (PR) according to RECIST 1.1 criteria [1]. CBR is defined as the proportion of patients who achieve a best 
response of CR, PR, or SD. The CBR will also be presented for a best response of CR, PR, and SD of at least 6 months. 
A stratified Cochran-Mantel-Haenszel test will be used to compare ORR and CBR between treatment arms. The 
Mantel-Haenszel estimate of the odds ratio and the associated 95% confidence intervals (CIs) will be presented for 
each pair-wise comparison.
TTP is defined as the time from the date of randomization to the date of first documentation of progression. For a 
patient whose disease has not progressed, TTP will be censored at the last response assessment that is SD or better. 
TTP will be analyzed using similar methods as the primary endpoint of PFS.
Sample Size Justification: Assuming that the median PFS is 4 months for single-agent fulvestrant and that the 
combination of fulvestrant+MLN0128 (administered either QD or QW) can improve the median PFS to 8 months (HR 
of 0.5), then a total of 72 PFS events are needed for each pair-wise comparison. Each treatment arm will require 
51 patients (1:1:1 randomization allocation). The calculations are based on a power of 90%, 2-sided alpha of 10%, and 
a dropout rate of 10% due to either lost to follow-up or withdrawal of consent.
The sample size for the study assumes the accrual duration will be approximately 14 months. The final analysis for the 
pair-wise comparison of PFS between fulvestrant+daily MLN0128 and fulvestrant, and between fulvestrant+weekly 
MLN0128 and fulvestrant, is estimated to occur approximately 20 months after the first patient is randomized. 
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier List (or equivalent). 
3.2
Principal Investigator/Coordinating Investigator
The sponsor 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
AE
adverse event
AI
aromatase inhibitor
AKT
serine/threonine-specific protein kinase (also known as protein kinase B)
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Oncology 
AST
aspartate aminotransferase
CAP
College of American Pathologists 
CBR
clinical benefit rate
CDK
cyclin-dependent kinase 
CI
confidence interval
CR
complete response
CT
computed tomography
CTC
circulating tumor cell
ctDNA
circulating tumor DNA
CYP
cytochrome P450
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer QLQ Questionnaire, 
version 3.0
EORTC QLQ-BR23
European Organization for Research and Treatment of Cancer Breast Cancer-Specific 
Quality of Life Questionnaire
EOT
End-of-Treatment
ER
estrogen receptor
FBG
fasting blood glucose
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEICAM
Grupo Español de Investigación en Cáncer de Mama
GI
gastrointestinal
HDPE
high-density polyethylene
HbA1c
glycosylated hemoglobin
HER2
human epidermal growth factor receptor-2 
Hgb
hemoglobin
HR
hazard ratio 
HRQL
health-related quality of life
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ICH
International Conference on Harmonisation
IEC
independent ethics committee
IM
intramuscular; intramuscularly 
IRB
institutional review board
IRT
interactive response technology
IV
intravenous; intravenously
MedDRA
Medical Dictionary for Regulatory Activities
MLN0128
also known as TAK-228 and INK-128
MRI
magnetic resonance imaging
mTOR
mechanistic target of rapamycin
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
objective response rate
OS
overall survival
PD
progressive disease, disease progression
PFS
progression-free survival
PgR
progesterone receptor
PI3K
phosphoinositide-3-kinase
PIK3CA
phosphoinositide-3-kinase, catalytic alpha polypeptide 
PK
pharmacokinetic(s)
PO
per os (orally administered)
PPI
proton pump inhibitor
PR
partial response
PRO
patient-reported outcome
PTE
pretreatment event
PTEN
phosphatase and tensin homolog 
QD
daily, once per day
QD x3
3 times, daily dosing
QD x5
5 times, daily dosing
QTc
corrected QT interval
QW 
weekly, once per week
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SERD
selective estrogen receptor downregulator
SERM
selective estrogen receptor modulator
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reactions
TAK-228
also known as MLN0128
TEAE
treatment-emergent adverse event
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TORC1
target of rapamycin complex 1
TORC2
target of rapamycin complex 2
TTP
time to progression
ULN
upper limit of the normal range
US
United States
USPI
United States prescribing information
WHO
World Health Organization
3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited.
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
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
Disease Under Treatment: Breast Cancer
Breast cancer is the most frequent cancer diagnosis in women and is the leading cause of 
cancer-related deaths in women in Europe and the second leading cause of cancer-related deaths in 
women in the United States. The American Cancer Society estimates that approximately 232,340 
women in the US will receive a new diagnosis of breast cancer in 2013 [2,3]. According to 
GLOBOCAN 2012, the incidence of breast cancer across Europe in 2012 was 458,718 
(http://globocan.iarc.fr/pages/fact_sheets_population.aspx, accessed 19 November 2015). 
Approximately 39,620 women in the United States and 131,347 women in Europe were predicted 
to die from their disease in 2013.
Breast cancer is a heterogeneous disease with different histologies, prognoses, natural history, 
responses to treatment, and molecular characteristics [4-6]. Breast cancer can be classified into 
3 major categories or subtypes: hormone receptor-positive tumors that express estrogen receptor 
(ER), or progesterone receptors (PgRs), or both; tumors that over-express the receptor for human 
epidermal growth factor receptor-2 (HER2); and basal epithelial-like or “triple-negative tumors” 
that do not express hormone receptors or HER2 [4,7]. Approximately 66% to 75% of breast 
cancers are hormone receptor-positive tumors [4,6,8-10].
Standard therapy for ER-positive tumors in postmenopausal women, both in the adjuvant and 
metastatic disease settings, consists of single-agent antiestrogen therapy. Antiestrogen therapy for 
postmenopausal women with hormone receptor-positive breast cancer involves the sequential use 
of selective ER modulators (SERMs; eg, tamoxifen), nonsteroidal or steroidal aromatase inhibitors 
(AIs) either as single agents or in combinations, and selective ER downregulators (SERDs; eg, 
fulvestrant) [10]. A combination therapy of the steroidal AI letrozole plus the cyclin-dependent 
kinase 4/6 (CDK4/6) inhibitor palbociclib is an additional treatment option for postmenopausal 
women as initial endocrine-based therapy in the metastatic setting [11,12]. 
Resistance to antiestrogen treatment occurs commonly in patients and is an important therapeutic 
limitation. Approximately 30% of patients with metastatic disease have primary resistance to 
initial endocrine therapy and develop progressive disease (PD) within 6 months after initiation of 
antiestrogen therapy [10,13]. Many other patients may initially respond to hormonal therapy but 
then develop secondary resistance, defined as PD occurring more than 6 months after initiation of 
antiestrogen therapy [10,13]. The resistant tumors have not completely lost estrogen dependence 
and may respond to an additional or alternative antiestrogen therapy, such as the SERD 
fulvestrant, or to a combination of antihormonals plus agents directed against cellular targets that 
mediate endocrine resistance [14,15]. However, the duration of response or remission after 
subsequent, alternative therapy is often shorter than that achieved with earlier therapy [15]. 
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4.1.2
Study Drug: MLN0128
4.1.3
Nonclinical Experience
MLN0128 (also known as TAK-228 and INK-0128) is an orally available, potent, and highly 
selective ATP-competitive inhibitor of mechanistic target of rapamycin (mTOR) kinase that 
exhibits dual specificity against both target of rapamycin complexes 1 and 2 (TORC1 and TORC2 
[TORC1/2]). MLN0128 is a second-generation mTOR inhibitor that targets the kinase domain of 
the mTOR enzyme to suppress TORC1 and TORC2 functions. Currently the only mTOR inhibitor 
drugs available are the derivatives of rapamycin, called rapalogs, which are allosteric inhibitors 
that target only the TORC1 complex. 
MLN0128 selectively and potently inhibited the mTOR kinases (1 nM) in in vitro studies, but 
relative to mTOR inhibition, MLN0128 had >100-fold less potency on class I 
(phosphoinositide-3-kinase [PI3K] isoforms α, β, ɣ, δ), class II (PI3KC2α and PI3K2Cβ), and 
class III (VPS34) PI3K family members. MLN0128 inhibited (>80%) the biochemical activity of 
5 kinases (mTOR, DNA-PK, PDGFRα, Flt3, and CK1 epsilon kinases) out of a panel of 
222 protein kinases. Out of a panel of 402 distinct kinases, MLN0128 inhibited the ligand binding 
of only 10 receptor and intracellular protein kinases (ACVR1, BMPR1B, CSF1R, CSNK1D, 
CSNK1E, DDR1, MEK1, MEK2, PDGFRα, and RIPK2). MLN0128 also displayed potent 
cellular inhibition of both the TORC1 and TORC2 pathway with cellular pharmacodynamic 
concentration producing 50% inhibition concentration values of less than 10 nM. 
MLN0128, administered orally (PO) in multiple human tumor xenograft mouse models, inhibited 
angiogenesis and tumor growth by inhibiting mTOR signaling at plasma concentrations associated 
with in vitro inhibition of mTOR in a dose- and time-dependent manner. These effects display a 
clear pharmacokinetic (PK)-to-pharmacodynamic relationship [16]. MLN0128 inhibits both the 
phosphorylation of S6 and 4E-BP1, the downstream substrates of TORC1, and selectively inhibits 
serine/threonine-specific protein kinase (AKT) phosphorylation at Serine 473 (S473), as 
evidenced by decreased pAKT, the downstream substrate of TORC2 [16-18]. MLN0128 inhibits 
mTOR signaling and has demonstrated anticancer activity against a number of human solid tumor 
cell-line xenograft mouse models, including phosphatase and tensin homolog (PTEN) mutant 
endometrial, breast, and renal cell carcinomas.
4.1.3.1
Clinical Experience with MLN0128
The first-in-human, phase 1 study of single-agent MLN0128 is currently ongoing in patients with 
advanced solid malignancies (Study INK128-001). In the dose-escalation phase of this study, 
4 dosing schedules were studied: daily dosing (QD) (31 patients), 3 times daily dosing (QD×3) 
(33 patients), 5 times daily dosing (QD)×5 (22 patients), and weekly dosing (QW) (30 patients). 
Based on the safety profile, PK/pharmacodynamics, and preliminary efficacy during the 
dose-escalation phase, MLN0128 dosing regimens of 5 mg QD and 40 mg QW were selected for 
further evaluation in the expansion phase in patients with renal cell carcinoma, endometrial cancer, 
or bladder cancer. The QW schedule started at 40 mg but was subsequently reduced to 30 mg due 
to poor long-term tolerability requiring high rates of dose modification and interruption. As of a 
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March 2015 data cutoff, the top 5 drug-related adverse events (AEs) by frequency were fatigue 
(67%), nausea (61%), hyperglycemia (59%), vomiting (49%), and stomatitis (46%), consistent 
with other agents that inhibit the PI3K/AKT/mTOR pathway. Preliminary signs of antitumor 
activity have been seen in an assessment of 70 evaluable patients with bladder, endometrial, and 
renal cell carcinoma that have been treated with MLN0128 either on daily or once weekly dosing 
schedules. Three partial responses (PRs) and 5 patients with stable disease (SD) ≥6 months were 
observed among patients treated with daily MLN0128 compared to 1 complete response (CR), 
2 PRs, and 3 patients with SD ≥6 months observed in patients treated with weekly MLN0128 [19]. 
Another phase 1 study of single-agent MLN0128 has been completed in patients with relapsed or 
refractory multiple myeloma or Waldenström macroglobulinemia (Study INK128-002). The AE 
profile observed in this study was also consistent with other drugs of the same class, and while 
there was some preliminary antitumor activity in this patient population, further development in 
this indication is not being evaluated at this time [20]. A combination study evaluating the use of 
MLN0128 in combination with paclitaxel with or without trastuzumab in patients with advanced 
solid tumors (Study INK128-003) has been completed. MLN0128 was generally well tolerated in 
combination with weekly paclitaxel while exhibiting promising preliminary therapeutic activity.
The effect of MLN0128 on the corrected QT interval (QTc) in patients with advanced solid tumors 
has been tested in the ongoing, single-arm, designated QTc study (Study C31002). Study C31002 
has completed enrollment and the primary analysis of the effect of a single dose of 40 mg 
MLN0128 on the QT/QTc interval in patients with advanced solid tumors has been concluded. The 
study results indicate that treatment with MLN0128 is not associated with clinically meaningful 
effects on the overall electrocardiographic safety profile.
Milled MLN0128 is being investigated either as a single agent or in combination with paclitaxel in 
an additional phase 1 study in patients with advanced solid tumors (Study MLN0128-1004). 
Study MLN0128-1004 also investigates the effects of food on MLN0128 exposures. In addition, 
combinations of milled MLN0128 with MLN1117 (an oral PI3Kα inhibitor) are being evaluated in 
a phase 1b study in adult patients with advanced nonhematologic malignancies (Study C32001), 
and combinations of milled MLN0128 with exemestane or fulvestrant are being evaluated in 
patients with ER-positive/HER2-negative breast cancer (Study C31001; see Section 4.1.3.2). 
4.1.3.2
Preliminary Data in Women With ER-Positive/HER2-Negative Breast Cancer With
MLN0128 in Combination With Exemestane or Fulvestrant
The ongoing phase 1b/2 Study C31001 examines the safety and efficacy of daily MLN0128 given 
in combination with exemestane or fulvestrant therapy in postmenopausal women with 
ER-positive/HER2-negative advanced or metastatic breast cancer that has progressed on treatment 
with everolimus in combination with exemestane or fulvestrant. The completed phase 1b portion 
of the study tested combination doses of MLN0128 from 3 to 5 mg QD. As of November 2015, 9 
patients received treatment with MLN0128 plus fulvestrant and 15 patients received MLN0128 
plus exemestane. Of 23 disease-evaluable patients, 3 achieved a PR (all treated in combination 
with fulvestrant) and 13 had SD. The clinical benefit rate (CBR) at 6 months was 75% in the 
fulvestrant-treated patients and 40% in the exemestane-treated patients. Four patients were 
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ongoing. Based on the available preliminary data, the most common (occurring in ≥50% of 
patients) drug-related AEs included fatigue, nausea, diarrhea, pruritus, and stomatitis.
The observed safety profile of MLN0128 in combination with either exemestane or fulvestrant 
was generally consistent with that of single-agent MLN0128. Per protocol, cohort safety reviews 
were conducted with the investigators during phase 1b, and 4 mg was selected as the starting dose 
of MLN0128 for the phase 2 portion of the study. As of 09 November 2015, 14 patients have been 
enrolled in the phase 2 part of the study.
4.1.3.3
Risk-Benefit Assessment for the Use of MLN0128 in ER-Positive/HER2-Negative Breast 
Cancer
The most common treatment-emergent AEs (TEAEs) observed with MLN0128 are consistent with 
the pharmacodynamic mechanism of mTOR inhibition that is also seen with rapalogs (TORC1 
inhibition) or other dual TORC1/2 inhibitors. The TEAEs observed across the MLN0128 
single-agent studies include diarrhea, fatigue, vomiting, rash, mucosal inflammation, asthenia, 
dysgeusia, thrombocytopenia, stomatitis, blood creatinine increased, hyperglycemia, nausea, 
anorexia, and decreased appetite. Further details are provided in the current version of the 
Investigator’s Brochure.
During this study, risk mitigation strategies include, but are not limited to, strict application of the 
study inclusion and exclusion criteria, frequent monitoring of clinical and laboratory results, 
guidelines for prophylaxis and management of potential toxicities, criteria for dose modification, 
and regular monitoring of AEs and serious adverse events (SAEs) by the sponsor.
Nonclinical data supporting the potential benefits of MLN0128 as an anticancer therapy are 
summarized in Section 4.1.3. Observed indications of clinical activity of the combination of 
fulvestrant+MLN0128 are presented in Section 4.1.3.2.
4.2
Rationale for the Proposed Study
Approximately 70% of breast cancers express hormone receptors, either PgR or ER [8]. 
Historically, single-agent endocrine therapy has been the cornerstone of treatment for patients with 
ER/PgR-positive advanced breast cancer. Tamoxifen, a SERM that exhibits antagonistic activity 
against the ER in breast tissue, and nonsteroidal AIs such as letrozole and anastrozole, which block 
the conversion of androgenic steroids into estrogenic steroids, have routinely been used in 
succession in the adjuvant and/or the first-line setting of advanced and/or metastatic 
ER/PgR-positive breast cancer. In fact, a lack of complete cross-resistance between steroidal and 
nonsteroidal AIs has been demonstrated in several trials [21,22].
An alternate second-line or subsequent antihormonal treatment option is the SERD fulvestrant, 
which is currently indicated for the treatment of postmenopausal women with metastatic hormone 
receptor-positive breast cancer following the failure of antiestrogen therapy. Fulvestrant provides 
a distinct mechanism of action from AIs by directly targeting ER for proteasomal degradation, 
which downregulates E2F transcription and thereby the proliferation signal.
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Preclinical data suggest that breast cancer cells critically rely on PI3K-mTOR signaling for 
survival after complete abrogation of ER signaling [23]. Data from a study with fulvestrant 
administered 500 mg monthly to patients with recurrent hormone 
receptor-positive/HER2-negative breast cancer indicate significant antitumor activity after both 
antiestrogen and AI failure [24].
Acquired resistance to antihormonal therapy remains a major clinical problem in the treatment of 
patients with ER/PgR-positive breast cancer [25]. Preclinical and clinical research focused on 
mechanisms of resistance has confirmed that various signal transduction pathways are activated in 
breast cancer cells to escape the effect of endocrine therapy. In particular, activation of the 
PI3K/mTOR pathway was identified as a key adaptive change driving acquired resistance to 
endocrine therapy. In addition, a strong link between proliferative properties and the emergence of 
hormone-independent breast cancer cells has been identified [26,27]. These results suggested that 
simultaneous inhibition of ER and either PI3K/mTOR signaling or cell cycle regulation could 
prevent or delay the emergence of hormone-independent breast cancer cells.
A strategy of targeting both ER and mTOR was tested in the BOLERO-2 study through the 
addition of everolimus (an mTOR inhibitor) to the steroidal AI exemestane. The combination 
significantly improved progression-free survival (PFS) in women with advanced 
ER-positive/HER2-negative breast cancer after failure of treatment with letrozole or anastrozole 
[28] and led to the US Food and Drug Administration (FDA) approval of everolimus in this setting 
in 2012. Of note, the BOLERO-2 study primarily included patients whose disease recurred during 
or soon after antihormonal therapy, a population that was thought to be more sensitive to combined 
ER/mTOR inhibition than patients who are naive to endocrine therapy or who progress after a long 
treatment-free interval. The HORIZON trial, in which women without prior antihormonal therapy 
were treated either with single-agent letrozole or with the combination of letrozole plus the rapalog 
temsirolimus, failed to show improvement in PFS with the combination (median PFS=9 months 
for both groups; hazard ratio [HR] 0.90) [29].
In February 2015, a combination of the nonsteroidal AI letrozole plus the CDK4/6 inhibitor 
palbociclib was approved by the FDA for the treatment of postmenopausal women with 
ER-positive/HER2-negative advanced breast cancer as initial endocrine-based therapy for their 
metastatic disease. The results of the PALOMA-1 study on which this approval was based 
demonstrated that the addition of palbociclib to letrozole significantly improved PFS (20.2 vs 
10.2 months; HR 0.488) in advanced ER-positive/HER2-negative breast cancer [12]. 
Another potentially beneficial combination is the ER-targeted SERD fulvestrant+everolimus (an 
mTOR inhibitor that targets the TORC1 complex). This combination has shown efficacy in 
postmenopausal women after failure of AI treatment similar to that of the combination of 
tamoxifen with everolimus (median time to progression [TTP] 7.4 months) [30]. Furthermore, the 
combination of fulvestrant and a dual TORC1/TORC2 inhibitor induced significantly higher rates 
of tumor cell death when compared to the combination of fulvestrant+everolimus [27,31], 
suggesting synergistic effects on tumor cell death through a more complete inhibition of 
mTOR-related survival signaling in the presence of complete ER abrogation by fulvestrant. These 
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data suggest that by simultaneously targeting both the ER and survival pathways, there is a 
synergistic effect on tumor cell death. 
Collectively, these data suggest that the combination of fulvestrant+MLN0128 may improve the 
outcome of patients with ER-positive breast cancer that has progressed on antiestrogen directed 
antihormonal therapy. The goal of this study is to test the hypothesis that dual TORC1/2 inhibition 
in combination with fulvestrant has the potential to overcome endocrine therapy resistance in 
ER-positive breast cancer through the inhibition of growth and survival of tumor cells as well as 
the emergence of resistant cells following therapy with AI or AI combined with CDK4/6 
inhibitors. 
RATIONALE FOR SELECTED DOSES AND SCHEDULES OF MLN0128
The selected doses and schedules of 4 mg QD (Arm B) and 30 mg MLN0128 QW (Arm C) to be 
given in combination with fulvestrant are based on the findings from 3 studies: 
Studies INK128-001, MLN0128-1004, and C31001.
Study INK128-001 was the first-in-human study of MLN0128. Study INK128-001 was an 
open-label study designed to determine the maximum tolerated dose and to identify dose-limiting 
toxicity (DLT) for oral administration of single-agent unmilled MLN0128 and to characterize the 
safety and tolerability of escalating doses of MLN0128 in patients with advanced solid tumors. In 
this study, 116 patients with advanced solid tumors received single-agent MLN0128 (2 to 40 mg 
via 4 dosing schedules) in the dose escalation phase.
Doses of 40 mg QW, 30 mg QW, and 5 mg QD were further evaluated in an additional 82 patients 
in the expansion phase, where 30 mg QW and 5 mg QD were selected as the recommended phase 2 
doses and schedules of MLN0128 for further development.
Weekly Dosing
Scale-up manufacturing of MLN0128 required the introduction of a physical milling step to 
control particle size distribution of MLN0128 drug substance. With the introduction of milled 
MLN0128, the recommended dose to be used in Arm C of this study (30 mg milled MLN0128 
QW) was further confirmed in Study MLN0128-1004 (Table 4.a). A total of 14 patients were 
enrolled and assigned, sequentially, to 2 QW dosing cohorts. PK, safety, and tolerability were 
assessed.
Table 4.a
DLT Observed With Weekly MLN0128 in Study MLN0128-1004
Dose of Milled MLN0128
Number of Evaluable Patients
DLTs Observed in Cycle 1
20 mg QW
6
None
30 mg QW
6
None
DLT=dose-limiting toxicity, QW=once weekly.
As none of the patients in either dose cohort experienced DLT in Cycle 1, a dose of 30 mg 
MLN0128 QW was selected for further development. No clinically meaningful differences in PK 
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of MLN0128 were noted between the unmilled MLN0128 (Study INK128-001) and milled 
MLN0128 (Study MLN0128-1004) when given QW. The tolerability of 30 mg milled MLN0128 
QW in combination with fulvestrant will be tested in a safety lead-in of 6 patients in Arm C of this 
study (as detailed in Section 7.1.2).
Daily Dosing
The recommended phase 2 dose of 4 mg milled MLN0128 QD in combination with either 
exemestane or fulvestrant was determined in the phase 1b dose finding portion of Study C31001 
(see Section 4.1.3.2). In the phase 1b portion of the study, 12 patients were initially dosed in a 
safety lead-in with 5 mg QD of the unmilled MLN0128 material in combination with either 
fulvestrant or exemestane (6 patients each). No DLTs were observed during Cycle 1 of treatment; 
however, 6 of the 12 patients did require dose reductions in Cycles 2 and 3 (2 patients each), and 
1 patient each in Cycles 4 and 7. In order to evaluate the safety of milled MLN0128 material, 
escalation cohorts of 3 and 4 mg QD of the milled material were tested in combination: 6 patients 
at the 3 mg dose (3 in combination with exemestane and 3 with fulvestrant) and 6 patients at the 
4 mg dose (all with exemestane). Of the 6 patients treated with 4 mg MLN0128 in combination 
with exemestane, 1 patient experienced a DLT of nausea and diarrhea. After review of the data 
with the investigators, including events occurring outside of the DLT evaluation period, it was 
agreed to stop escalation and move forward with 4 mg QD in the phase 2 portion of the study (in 
combination with either exemestane or fulvestrant), as well as in Study C31006 (in combination 
with fulvestrant).
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5.0
STUDY OBJECTIVES
5.1
Primary Objectives
The primary objectives are:
!
To compare the PFS of patients treated with the combination of fulvestrant+daily MLN0128 
versus patients treated with single-agent fulvestrant.
!
To compare the PFS of patients treated with the combination of fulvestrant+weekly MLN0128 
versus patients treated with single-agent fulvestrant.
5.2
Secondary Objectives
The secondary objectives are:
!
To compare secondary efficacy endpoints in patients treated with the combination of 
fulvestrant+daily MLN0128 versus patients treated with single-agent fulvestrant.
!
To compare secondary efficacy endpoints in patients treated with the combination of 
fulvestrant+weekly MLN0128 versus patients treated with single-agent fulvestrant.
!
To assess the safety and tolerability of the combination of fulvestrant+MLN0128.
!
To collect plasma concentration-time data with sparse PK sampling (combination 
fulvestrant+MLN0128 treatment arms [Arm B and Arm C] only), to contribute to future 
population PK analysis.
5.3
Health-Related Quality of Life Objective
The health-related quality of life (HRQL) objective is:
!
To assess the HRQL and symptoms, as measured by the European Organization for Research 
and Treatment of Cancer QLQ Questionnaire, version 3.0 (EORTC QLQ-C30) and the 
EORTC QLQ Breast Cancer-Specific Questionnaire (EORTC QLQ-BR23), among the 
3 treatment arms.
5.4
Exploratory Objectives
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6.0
STUDY ENDPOINTS
6.1
Primary Endpoint
The primary endpoint is:
!
PFS.
6.2
Secondary Endpoints
The secondary endpoints are:
!
Overall survival (OS).
!
TTP.
!
Objective response rate (ORR); defined as CR∀PR per Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1 [1].
!
CBR; defined as CR∀PR∀SD with SD of any duration, and CBR with SD duration of at least 
6 months. 
!
The number and percentage of patients with TEAEs.
6.3
Health-Related Quality of Life Endpoints
The HRQL endpoints are:
!
Changes from Baseline in functional and symptom scores, and global health status and quality 
of life score from the EORTC QLQ-C30 questionnaire.
!
Changes from Baseline in functional and symptom scales from the EORTC QLQ-BR23 
questionnaire.
6.4
Exploratory Endpoints
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7.0
STUDY DESIGN
7.1
Overview of Study Design
7.1.1
Enrollment and Randomization
This is an open-label, randomized, 3-arm, multicenter, phase 2 study of the efficacy and safety of 
the combination of fulvestrant+daily MLN0128 compared with single-agent fulvestrant, and the 
combination of fulvestrant+weekly MLN0128 compared with single-agent fulvestrant, in the 
treatment of postmenopausal women with advanced or metastatic ER-positive/HER2-negative 
breast cancer that has progressed during or after AI therapy. Patients who provide written informed 
consent and meet all eligibility criteria will be randomized 1:1:1 to 1 of 3 treatment arms via the 
interactive response technology (IRT):

Arm A, single-agent fulvestrant: fulvestrant, 500 mg intramuscularly (IM), on Cycle 1 Days 1 
and 15 (loading regimen), and then on Day 1 of each subsequent 28-day cycle.

Arm B, combination of fulvestrant+daily MLN0128: fulvestrant as above and MLN0128, 
4 mg PO QD continuously.

Arm C, combination of fulvestrant+weekly MLN0128: fulvestrant as above and MLN0128, 
30 mg PO QW continuously.
Patients will be stratified at randomization according to the presence or absence of visceral 
metastasis, previous sensitivity to hormonal therapy, and previous exposure to CDK 4/6 inhibitors. 
Visceral metastasis is defined as all lesions not included in the following list: breast, skin, 
subcutaneous tissue, lymph node or bone. Previous sensitivity to hormonal therapy is defined as at 
least 24 months of endocrine therapy before recurrence in the adjuvant setting (ie, in patients who 
have not received previous endocrine therapy in the metastatic setting) or a response or 
stabilization for at least 24 weeks of the most recent endocrine therapy for advanced/metastatic 
disease.
Enrollment will be managed via the IRT to ensure that approximately 40% of enrolled patients 
have previously received a CDK4/6 inhibitor in combination with an AI. Enrollment of 
non-CDK4/6 pretreated patients may be stopped in the case that 60% or greater of enrollment has 
occurred with only non-CDK4/6 pretreated patients.
Enrollment is defined as being randomized to a treatment arm. The first dose of study drug must be 
administered within 5 days after randomization on study. Patients will receive study medication(s) 
in 28-day cycles. The study design is displayed in Figure 7.a.
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Figure 7.a
C31006 Study Design
DC for disease 
progression            
DC for    
other reasons 
Screening
&
Confirm
Eligibility
RAND
Fulvestrant 
daily MLN0128
Fulvestrant 
weekly MLN0128(a)
Single-agent     
fulvestrant 
EOT
visit
Single-agent 
fulvestrant only:
DC for
disease progression
Precrossover
EOTvisit
RAND
Crossover therapy option
Fulvestrant 
daily MLN0128
Fulvestrant 
weekly MLN0128
OS 
Follow-up
PFS 
Follow-up
EOT
visit
DC for disease 
progression            
DC for    
other reasons 
OS 
Follow-up
PFS 
Follow-up
DC=discontinuation, EOT=End-of-Treatment, OS=overall survival, PFS=progression-free survival, 
RAND=randomization.
(a) The weekly dose of 30 mg MLN0128 will be tested in a safety lead-in of 6 patients in this study (as detailed in 
Section 7.1.2) to ensure safety and tolerability of the combination with fulvestrant.
7.1.2
Weekly MLN0128 Dose Confirmation (Arm C)
This will be the first study in which weekly MLN0128 will be combined with fulvestrant. 
Therefore, a safety and tolerability assessment will be performed for patients treated with 
fulvestrant+weekly MLN0128 (30 mg) after the first 6 DLT-evaluable patients have completed 
1 cycle (ie, Cycle 1 Day 28). Patients will be considered evaluable for DLT assessment if they 
have completed all scheduled study visits during the first cycle and have received at least 3 (75%) 
of the 4 planned doses of MLN0128 in combination with fulvestrant in Cycle 1. The 30 mg starting 
dose for weekly MLN0128 will be confirmed or adjusted based on the DLTs observed (see 
Section 9.3 for DLT definitions):

If ≤1 DLT occurs, the MLN0128 dose for this treatment arm will remain the same (ie, 30 mg 
weekly MLN0128, in combination with fulvestrant).

If ≥2 DLTs occur, all patients subsequently randomized to this treatment arm will receive a 
starting dose of 20 mg weekly MLN0128, in combination with fulvestrant. The starting dose 
reduction will be documented in formal written communication to all study sites.
DLTs will be assessed and collected in the database for the first 6 evaluable patients in Arm C only 
(fulvestrant+weekly MLN0128). DLTs are not applicable to patients in Arm A or Arm B at any 
time in the study, or to patients in Arm C who are not included in the safety and tolerability 
assessment, or to cross-over patients. Enrollment of patients into the study will continue while this 
safety and tolerability assessment is conducted. For any patients initially assigned to the 30 mg 
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QW starting dose, the MLN0128 dose may be decreased if necessary per the dose modification 
criteria in Section 9.4.
7.1.3
Study Evaluations (All Treatment Arms)
Safety assessments (including AEs, SAEs, laboratory assessments, vital signs, electrocardiograms 
(ECGs), Eastern Cooperative Oncology Group [ECOG] performance status, and weight) will be 
performed throughout the treatment period, including the End-of-Treatment (EOT) Visit, to 
evaluate the safety and tolerability of MLN0128. Toxicity will be evaluated according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03, 
effective date 14 June 2010 [32].
HRQL will be assessed via the EORTC QLQ-C30 and EORTC QLQ-BR23 instruments 
throughout the treatment period, including the EOT Visit.
Radiological tumor evaluations (computed tomography [CT] scan with intravenous [IV] contrast 
or magnetic resonance imaging [MRI] as clinically indicated) of the chest, abdomen, and pelvis 
will be used to evaluate disease response according to RECIST guidelines (Version 1.1) [1]. 
Radiographic tumor evaluations will be performed by the investigator at the time points specified 
in the Schedule of Events.
Blood samples will be collected (from patients in the combination fulvestrant+MLN0128 
treatment arms [Arm B and Arm C] only) to contribute data to an overall population plasma PK 
analysis, in combination with data from the other clinical studies of MLN0128.
Patients will receive study medication(s) until PD, unacceptable toxicity, or withdrawal of 
consent. Patients who discontinue study medication will complete an EOT Visit 30 to 40 days after 
the last dose of study drug. The EOT Visit should be conducted before the initiation of subsequent 
anticancer therapy, even if it occurs sooner than 30 days after the last dose of study drug. Patients 
who discontinue study treatment for reasons other than PD will continue to have PFS follow-up 
visits every 2 months (±1 week) for the first 6 months after the EOT Visit and then every 3 months 
(±1 week), until PD or start of another anticancer therapy, whichever occurs first. After PD or start 
of another anticancer therapy, patients will be followed for survival every 6 months (±1 week).
7.1.4
Potential for Crossover Treatment
Patients in the single-agent fulvestrant arm (Arm A) who have radiographically confirmed PD may 
be allowed to receive crossover treatment with the combination of fulvestrant+MLN0128 (see 
Figure 7.a). Once documented PD has been confirmed, patients referred for crossover will 
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complete the Precrossover EOT Visit as soon as possible (see the Schedule of Events for details). 
Patients must meet all applicable study eligibility criteria at the time of crossover (eg, the 
exclusion for prior fulvestrant therapy would not apply), and eligibility for crossover will be 
confirmed by the sponsor’s project clinician (or designee). Eligible patients will then be 
randomized via the IRT in a 1:1 ratio to either fulvestrant+daily MLN0128 or fulvestrant+weekly 
MLN0128.
It is recommended that crossover treatment begin within 28 days (+10 days) after documented
disease progression (imaging date of PD), with the goal of maintaining the ongoing schedule of 
fulvestrant therapy (ie, dosing every 28 days). Whenever possible, MLN0128 should be initiated 
at the next scheduled dose of fulvestrant but only when the patient has completed the precrossover 
screening requirements and is eligible to continue. If the crossover treatment cannot begin within 
28 days (+10 days) after documented PD, contact the medical monitor.
Patients may receive crossover treatment until they experience PD on crossover treatment, 
unacceptable toxicity, they withdraw consent, or they are no longer considered by the investigator 
to be deriving clinical benefit from the crossover treatment.
Only the data collected during the study treatment in the initial single-agent fulvestrant arm will be 
included in the planned efficacy and safety analyses for the study. After crossover treatment 
begins, safety and efficacy data will be collected (as detailed in the Schedule of Events) and 
presented separately.
7.1.5
Potential for Single-Agent MLN0128 Dosing
If fulvestrant is discontinued for a patient in either combination arm (Arm B or Arm C), the patient 
may continue receiving MLN0128 at their current dose if, after discussion between the 
investigator and sponsor, it is determined that the patient would derive benefit from continued 
treatment with single-agent MLN0128 and there are no safety concerns.
7.2
Number of Patients
Approximately 153 patients (51 patients per treatment arm) will be enrolled in this study from 
approximately 65 study centers in North America and Europe. A patient is considered to be 
enrolled in the study when she has been randomized into a treatment arm.
7.3
Duration of Study
Patients will receive study medication(s) until PD, unacceptable toxicity, or withdrawal of 
consent. Patients who discontinue study medication will complete an EOT Visit 30 to 40 days after 
the last dose of study drug. The EOT Visit should be conducted before the initiation of subsequent 
anticancer therapy, even if it occurs sooner than 30 days after the last dose of study drug. Patients 
who discontinue study treatment for reasons other than PD will continue to have PFS follow-up 
visits every 2 months (±1 week) for the first 6 months after the EOT Visit and then every 3 months 
(±1 week), until PD or start of another anticancer therapy, whichever occurs first. After PD or start 
of another anticancer therapy, patients will be followed for OS every 6 months (±1 week).
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The accrual duration will be approximately 14 months. A final analysis of PFS will be performed 
after the required number of events has been observed which is expected approximately 20 months 
after the first patient is randomized. The study will be closed approximately 20 months after the 
first patient is randomized, or when the last patient discontinues study treatment.
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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:
1. Female patients aged 18 years or older who are postmenopausal. Postmenopausal is defined as:

Aged 55 years and 1 year or more of natural amenorrhea prior to Screening, or

Aged <55 years and 1 year or more of amenorrhea prior to Screening, with a 
follicle-stimulating hormone level >40 mIU/mL and an estradiol level of <20 pg/mL, or 

Surgical menopause with bilateral oophorectomy.
Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone 
agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian 
suppression.
2. Histologically proven diagnosis of breast cancer with evidence of metastatic disease or 
locoregional recurrence, not amenable to resection or radiation therapy with curative intent.
3. Histological confirmation and documentation of ER-positive status (≥1% positive stained 
cells) by local laboratory testing utilizing an assay consistent with local standards.
4. Histological or cytological confirmation and documentation of HER2-negative status by local 
laboratory testing using criteria in the American Society of Oncology (ASCO)/College of 
American Pathologists (CAP) Clinical Practice Guideline update [33].
5. Measureable disease defined as either of the following:

At least 1 extra-osseous lesion that can be accurately measured in at least 1 dimension. The 
lesion must measure ≥20 mm with conventional imaging techniques or ≥10 mm with spiral 
CT or MRI. Lymph nodes must be ≥1.5 cm in the short axis to be considered measurable.

Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as 
defined above.
Note: Patients with sclerotic/osteoblastic bone lesions only, in the absence of measurable 
disease, are not eligible.
6. PD during prior AI therapy defined as:

Recurrence during or within 12 months after completion or discontinuation of adjuvant 
therapy or

Progression during or within 1 month after the end of therapy in the metastatic setting.
Note: AI is not required to be the most recent therapy, but progression on AI and
progression on most recent therapy are both required for eligibility.
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7. Patients who have a history of brain metastasis are eligible for the study provided that all of the 
following criteria are met: 

Brain metastases have been treated.

No evidence of PD for 3 months before the first dose of study drug.

No hemorrhage after treatment.

Off dexamethasone treatment for ≥4 weeks before the first dose of study drug.

No ongoing requirement for dexamethasone or antiepileptic drugs.
8. ECOG performance status of 0 or 1 (refer to Appendix D).
9. Clinical laboratory values as specified below within 4 weeks before the first dose of study 
drug:

Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥1.5109/L; 
platelet count ≥100109/L; hemoglobin (Hgb) ≥9 g/dL.

Total bilirubin ≤1.5 the upper limit of the normal range (ULN), aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5ULN (≤5ULN if liver 
metastases are present).

Creatinine clearance ≥40 mL/min based on Cockcroft-Gault estimate (refer to 
Appendix E) or based on a 12- or 24-hour urine collection.

Fasting serum glucose ≤130 mg/dL and fasting triglycerides ≤300 mg/dL.
10. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and 
suitable venous access for the study-required blood sampling.
11. Voluntary written consent must be given by the patient (or the patient’s legally acceptable 
representative) before performance of any study-related procedure that is not part of standard 
medical care, with the understanding that consent may be withdrawn at any time without 
prejudice to the patient’s future medical care.
8.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Prior therapy with mTOR, PI3K, or dual PI3K-mTOR inhibitors, AKT inhibitors, or 
fulvestrant.
2. Prior treatment with >1 line of chemotherapy for metastatic breast cancer or for locoregional 
recurrence that was not amenable to resection or radiation therapy with curative intent.
3. Experienced PD on >2 endocrine therapies for metastatic breast cancer or for locoregional 
recurrence that was not amenable to resection or radiation therapy with curative intent.
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4. Life-threatening metastatic visceral disease (defined as extensive hepatic involvement or 
symptomatic pulmonary lymphangitic spread). Patients with discrete pulmonary parenchymal 
metastases are eligible, provided their respiratory function is not compromised as a result of 
disease.
5. Other clinically significant comorbidities, such as uncontrolled pulmonary disease, active 
central nervous system disease, active infection, or any other condition that could compromise 
the patient’s participation in the study.
6. History of any of the following within the last 6 months before the first dose of study drug:

Ischemic myocardial event, including angina requiring therapy and artery 
revascularization procedures.

Ischemic cerebrovascular event, including transient ischemic attack and artery 
revascularization procedures.

Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac 
arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or ventricular 
tachycardia). 

Placement of a pacemaker for control of rhythm.

New York Heart Association Class III or IV heart failure (see Appendix F).

Pulmonary embolism.
7. Significant active cardiovascular or pulmonary disease, including:

Uncontrolled hypertension (ie, either systolic blood pressure >180 mm Hg or diastolic 
blood pressure >95 mm Hg).

Pulmonary hypertension.

Uncontrolled asthma or oxygen saturation <90% by arterial blood gas analysis or pulse 
oximetry on room air.

Significant valvular disease; severe regurgitation or stenosis by imaging independent of 
symptom control with medical intervention; or history of valve replacement.

Medically significant (symptomatic) bradycardia.

History of arrhythmia requiring an implantable cardiac defibrillator.

Baseline prolongation of QTc (eg, repeated demonstration of QTc interval >480 msec, or 
history of congenital long QT syndrome, or torsades de pointes).
8. Diagnosed with or treated for another malignancy within 2 years before the first dose of study 
drug, or previously diagnosed with another malignancy and have any evidence of residual 
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not
excluded if they have undergone complete resection.
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9. Receipt before the first dose of study drug of any of the following:

Any investigational agent within 4 weeks.

Chemotherapy within a period of time that is less than the cycle length used for that 
treatment (eg, within 3 weeks for fluorouracil, doxorubicin, or epirubicin or within 1 week 
for weekly chemotherapy).

Previous endocrine therapy is permitted without any window.

Radiotherapy within 2 weeks. All acute toxic effects, except toxicities not considered a 
safety risk for the patient at the investigator´s discretion, must be resolved to Grade <1 per 
NCI CTCAE version 4.0.

Major surgery or other anticancer therapy not previously specified within 4 weeks. All
acute toxic effects, except toxicities not considered a safety risk for the patient at the 
investigator´s discretion, must be resolved to Grades <1 per NCI CTCAE version 4.0.
10. Chronic concomitant therapy with bone-targeting agents (eg, bisphos, denosumab) for the 
prevention of bone metastases. Concomitant treatment with bone-targeting agents is permitted 
for treatment of osteoporosis or management of existing bone metastases if initiated at least 
4 weeks before the first dose of study drug.
11. Requirement for chronic use of systemic corticosteroids (either IV or oral steroids). Inhalers 
and low-dose replacement therapy are allowed.
12. Requirement for daily or chronic use of a proton pump inhibitor (PPI). All patients are required 
to stop taking PPIs at least 7 days before receiving the first dose of study drug.
13. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an 
unknown reason that may alter the absorption of MLN0128.
14. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) >7%; 
patients with a history of transient glucose intolerance due to corticosteroid administration 
may be eligible if all other inclusion/exclusion criteria are met.
15. Known human immunodeficiency virus infection.
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9.0
STUDY DRUG
9.1
Study Drug Administration: Fulvestrant Plus MLN0128
All protocol-specific criteria for administration of study drug (MLN0128 or fulvestrant) must be 
met and documented prior to the first dose of study drug. Study drug will be administered only to 
eligible patients under the supervision of the investigator or identified subinvestigator(s).
For all treatment arms, fulvestrant (500 mg) will be administered IM, according to the current US 
Prescribing Information (USPI) or the current Summary of Product Characteristics (SmPC), on 
Cycle 1 Days 1 and 15 (loading regimen), and then on Day 1 of each subsequent 28-day cycle. 
Fulvestrant will be administered at the study site by appropriately trained clinical staff, under the 
supervision of the investigator or identified subinvestigator(s).
For Arm B, daily MLN0128 will be administered on an empty stomach. It is recommended that 
each dose of MLN0128 be given PO with 8 ounces (240 mL) of water. Patients should be 
instructed to refrain from eating and drinking (except for water and prescribed medications) for 
2 hours before and 1 hour after each dose.
For Arm C, weekly MLN0128 will be administered with a light meal. Examples of a light meal are 
provided in Table 9.a. Patients should begin consuming the light meal no more than 30 minutes 
before taking the weekly dose of MLN0128. It is recommended that each dose of MLN0128 be 
given PO with 8 ounces (240 mL) of water.
Table 9.a
Examples of a Light Meal
Low-Fat Breakfast
Light Snack
Nutritional information
Approximately 330 calories, with 9 g 
of fat
Approximately 100 to 300 calories, with 1.5 g 
of fat
Example
2 slices of toast with 1 teaspoon of 
low-fat margarine, 1 teaspoon of jelly, 
and 8 oz of skimmed milk
3.63 oz pudding cup or 1 slice of toast with 
1 teaspoon of jelly and 8 oz of skimmed milk
Patients should be instructed to take MLN0128 at approximately the same time on each scheduled 
dosing day and not to take more than the prescribed dose at any time. Patients should swallow the 
MLN0128 capsules whole and not chew, open, or manipulate the capsules in any way before 
swallowing. If a patient does not take their MLN0128 dose within 12 hours after the scheduled 
dosing time (for patients in Arm B) or within 24 hours after the scheduled dosing time (for patients 
in Arm C), then the dose should be skipped and considered a missed dose. Patients should record 
any missed doses in their dosing diary (see Dosing Diary Arm A and Dosing Diary Arm B) and 
resume drug administration at the next scheduled time with the prescribed dosage. Patients should 
be instructed not to take their MLN0128 dose at home on days they have a study visit at the clinic. 
The MLN0128 dose should be taken at the clinic after the required procedures are performed as 
described in the Schedule of Events.
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If severe emesis or mucositis prevents the patient from taking scheduled doses, that dose will be 
skipped. If emesis occurs after MLN0128 ingestion, the dose will not be readministered, and 
patients should resume dosing at the next scheduled time with the prescribed dosage. Patients 
should record the occurrence of the emesis in their patient dosing diary. Under no circumstance 
should a patient repeat a dose or double-up doses.
9.2
Reference/Control Therapy: Single-Agent Fulvestrant
Fulvestrant (500 mg) will be administered IM, according to the current USPI or SmPC, on Cycle 1 
Days 1 and 15 (loading regimen), and then on Day 1 of each subsequent 28-day cycle. Fulvestrant 
will be administered at the study site by appropriately trained clinical staff, under the supervision 
of the investigator or identified subinvestigator(s).
9.3
Definitions of DLT (Weekly MLN0128 Dose Confirmation)
Dose-limiting toxicities are defined according to the AE profile observed during the first 28 days 
of study drug administration as described below. Occurrence of DLTs in the first 6 evaluable 
patients in the combination fulvestrant+weekly MLN0128 treatment arm (Arm C) will be 
reviewed to evaluate the safety and tolerability of 30 mg weekly MLN0128 in combination with 
fulvestrant (see Section 7.1.2):

If ≤1 DLT occurs, the MLN0128 dose for this treatment arm will remain the same (ie, 30 mg 
weekly MLN0128 in combination with fulvestrant).

If ≥2 DLTs occur, all patients subsequently randomized to this treatment arm will receive a 
starting dose of 20 mg weekly MLN0128 in combination with fulvestrant. The starting dose 
reduction will be documented in formal written communication to all study sites.
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 14 June 2010 
[32]. A DLT will be defined as any of the following events that are considered by the investigator 
to be at least possibly related to treatment with weekly MLN0128 in combination with fulvestrant:

Grade 3 or higher nonhematologic toxicity, despite adequate treatment, except for the 
following:
–
Grade 3 hyperglycemia lasting ≤14 days (all patients should receive optimal antiglycemic 
treatment, including insulin).
–
Grade 3 rash lasting ≤3 days (all patients should receive topical steroid treatment, oral 
antihistamines, and oral steroids, if necessary).

Grade 4 neutropenia lasting >7 days in the absence of growth factor support.

Grade 4 neutropenia of any duration accompanied by fever ≥38.5°C and/or systemic infection.

Any other ≥Grade 4 hematologic toxicity.

Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 due to study 
drug-related toxicity.
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
Any clinically significant occurrence that the investigator and sponsor agree would place 
patients at an undue safety risk.
9.4
Dose Modification Guidelines
This section describes dose modification guidelines for MLN0128. Any dose modifications for 
fulvestrant should follow the guidelines provided in the current USPI or SmPC for fulvestrant.
MLN0128 should be administered QD or QW in 28-day cycles, and dosing should continue unless 
the patient has a Grade 3 or higher MLN0128-related event. In the case of multiple less severe AEs 
occurring together for which, in the investigator’s judgment, the patient would benefit from a dose 
modification (ie, reduction or delay), dose modification may be considered. General guidelines for 
MLN0128 dose interruption and dose reduction are provided in Section 9.4.1 and Section 9.4.2. 
Detailed dose modification requirements for specific clinical events are provided in Section 9.8.
Dose modifications (including dose interruption, reduction, or discontinuation) for fulvestrant, if 
necessary, should be based on the current fulvestrant SmPC or USPI, local institution standards, 
and the investigator’s best clinical judgement. In the single-agent fulvestrant arm (Arm A): if 
fulvestrant is discontinued for a patient in the single-agent fulvestrant arm due to PD, the patient 
may be eligible for crossover treatment as described in Section 7.1.4; if fulvestrant is discontinued 
due to safety concerns or intolerability, the patient will complete the EOT Visit and be followed 
for PFS/OS as described in Section 10.7. If fulvestrant is discontinued for a patient in either of the 
combination treatment arms (Arm B or Arm C), the patient may be eligible to continue receiving 
MLN0128 at their current dose as described in Section 7.1.5. If MLN0128 is discontinued for a 
patient in either of the combination treatment arms (Arm B or Arm C), the patient will complete 
the EOT Visit and be followed for PFS/OS as described in Section 10.7.
9.4.1
MLN0128 Dose Interruption
Administration of MLN0128 should be withheld (for up to 3 weeks) for treatment-related 
toxicities that are Grade 3 or higher despite supportive treatment per standard clinical practice. 
MLN0128 may resume treatment at a lower dose (as detailed in Section 9.4.2) if the toxicity 
resolved to baseline level or Grade 1 (or Grade 2 for hyperglycemia or rash, as detailed in 
Sections 9.8.1 and 9.8.4, respectively). If the event does not resolve to baseline level or Grade 1 
within 3 weeks, MLN0128 will be discontinued permanently and the patient will complete the 
EOT Visit and be followed for PFS/OS as described in Section 10.7.
The following nonhematologic toxicities attributed to MLN0128 would not require dose 
interruption:

Grade 3 or higher nausea and/or emesis in the absence of optimal antiemetic prophylaxis. 
Optimal antiemetic prophylaxis is defined as an antiemetic regimen that employs both a 
5-hydroxytryptamine antagonist and a corticosteroid given in standard doses and according to 
standard schedules.

Grade 3 or higher diarrhea that occurs in the absence of optimal supportive therapy.
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
Grade 3 fatigue.
9.4.2
MLN0128 Dose Reduction
As detailed in Section 9.4.1, MLN0128 administration should be withheld for treatment-related 
AEs that are Grade 3 or higher despite supportive treatment per standard clinical practice. If the 
event resolves to Grade 1 or to baseline values within 3 weeks of interrupting treatment, then the 
patient may resume study treatment at a dose reduced by 1 level (Table 9.b). If a patient does not 
tolerate the reduced dose, then the investigator and the project clinician should discuss whether the 
patient would benefit from a further dose reduction.
Table 9.b
Dose Reductions for MLN0128
Dose Level
Daily Dose Regimen 
Weekly Dose Regimen
0
4 mg QD
30 mg QW
1
3 mg QD
20 mg QW
2
2 mg QD
15 mg QW
3
2 mg, 5 days on and 2 days off per week
10 mg QW
QD=once daily, QW=once weekly.
When a dose reduction of MLN0128 is required, no re-escalation of dose will be permitted.
9.4.3
Discontinuation of MLN0128
If MLN0128 administration is delayed for more than 3 weeks (21 consecutive days) due to study 
drug-related toxicity despite supportive treatment per standard clinical practice, or more than 
3 dose reductions of study drug are required in a patient, MLN0128 will be permanently 
discontinued and the patient will complete the EOT Visit and be followed for PFS/OS as described 
in Section 10.7.
9.5
Excluded Concomitant Medications and Procedures
9.5.1
Excluded Concomitant Medications and Procedures for Single-Agent Fulvestrant 
Treatment Arm (Arm A)
Refer to the current fulvestrant USPI or SmPC for excluded medications for patients receiving 
single-agent fulvestrant in this study.
In addition, these specific exclusions also apply to Arm A (single-agent fulvestrant):

Other investigational agents including mTOR, PI3K, dual PI3K-mTOR, and AKT inhibitors.

Other anticancer therapies, including chemotherapy, immunotherapy, radioimmunotherapy, 
targeted agents, radiation, or surgery. Patients can have palliative radiation or surgery during 
the study for pre-existing lesions.
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9.5.2
Excluded Concomitant Medications and Procedures for Combination MLN0128 Plus 
Fulvestrant Treatment Arms (Arm B and Arm C)
Refer to the current fulvestrant USPI or SmPC for excluded medications for patients receiving 
fulvestrant in this study.
In addition, the following medications, therapies, and procedures are prohibited during the study 
for patients receiving combination treatment:

Other investigational agents including mTOR, PI3K, dual PI3K-mTOR, and AKT inhibitors.

Other anticancer therapies, including chemotherapy, immunotherapy, radioimmunotherapy, 
targeted agents, radiation, or surgery. Patients can have palliative radiation or surgery during 
the study for pre-existing lesions.

Systemic corticosteroids (either IV or oral steroids), unless necessary for treatment of a study 
drug-related AE (eg, rash). Inhalers and low-dose replacement therapy are allowed.

Strong cytochrome P450 (CYP) 1A2 inhibitors and CYP inducers should be administered with 
caution and at the discretion of the investigator (see Appendix G for a list of these agents).

Concomitant administration of any PPI is not permitted during the study. All patients are 
required to stop taking PPIs at least 7 days before receiving the first dose of study drug. 
Examples of PPIs include omeprazole, esomeprazole, pantoprazole, lansoprazole, and 
rabeprazole.

Histamine H2 receptor antagonists may be allowed if needed, provided that the histamine H2 
receptor antagonist is not taken within 12 hours before or within 6 hours after study drug 
administration. Patients receiving histamine H2 receptor antagonists before enrollment must 
stop using these medications for at least 24 hours before their first dose of study drug. 
Examples of histamine H2 receptor antagonists include ranitidine, famotidine, and nizatidine.
Cimetidine, a moderate CYP1A2 inhibitor, is not recommended as a first choice H2 receptor 
antagonist (see Appendix G).

Administration of neutralizing antacids and calcium preparations is permitted except from 
4 hours before until 2 hours after study drug administration. Some antigas preparations may 
also have antacid properties and should also not be permitted from 4 hours before until 2 hours 
after study drug administration.
9.6
Permitted Concomitant Medications and Procedures (All Treatment Arms)
All prescription and over-the-counter medications, including influenza vaccines, taken by a patient 
from the first dose of study drug through 30 days after the last dose will be recorded on the 
designated electronic case report form (eCRF).
Prophylactic use of antiemetic, antinausea, and antidiarrheal medications is encouraged, and these 
may be administered before the first dose of study drug, as needed throughout the study before 
each dosing, and as clinically indicated per standard practice.
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Concomitant treatment with bone-targeting agents (eg, bisphos, denosumab) is permitted for
treatment of osteoporosis or management of existing bone metastases if initiated at least 4 weeks 
before administration of the first dose of study drug. To minimize confounding factors that may 
contribute to assessment of potential drug-related toxicities, the dosage of any ongoing 
bone-targeting agents should not be changed, and no new bone-targeting agents should be initiated 
during Screening (within 4 weeks before the first dose of study drug) or during Cycle 1.
Other medications considered necessary for the safety and well being of the patient may be 
administered at the discretion of the investigator. Any concomitant medications added or 
discontinued during the study should be recorded on the eCRF.
9.7
Precautions and Restrictions
The use of live vaccines and close contact with those who have received live vaccines should be 
avoided during treatment with study drug. Examples of live vaccines include the intranasal 
influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin, yellow fever, varicella, 
and TY21a typhoid vaccines.
No dietary restrictions will be imposed on study patients. Patients are required to fast for glucose 
monitoring (refer to Section 9.8.1 and Section 10.4.16). Patients receiving daily MLN0128 in 
Arm B should refrain from eating or drinking for 2 hours before and 1 hour after each dose (per 
Section 9.1). 9.1).
Patients who show evidence of hyperglycemia during the study should be encouraged to follow a 
low carbohydrate diet.
Patients should be encouraged to drink at least 20 ounces of fluids a day, especially on days 
requiring fasting (per protocol), with administration of IV fluids in the clinic as indicated to avoid 
dehydration.
9.8
Management of Clinical Events
Detailed MLN0128 dose modification and prevention/prophylaxis guidelines for specific clinical 
events are provided in the following sections. General guidelines for MLN0128 dose interruption 
and dose reduction are provided in Section 9.4.1 and Section 9.4.2. 
9.8.1
Management of Hyperglycemia
On the basis of the clinical experience in MLN0128 trials, most episodes of hyperglycemia 
observed occurred within the first 60 days after initiation of treatment with MLN0128 and have 
been either Grade 1 or Grade 2, and have responded quickly to oral metformin. Hyperglycemia has 
not been dose-limiting since the institution of a standard regimen for early treatment of 
hyperglycemia. 
All patients developing hyperglycemia during the study should have their glucose closely 
monitored by study staff. The investigator may choose to continue close monitoring of patients 
who develop Grade 1 hyperglycemia (fasting glucose >ULN ≤160 mg/dL) or, alternatively, 
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consider initiating treatment with an oral hypoglycemic agent, such as metformin. All patients 
with ≥Grade 2 hyperglycemia (fasting glucose >160 mg/dL) must be treated aggressively with oral 
hypoglycemic agents and/or insulin as clinically indicated. The investigator should consult an 
endocrinologist, if needed, to aid in optimizing the patient’s hyperglycemia treatment plan.
It is recommended that patients be initially treated with a fast-acting insulin sensitizer such as 
metformin at 500 mg PO QD, and titrate up to a maximum of 1000 mg PO twice daily as needed. 
Concurrent addition to metformin of DPP-4 inhibitors (eg, sitagliptin or vildagliptin) and/or 
insulin should also be considered. Oral sulfonylureas (eg, glipizide or glyburide) should be used 
with caution, due to the higher risk of inducing hypoglycemia in patients. The dose of oral 
hypoglycemic agents should be adjusted in patients with renal insufficiency. In addition, patients 
should be encouraged to follow a low carbohydrate diet once hyperglycemia is first observed.
If any fasting serum glucose reading performed at the site indicates hyperglycemia (>ULN or 
≥110 mg/dL), the study staff should first confirm that the patient was fasting at the time of blood 
specimen collection (ie, nothing by mouth for at least 8 hours before collection). To aggressively 
manage the hyperglycemia per standard clinical practice, the following guidelines (Table 9.c) are 
provided to aid the investigator in initiating antiglycemic therapies.
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Table 9.c
Management of Hyperglycemia
Grade
Description
Treatment
MLN0128 Dose Modification
1
FBG>ULN–160 
mg/dL.
Continue close monitoring of 
blood glucose. Initiate oral 
hypoglycemic agent.
None
2
FBG>160–250 
mg/dL.
Initiate oral hypoglycemic agent 
and/or insulin if not well 
controlled on oral agent.
None
≥3
FBG>250 mg/dL.
Initiate oral hypoglycemic agent 
and/or insulin.
Hold drug until ≤Grade 2.
Resume MLN0128 based on timing of 
recovery:
≤1 week: resume MLN0128 at same dose.
>1 but ≤2 weeks: resume MLN0128 with 
the dose reduced by 1 level (a).
>2 weeks: discontinue MLN0128 treatment 
permanently.
Prevention/Prophylaxis:
Follow fasting serum glucose levels during clinic visits.
Monitor home glucometer test results.
Check HbA1c levels every 3 months during therapy.
Recommend lifestyle modifications, as appropriate (balanced diet, limited alcohol consumption, increased physical 
activity).
Most episodes of Grade 1 and 2 hyperglycemia respond quickly to oral metformin. Early initiation of therapy is 
recommended to prevent higher grade hyperglycemia.
FBG levels ≥150 mg/dL by glucometer should be followed by closer monitoring of serum glucose and possible 
intervention.
FBG=fasting blood glucose, HbA1c=glycosylated hemoglobin, ULN=upper limit of the normal range.
(a) Refer to Table 9.b.
9.8.2
Management of Hyperlipidemia
Guidance on MLN0128 dose modification for patients with hyperlipidemia is provided in 
Table 9.d.
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Table 9.d
Management of Hyperlipidemia
Grade
Description
Treatment
MLN0128 Dose Modification
1
Cholesterol:
>ULN-300 mg/dL
Triglycerides:
>150-300 mg/dL
None
None
2
Cholesterol:
>300-400 mg/dL
Triglycerides:
>300-500 mg/dL
Treat hyperlipidemia according to 
standard guidelines. Triglycerides 
≥500 mg/dL should be treated 
urgently due to risk of 
pancreatitis.
Maintain dose if tolerable. If 
toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤Grade 1. Resume 
MLN0128 at same dose.
3
Cholesterol:
>400-500 mg/dL
Triglycerides:
>500-1000 mg/dL
Same as for Grade 2
Hold dose until recovery to 
≤Grade 1, then resume MLN0128 
with the dose reduced by 1 level. 
(a)
4
Cholesterol:
>500 mg/dL
Triglycerides:
>1000 mg/dL
Same as for Grade 2
Same as for Grade 3
Prevention/Prophylaxis:
Lifestyle modifications, as appropriate (balanced diet, limited consumption of alcoholic beverages, increased 
physical activity).
ULN=upper limit of the normal range.
(a) Refer to Table 9.b.
9.8.3
Management of Oral Mucositis
Guidance for the prevention and management of oral mucositis is provided in Table 9.e. Mucositis 
prophylaxis is strongly recommended for all patients while receiving MLN0128.
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Table 9.e
Management of Oral Mucositis
Grade
Description
Treatment
MLN0128 Dose Modification
1
Asymptomatic or mild 
symptoms. 
Nonalcoholic mouth wash or 0.9% 
salt water rinse; consider topical 
corticosteroids at earliest signs of 
mucositis.
None
2
Moderate pain not interfering 
with oral intake; modified diet 
indicated. 
Topical analgesic mouth 
treatments; topical corticosteroids; 
initiate antiviral or antifungal 
therapy, if indicated.
Maintain dose if tolerable. If 
toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤Grade 1. Resume 
MLN0128 at same dose.
3
Severe pain interfering with 
oral intake.
Same as for Grade 2; consider 
intralesional corticosteroids.
Hold dose until recovery to ≤Grade 
1, then resume MLN0128 with the 
dose reduced by 1 level. (a)
4
Life-threatening 
consequences. 
Same as for Grade 2; consider 
intralesional corticosteroids.
Discontinue MLN0128 treatment 
permanently.
Prevention/Prophylaxis:
Initiate a nonalcoholic mouth wash or 0.9% salt water rinses 4-6 times per day with start of therapy before signs of 
mucositis develop.
Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as 
they may worsen mouth ulcers.
(a) Refer to Table 9.b.
9.8.4
Management of Rash
Patients who develop Grade 4 rash should permanently discontinue MLN0128, unless they derive 
clinical benefit, in which case they may be retreated at a reduced dose level after recovery to 
Grade 1 severity. Grade 4 rash is defined as rash acneiform/papulopustular with papules and/or 
pustules covering any percent body surface area, which may or may not be associated with 
symptoms of pruritus or tenderness, and are associated with extensive superinfection with IV 
antibiotics indicated; life threatening consequences (NCI CTCAE Version 4.03, effective date 
14 June 2010 [32]). 
Guidance for management of rash is provided in Table 9.f.
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Table 9.f
Management of Rash
Grade
Description
Treatment
MLN0128 Dose Modification
≤2
Macules/papules covering 
≤30% body surface area with or 
without symptoms. 
Consider treatment with topical 
steroid cream/ointment and/or 
oral antihistamines.
None
3
Macules/papules covering 
30% body surface area with or 
without symptoms. 
Consider treatment with topical 
steroid cream/ointment, oral 
antihistamines, and/or pulsed 
steroids.
Hold until ≤Grade 2; resume 
MLN0128 based on timing of 
recovery:
≤3 weeks: resume MLN0128 with 
the dose reduced by 1 level. (a)
>3 weeks: discontinue MLN0128 
treatment.
4
Rash acneiform/ 
papulopustular with papules 
and/or pustules covering any 
percentage of body surface 
area, which may or may not be 
associated with symptoms of 
pruritus or tenderness, and are 
associated with extensive 
superinfection with IV 
antibiotics indicated; life 
threatening consequences.
Permanently discontinue MLN0128, 
unless patient is deriving clinical 
benefit, in which case resume at a 
reduced dose level (a) after recovery 
to Grade 1 severity.
Prevention/Prophylaxis:

Rash should be managed aggressively. The investigator should consider consulting a dermatologist or other 
specialist, if needed.

A skin biopsy at the site of rash should be considered as soon as possible after the initial episode.
IV=intravenous.
(a) Refer to Table 9.b.
9.8.5
Management of Nausea and/or Vomiting
Patients who experience Grade 3 nausea or vomiting for >72 hours despite optimal therapy may 
resume MLN0128 at a dose reduced by 1 level.
Guidance for the management of nausea and/or vomiting is provided in Table 9.g.
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Table 9.g
Management of Nausea and/or Vomiting
Grade
Description
Treatment
MLN0128 Dose Modification
≤2
Loss of appetite with or 
without decreased oral intake; 
1-5 episodes of vomiting 
within 24 hours.
Maximize antiemetic therapy; 
consider IV fluid hydration.
None
≥3
Inadequate oral intake; ≥6 
episodes of vomiting within 24 
hours.
Maximize antiemetic therapy; 
initiate tube feeding, IVF, or 
TPN.
If experienced for ≤72 hours, hold 
MLN0128 until ≤Grade 1, then 
resume MLN0128 without dose 
modification.
If experienced for >72 hours despite 
optimal therapy, hold MLN0128 until 
≤Grade 1, then resume MLN0128 
with the dose reduced by 1 level. 
Prevention/Prophylaxis:
Prophylactic use of antiemetic, antinausea, and antidiarrheal medications is encouraged, and these may be 
administered before each dose of MLN0128 as needed throughout the study.
IV=intravenous, IVF=intravenous fluids, TPN=total parenteral nutrition.
9.8.6
Management of Noninfectious Pneumonitis
Guidance for the management of pneumonitis is provided in Table 9.h.
Table 9.h
Management of Noninfectious Pneumonitis
Grade
Description 
Treatment
MLN0128 Dose Modification
1
Asymptomatic: Radiographic 
findings only.
Rule out infection and 
closely monitor.
None
2
Symptomatic:
Not interfering with activities of 
daily living.
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1.
Hold MLN0128 treatment:
When symptoms ≤Grade 1, resume 
MLN0128 with the dose reduced by 
1 level. (a)
If no recovery within 4 weeks, then 
discontinue MLN0128 treatment 
permanently.
3
Symptomatic:
Interfering with activities of daily 
living;
Requires administration of oxygen.
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1.
Hold MLN0128 treatment until 
symptoms resolve to ≤Grade 1.
Consider re-initiating MLN0128 
treatment with a dose reduction. (a)
If toxicity recurs at Grade 3, 
discontinue MLN0128 treatment 
permanently.
4
Life-threatening:
Ventilatory support indicated.
Rule out infection and 
consider treatment with 
corticosteroids.
Discontinue MLN0128 treatment 
permanently.
(a) Refer to Table 9.b.
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9.8.7
Management of Other Nonhematologic Toxicities
Guidance on dose adjustment for patients with other nonhematologic toxicities, specifically 
fatigue, asthenia, and weakness, is provided in Table 9.i.
Table 9.i
Management of Asthenia, Weakness, and Fatigue
Grade
Description
Treatment
Dose Modification
1
Mild; asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention 
not indicated.
Initiate appropriate medical 
therapy and monitor.
If tolerable, then no adjustment is 
required.
2
Moderate; minimal, local or 
noninvasive intervention 
indicated.
Initiate appropriate medical 
therapy and monitor.
If tolerable, no adjustment required.
If toxicity becomes intolerable, hold 
MLN0128 treatment until symptoms 
resolve to ≤Grade 1, then re-initiate at 
same dose. 
≥ 3
Severe or medically significant 
but not immediately 
life-threatening; hospitalization 
or prolongation of 
hospitalization indicated.
Hold MLN0128 treatment until 
symptoms resolve to ≤Grade 1. 
Re-initiate MLN0128 treatment with 
a dose reduction. (a)
(a) Refer to Table 9.b.
9.9
Blinding and Unblinding
This is an open-label study.
9.10
Description of Investigational Agents
MLN0128 will be supplied as capsules for oral administration. MLN0128 is available in 3 dose 
strengths (1, 3, and 5 mg of MLN0128). The capsules contain milled drug substance, 
microcrystalline cellulose, and magnesium stearate. All 3 dose strengths are formulated into size 2 
hard-gelatin capsules, and each dose strength is differentiated by color:

1 mg MLN0128 capsules: white opaque.

3 mg MLN0128 capsules: Swedish orange opaque.

5 mg MLN0128 capsules: gray opaque.
Fulvestrant is a commercially available drug supplied as a solution for IM injection and will be 
procured or distributed according to the Pharmacy Manual. Please refer to the most recent USPI or 
SmPC for more information regarding fulvestrant.
9.11
Preparation, Reconstitution, and Dispensation
MLN0128 will be provided in 60 cc high-density polyethylene (HDPE) bottles with 
polypropylene, child-resistant caps and induction seal. MLN0128 will be dispensed with dosing 
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instructions for home use, including the requirement that capsules are stored in their original 
containers and that capsules be swallowed whole and not opened, chewed, or manipulated in any 
way. Materials provided by the sponsor should be dispensed to patients with clear administration 
instructions from the investigator.
MLN0128 is an anticancer drug and, as with other potentially toxic compounds, caution should be 
exercised when handling MLN0128 capsules.
Refer to the fulvestrant USPI or SmPC for details regarding the preparation, reconstitution, and 
dispensation of fulvestrant.
9.12
Packaging and Labeling
MLN0128 will be provided by Millennium and will be handled at the investigative site as 
open-label material. MLN0128 capsules are packaged in 60 cc HDPE bottles with polypropylene, 
child-resistant caps and an induction seal. For all 3 dose strengths, each bottle contains 30 capsules 
and will have a label containing pertinent study information, country-specific requirements, and a 
caution statement.
While the patient is enrolled in the study, fulvestrant may be supplied either by the site from 
commercial sources (US sites) or provided by Millennium (ex-US sites). When provided by 
Millennium, fulvestrant will be appropriately labeled in compliance with local and regional 
regulations.
9.13
Storage, Handling, and Accountability
Upon receipt at the investigative site, MLN0128 should be stored in the original bottles until use 
and stored at room temperature from 15C to 30C (59F to 86F). 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 MLN0128 should be used before the retest expiry date.
Refer to the current fulvestrant USPI or SmPC for details regarding the storage and handling of 
fulvestrant.
A drug dispensing log, including records of drug received from the sponsor and drug dispensed to 
the patients, 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 MLN0128 is an investigational agent, it should be handled with due care. In case of 
contact with broken capsules, raising dust should be avoided during the clean-up operation. The 
product may be harmful if inhaled, ingested, or absorbed through the skin. Gloves and protective 
clothing should be worn during the clean-up operation. The area should be ventilated and the spill 
site washed after material pick-up is complete. The spilled material should be disposed of as 
hazardous medical waste in compliance with federal, state, and local regulations. In case of contact 
with the powder (eg, from a broken capsule), the 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 
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amounts of water should be used to flush the eyes for at least 15 minutes. Medical personnel 
should be notified.
Patients will receive instructions for home storage and administration of MLN0128.
Patients will be instructed to return any unused study drug in the original packaging along with 
their completed patient dosing diary at the appropriate visits per the Schedule of Events.
Please refer to the Investigator Site File for additional instructions.
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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 laboratory and any 
additional clinical laboratories, the coordinating investigator for each member state/country 
(where applicable), the IRT provider, and the study monitoring team may be found in the 
Investigator Site File. 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 institutional review board 
(IRB)/independent ethics committee (IEC).
10.3
Treatment Group Assignments
Patient eligibility will be established before randomization into the study. Patient eligibility will be 
confirmed by the sponsor’s project clinician (or designee) before randomization by the 
investigator into the study. A centralized randomization IRT will be used for treatment group 
assignment.
Enrollment will be managed via the IRT to ensure that approximately 40% of enrolled patients 
have previously received CDK4/6 inhibitors in combination with an AI. Enrollment of 
non-CDK4/6 pretreated patients may be stopped in the case that 60% or greater of enrollment has 
occurred with only non-CDK4/6 pretreated patients.
Patients who meet the eligibility criteria will be stratified according to the presence or absence of 
visceral metastasis, previous sensitivity to hormonal therapy, and previous exposure to CDK4/6 
inhibitors. Visceral metastasis is defined as all lesions not included in the following list: breast, 
skin, subcutaneous tissue, lymph node, or bone. Previous sensitivity to hormonal therapy is 
defined as at least 24 months of endocrine therapy before recurrence in the adjuvant setting (ie, in 
patients who have not received previous endocrine therapy in the metastatic setting) or a response 
or stabilization for at least 24 weeks of the most recent endocrine therapy for advanced/metastatic 
disease. Patients will be randomized 1:1:1 to 1 of 3 treatment arms (51 patients per arm):

Arm A: Single-agent fulvestrant.

Arm B: Combination of fulvestrant+daily MLN0128.

Arm C: Combination of fulvestrant+weekly MLN0128.
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Patients in the single-agent fulvestrant arm (Arm A) who have PD may be allowed to receive 
crossover treatment with the combination of fulvestrant+MLN0128, as detailed in Section 7.1.4. A 
centralized randomization IRT will be used to randomize crossover patients in a 1:1 ratio to either 
fulvestrant+daily MLN0128 or fulvestrant+weekly MLN0128. Patients who discontinue 
fulvestrant in either of the combination treatment arms (Arm B or Arm C) may be eligible to 
continue receiving MLN0128 at their current dose as described in Section 7.1.5. If MLN0128 is 
discontinued for a patient in either of the combination treatment arms (Arm B or Arm C), the 
patient will complete the EOT Visit and be followed for PFS/OS as detailed in Section 10.7.
10.4
Study Procedures
Patients will be evaluated at scheduled visits over the following study periods: Screening,
Treatment, EOT, and PFS/OS Follow-Up. Unless otherwise noted, evaluations during the 
Screening period are to be conducted within 28 days before administration of the first dose of 
study drug. Evaluations during the Treatment Period must occur before study drug administration 
on that day. Tests and procedures should be performed on schedule for all visits but occasional 
changes are allowable (±2 days) for holidays, vacations, and other administrative reasons, starting 
after the completion of Cycle 2 Day 1.
All EOT evaluations should occur within 30 to 40 days after the last dose of study drug, or before 
the start of subsequent antineoplastic therapy (or crossover treatment if applicable; see 
Section 7.1) if that occurs earlier than 30 days after the last dose.
Refer to the Schedule of Events 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 Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening.
10.4.3 Medical History
During 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. 
10.4.4 Enrollment
Enrollment is defined as being randomized to a treatment arm.
Enrollment will be managed via the IRT to ensure that approximately 40% of enrolled patients 
previously received CDK4/6 inhibitors in combination with an AI.
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10.4.5 Patient Height and Weight
Height will be measured only during Screening. Body weight will be measured at the visits 
specified in the Schedule of Events.
10.4.6 Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.
10.4.7 Vital Signs
Vital sign measurements, including diastolic and systolic blood pressure, heart rate, and 
temperature will be measured at the visits specified in the Schedule of Events.
10.4.8 ECOG Performance Status
Performance status will be assessed according to the ECOG scale (see Appendix D) at the time 
points specified in the Schedule of Events.
10.4.9 ECG
A single, 12-lead ECG will be performed predose on Day 1 of every cycle and during the EOT 
Visit. When the timing of an ECG coincides with blood samples, the ECG should be completed 
first. Additional ECGs may be obtained as clinically indicated.
10.4.10Disease Assessment
10.4.10.1
CT Scan or MRI
Patients will undergo CT scan (with contrast) as appropriate to monitor and assess PD, using 
RECIST guidelines (Version 1.1), where measureable disease is defined as at least 1 extra-osseous 
lesion that can be accurately measured in at least 1 dimension [1]. An MRI may be performed for 
patients who are allergic to CT contrast or for patients with specific disease sites that cannot be 
adequately imaged by CT scan. Anatomical measurements (summed across target lesions) will be 
collected at Baseline and at each subsequent evaluation using an imaging modality consistent with 
that used at Screening. Objective assessments will be performed at each time point specified in the 
Schedule of Events. When possible, the same qualified physician will interpret results to reduce 
variability.
In the absence of measurable disease at Baseline, the following will be considered PD among 
patients with bone-only disease:

The appearance of 1 or more new lytic lesions in bone.

The appearance of any extra-osseous lesions.

Unequivocal progression of existing bone lesions.
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All images will be collected and quality controlled by a sponsor-specified central imaging vendor. 
Radiographic images will be maintained at the site, and test results and physicians’ findings will be 
filed in patient source documents. The sponsor may request electronic images for those patients 
who demonstrate a response.
10.4.10.2
Bone Scan
A bone scan will be required for all patients during Screening (within 21 days before the first dose 
of study drug), and thereafter at the discretion of the investigator to monitor representative areas.
10.4.10.3
Health-related Quality of Life Assessments
The HRQL instruments, EORTC QLQ-C30 and EORTC QLQ-BR23, will be administered as 
specified in the Schedule of Events, and they must be completed before other assessments are 
performed or study drug is administered.
The EORTC QLQ-C30 incorporates 5 functional scales (physical functioning, role functioning, 
emotional functioning, cognitive functioning, and social functioning); 1 global health status scale; 
3 symptom scales (fatigue, nausea and vomiting, and pain); and 6 single items (dyspnea, insomnia, 
appetite loss, constipation, diarrhea, and financial difficulties). (See Appendix H.) The time recall 
period for this instrument is 1 week (the past week). The EORTC QLQ-C30 is a reliable and valid 
measure of HRQL in patients with cancer [34]. The instrument consists of a brief (30-item) 
questionnaire that has been validated and used in many countries.
The EORTC QLQ-BR23 is an instrument specific to breast cancer that was designed to be used in 
conjunction with the EORTC QLQ-C30. The questionnaire comprises 23 items on issues relevant 
to patients with breast cancer that are not, or not sufficiently, covered by the core questionnaire. 
The EORTC QLQ-BR23 instrument incorporates 2 functional scales (body image and sexual 
functioning), 3 symptom scales (arm symptoms, breast symptoms, and systemic side effects), and 
single items related to sexual enjoyment, distress by hair loss, and future perspective (see 
Appendix I). The recall period for this instrument is 1 week (the past week), except for items 
related to sexual function (recall period of 4 weeks). The instrument has been validated in many 
languages and among patients varying in disease stage and treatment modality [35].
10.4.11Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient from the first 
dose of study drug through 30 days after the last dose of study drug will be recorded on the eCRF. 
See Section 9.5 and Section 9.6 for a list of medications and therapies that are prohibited and/or 
allowed during the study.
10.4.12AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the Schedule of Events. Refer to Section 11.0 for details regarding definitions, documentation, and 
reporting of pretreatment events (PTEs), AEs, and SAEs.
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10.4.13Patient Diary Instruction and Review
At the beginning of each cycle, patients in Arms B and C will receive a diary in which to record 
their dosing and fasting blood glucose (FBG) testing results. 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 
compliance with dosing. Patients who are not compliant with the dosing schedule may be 
withdrawn from the study.
10.4.14Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally.
Blood specimens for analysis of the clinical chemistry, hematology, and coagulation parameters 
shown in Table 10.a and urine specimens for analysis of the parameters shown in Table 10.b will 
be obtained as specified in the Schedule of Events.
Table 10.a
Clinical Chemistry, Hematology, and Coagulation Tests
Hematology and Coagulation
Chemistry
Hematocrit (Hct)
Hemoglobin (Hgb)
Leukocytes with differential
Neutrophils (ANC)
Platelets (count)
Activated partial thromboplastin time 
(aPTT)
Prothrombin time/international 
normalized ratio (PT/INR)
Albumin
Alkaline phosphatase (ALP)
ALT
Amylase
AST
Bilirubin (total and direct) (b)
Blood urea nitrogen (BUN) or Urea
Calcium (total)
Carbon dioxide (CO2) or bicarbonate
Chloride
Creatinine
Gamma glutamyl transferase (GGT)
Glucose
Glycosylated hemoglobin (HbA1c) (a)
Lactate dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Protein (total)
Sodium
Urate
(a) Assessed only at the time points specified in the Schedule of Events.
(b) Direct bilirubin will be measured only if total bilirubin is altered.
Table 10.b
Clinical Urinalysis Tests
Urinalysis (a)
Bilirubin
Color
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity
Urobilinogen
(a) The use of test strips is permitted.
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For Screening, creatinine clearance must be ≥40 mL/min based either on Cockroft-Gault estimate 
or based on a 12- or 24-hour urine collection.
Prospective monitoring for hyperlipidemia will be managed through fasting lipid testing. 
Sampling for the fasting lipid profile (Table 10.c) will be obtained at the times specified in the 
Schedule of Events.
Table 10.c
Fasting Lipid Profile
Fasting Lipid Profile
Cholesterol (total)
Triglycerides
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol
Fasting serum glucose will be measured in the clinic at the time points specified in the 
Schedule of Events. Patients are required to fast overnight (nothing except water and/or 
medications after midnight or for a minimum of 8 hours before the assessment) for each of these 
measurements. For patients receiving single-agent fulvestrant in Arm A or fulvestrant+MLN0128
QW in Arm C, the fasting serum glucose may be assessed as part of the predose chemistry panel. 
After fasted sampling is complete, patients receiving fulvestrant+MLN0128 QW in Arm C should 
consume a light meal prior to dosing (Section 9.1). For patients receiving fulvestrant+MLN0128 
QD in Arm B, a separate sample must be taken approximately 2 hours after study drug 
administration, with patients continuing to fast until that sample is taken.
In-home glucose monitoring is not required on days when fasting glucose is measured in the clinic.
10.4.15In-Home Daily FBG Monitoring (Combination Arms Only)
In addition to obtaining fasting serum glucose levels at the clinic visits as outlined in the 
Schedule of Events, all patients in the combination fulvestrant+MLN0128 treatment arms (Arm B 
and Arm C) will be given a glucometer to monitor their daily FBG levels at home. The level should 
be collected daily, predose on dosing days, and at approximately the same time each day. Before 
checking their blood glucose levels, patients should fast overnight (nothing except water and/or 
medications after midnight or for a minimum of 8 hours before the assessment). After fasted 
testing is complete, patients in Arm C should consume a light meal prior to MLN0128 dosing 
(Section 9.1).
On Cycle 1 Day 1, the patient will be provided an in-home glucometer. Patients will be trained on 
proper use of the glucometer and instructed to collect a daily fasting glucose level every morning 
(predose on dosing days), starting on Cycle 1 Day 2. Patients will be instructed to bring the 
glucometer with them to each study visit so that the data collected can be reviewed and recorded in 
the source documents. Investigators will be responsible for reviewing the home glucose 
monitoring logs for hyperglycemia.
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The patient will be instructed to contact the site immediately if the value is abnormal 
(ie, #150 mg/dL) for further instructions on the management of their hyperglycemia. 
Hyperglycemia observed during home glucose monitoring should be confirmed in the clinic.
If no irregularities in the FBG level are observed during a minimum of 2 consecutive months, then 
the frequency of in-home FBG testing can be reduced to a minimum frequency of once weekly, 
depending on the investigator’s judgement and approval. Patients will continue to notify the 
investigator of FBG levels that exceed 150 mg/dL and, if blood glucose levels are not well 
controlled, or if the patient requires either oral hypoglycemic agents or insulin to control blood 
glucose levels, then the frequency of in-home testing of FBG levels will be reinstated to daily.
See also Section 9.8.1.
10.4.16Biomarker Measurements in Blood
10.4.18Banked Tumor Specimen Measurements
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10.4.19PK Measurements (Combination Arms Only)
Blood sampling to characterize the PK of MLN0128 will be performed for patients randomized to 
the combination fulvestrant+MLN0128 treatment arms (Arm B and Arm C, including patients 
who receive crossover treatment), at the times indicated in the Schedule of Events. When the 
timing of a PK blood sample coincides with vital sign or ECG measurements, the vital sign or ECG 
measurement should be obtained before the PK blood sample. Details on the collection, storage, 
processing, handling, and shipping of PK samples are in the 
 Central Laboratory Manual.
PK data for MLN0128 will be combined with similar data from other studies for future population 
PK analysis. The results of the population PK analysis will not be presented in the clinical study 
report and may be presented in a separate population PK analysis report at a later time. 
10.5
Completion of Study Treatment
Patients will be considered to have completed treatment if they discontinue study drug for any of 
the reasons outlined in Section 10.7.
10.6
Completion of Study
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 
Treatment with study drug may be discontinued for any of the following reasons:
!
AE.
!
Protocol deviation.
!
PD.
!
Symptomatic deterioration.
!
Study terminated by sponsor.
!
Withdrawal by patient.
!
Lost to follow-up.
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
Other (eg, investigator’s decision to initiate a different therapy, patient noncompliance with 
study requirements).
Patients must discontinue study drug if they experience PD or unacceptable toxicity.
Once study drug has been discontinued, all study procedures outlined for the EOT Visit will be 
completed as specified in the Schedule of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Note that some patients may discontinue study drug for reasons other than PD. These patients will 
remain in the study for post-treatment assessments as outlined in the Schedule of Events and 
Section 10.10.
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.
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. Data on survival may be 
obtained from publically available databases and sources.
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 MLN0128 for each treatment cycle and a diary in 
which to record their dosing. The study center staff will check the patient’s dosing 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 Post-Treatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)
After the EOT Visit (or, for crossover patients, after their second and final EOT Visit), patients 
will be followed for PFS and OS. Patients who discontinue study treatment for reasons other than 
PD will continue to have PFS follow-up visits every 2 months (±1 week) for the first 6 months 
after the EOT Visit, then every 3 months (±1 week) until PD or start of another anticancer therapy 
for treatment of disease under study, whichever occurs first. After PD or the start of another 
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anticancer therapy, patients will be followed for OS every 6 months (±1 week). OS follow-up will 
continue until approximately 20 months after the first patient is randomized, or when the last 
patient discontinues study treatment. Survivor information and death details 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, the start of any other anticancer therapy 
for treatment of disease under study will be collected. Refer to the Schedule of Events for 
appropriate assessments during posttreatment follow-up.
NOTE: Any SAEs occurring after the EOT Visit that are considered related to study drug must be 
reported to Takeda Global Pharmacovigilance department or designee. This includes deaths that 
the investigator considers related to study drug that occur during the posttreatment follow-up. 
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 PTE Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent to participate in a study before administration of any study medication; it does not 
necessarily have to have a causal relationship with study participation.
11.1.2 AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event or a previous condition that has increased in severity or frequency since the 
administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered 
by the investigator to be a clinically significant change from Baseline.
11.1.3 SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 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 lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [32]. 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.
11.2
Procedures for Recording and Reporting AEs and SAEs
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 PTEs (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 Investigator Site File. Follow-up information on the SAE or serious PTE 
may be requested by Takeda. SAE report information must be consistent with the data provided on 
the eCRF.
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Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
first dose of study drug 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 PTEs, 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 laboratory abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [32].
Causality (relationship) to study drug administration will be determined by the investigator 
responding yes (Related) or no (Not Related) to this question: Is there a reasonable possibility that 
the AE is associated with the study drug?
11.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:
!
AEs will be reported from first dose of study drug through 30 days after administration of the 
last dose of study drug and recorded on the eCRFs.
!
Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the informed consent form up to first dose of study 
drug, but will not be recorded on 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 on the eCRF. After this period, only related SAEs 
must be reported to the Takeda Global Pharmacovigilance department or designee. SAEs 
should be monitored until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es).
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11.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Reporting procedures for pregnancy and birth events are not applicable for this study as enrollment 
is restricted to postmenopausal women only.
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 contact the Medical 
Information Call Center /
and report the complaint. The contact 
information is as follows: 
Medical Information Call Center:
Phone:
Fax:
E-mail:
Hours:
Whenever possible, the associated product should be maintained in accordance with the label 
instructions pending further guidance from a Millennium Quality representative.
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to 
 (refer to Section 11.2).
11.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 calendar days for fatal and 
life-threatening events and 15 calendar days for other serious events, unless otherwise required by 
national regulations. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational medicinal 
product’s administration or in the overall conduct of the trial. The investigational site also will 
forward a copy of all expedited reports to his or her IRB or IEC in accordance with national 
regulations.
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12.0
STUDY-SPECIFIC COMMITTEES
A Steering Committee, comprising Takeda clinical research and biostatistics representatives, 
study site investigators, and medical consultants from GEICAM will be responsible for 
performing the safety and tolerability assessment for the first 6 evaluable patients treated in Arm 
C. The purpose of this assessment is to confirm the weekly dose of 30 mg MLN0128 in 
combination with fulvestrant (see Section 7.1.2 for details). After this assessment is completed, the 
Steering Committee will be available to meet on an ad hoc basis to review study data as necessary. 
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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
Electronic Case Report Forms 
Completed eCRFs are required for each randomized subject. 
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 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 from 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, and the sponsor or its designees. Any 
source documentation printed on degradable thermal sensitive paper should be photocopied by the 
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site and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
ICH E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
Section 8 until at least 2 years after the last approval of a marketing application for a specified drug 
indication being investigated or, if an application is not approved, until at least 2 years after the 
investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
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14.0
STATISTICAL METHODS
14.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. The SAP 
will provide further details regarding the definition of analysis variables and analysis methodology 
to address all study objectives.
14.1.1 Analysis Sets
Full analysis set: all randomized patients. Patients will be analyzed according to the treatment 
assignment per the randomization schedule. 
Safety analysis set: patients who receive at least 1 dose of study drug. Patients will be analyzed 
according to the treatment actually received.
Response-evaluable analysis set: patients who receive at least 1 dose of study drug, have 
measurable disease at Baseline, and have 1 postbaseline disease assessment.
14.1.2 Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics (age, weight, height, and other parameters, as 
appropriate) will be summarized by treatment arm. 
14.1.3 Efficacy Analysis
14.1.3.1 Primary Efficacy Endpoint
The primary endpoint is PFS, defined as the time from the date of randomization to the date of first 
documentation of progression or death due to any cause, whichever occurs first. For a patient 
whose disease has not progressed and is last known to be alive, or started alternate therapy prior to 
PD, PFS will be censored at the last response assessment that is SD or better. The primary efficacy 
analysis will be based on the full analysis set. 
The Kaplan-Meier method will be used to analyze the distribution of PFS for each treatment arm. 
Kaplan-Meier survival curves, the 25th, 50th (median), and 75th percentiles, along with associated 
2-sided 95% confidence intervals (CIs), HR along with associated 95% CI, and Kaplan-Meier 
estimates at relevant time points will be presented. The primary hypothesis is to be tested at the 
0.10 significance level (2-sided). The p-values from a stratified log-rank test and HRs and will be 
presented for each pair-wise comparison.
14.1.3.2 Secondary Efficacy Endpoints
Secondary efficacy endpoints include OS, ORR, TTP, CBR with SD of any duration, and CBR 
with SD duration of at least 6 months.
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OS is defined as the time from the date of randomization to the date of death. Patients without 
documentation of death at the time of analysis will be censored at the date last known to be alive. 
OS will be analyzed using similar methods as the primary endpoint of PFS in the full analysis set.
ORR is defined as the proportion of patients who achieve a best response of CR or PR. CBR is 
defined as the proportion of patients who achieve a best response of CR, PR, or SD. The CBR will 
also be presented for a best response of CR, PR and SD of at least 6 months. A stratified 
Cochran-Mantel-Haenszel test will be used to compare ORR and CBR between treatment arms. 
The Mantel-Haenszel estimate of the odds ratio and the associated 95% CIs will be presented for 
each pair-wise comparison.
TTP is defined as the time from the date of randomization to the date of first documentation of
progression. For a patient whose disease has not progressed, TTP will be censored at the last 
response assessment that is SD or better. TTP will be analyzed using similar methods as the 
primary endpoint of PFS in the full analysis set.
14.1.4 PK Analysis
The sparse PK data are being collected to contribute to a future population PK analysis. These data 
may be combined with data from other studies in which the PK of MLN0128 is characterized for 
population PK analysis. The results of population PK analysis will be presented in a separate 
report.
14.1.5 Pharmacodynamic Analyses/Biomarker Analyses
14.1.6 Patient-Reported Outcomes
Patient-reported outcome (PRO) assessments of HRQL using the EORTC QLQ-C30 and EORTC 
QLQ-BR23 questionnaires will be analyzed to determine if response to therapy and side effects of 
CCI
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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therapy are accompanied by measurable changes in the PROs. Published scoring manuals and 
guidelines will be used to generate scale scores and handle missing data.
Descriptive statistics for baseline values, actual values, and the change from Baseline will be 
presented at each scheduled time point for each of the functional and symptom scores from the 
EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires, and the global health status/QOL 
score from the EORTC QLQ-C30 questionnaire. All analyses will be based on the full analysis set. 
Differences between treatment arms in the EORTC QLQ-C30 and EORTC QLQ-BR23 scores will 
be evaluated. Longitudinal analysis of PRO scores will be performed using linear mixed models.
14.1.7 Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
Baseline in the patient’s vital signs, weight, and clinical laboratory results using the safety analysis 
set. Exposure to each study drug (ie, MLN0128 and fulvestrant) will be summarized and reasons 
for discontinuation will be tabulated. Safety will be summarized by treatment arm.
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 
dictionary 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. 

SAEs.
A listing of AEs resulting in study drug discontinuation will be provided. A listing of all deaths 
within 30 days after the last dose of study drug will also be provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
Baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. 
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE grade 
from Baseline to the worst postbaseline value.
Concomitant medications will be coded using the WHO Drug Dictionary. The number and 
percentage of patients taking concomitant medications will be tabulated by WHO drug generic 
term in the safety analysis set.
ECG intervals (PR interval, QT interval, and QTc with Fridericia correction), QRS duration, and 
ventricular rate will be summarized at each scheduled time point, along with mean change from 
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Baseline to each post-treatment time point. The number and percentage of patients with ECG 
abnormalities will be summarized at each time point.
14.2
Interim Analysis and Criteria for Early Termination
No formal interim analysis is planned. Details on considerations and decision rules for early 
stopping for futility will be described in the SAP or a separate document.
14.3
Determination of Sample Size
The primary efficacy endpoint is PFS. Assuming that the median PFS is 4 months for fulvestrant 
[36] and that the combination of fulvestrant and MLN0128 (administered either QD or QW) can 
improve the median PFS to 8 months (HR of 0.5), then a total of 72 PFS events are needed for each 
pair-wise comparison. Each treatment arm will require 51 patients. The calculations are based on a 
power of 90%, 2-sided alpha of 10%, and a dropout rate of 10% due to either lost to follow-up or 
withdrawal of consent.
The accrual duration will be approximately 14 months. The final analysis for the pair-wise 
comparisons of PFS between fulvestrant+MLN0128 QD and fulvestrant, and between 
fulvestrant+MLN0128 QW and fulvestrant, is estimated to occur approximately 20 months after 
the first patient is randomized.
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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 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 IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form or equivalent 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 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 eCRF).
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’s 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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evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
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2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013.
3. Malvezzi M, Bertuccio P, Levi F, La Vecchia C, Negri E. European cancer mortality 
predictions for the year 2013. Ann Oncol 2013;24(3):792-800.
4. Ignatiadis M, Sotiriou C. Luminal breast cancer: from biology to treatment. Nat Rev Clin 
Oncol 2013.
5. Higgins MJ, Baselga J. Targeted therapies for breast cancer. J Clin Invest 
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6. Guiu S, Michiels S, Andre F, Cortes J, Denkert C, Di Leo A, et al. Molecular subclasses of 
breast cancer: how do we define them? The IMPAKT 2012 Working Group Statement. Ann 
Oncol 2012;23(12):2997-3006.
7. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits 
of human breast tumours. Nature 2000;406(6797):747-52.
8. Villarreal-Garza C, Cortes J, Andre F, Verma S. mTOR inhibitors in the management of 
hormone receptor-positive breast cancer: the latest evidence and future directions. Ann Oncol 
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9. Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns 
of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad 
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10. Pritchard KI, Gelmon KA, Rayson D, Provencher L, Webster M, McLeod D, et al. Endocrine 
therapy for postmenopausal women with hormone receptor-positive her2-negative advanced 
breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a 
Canadian consensus statement. Curr Oncol 2013;20(1):48-61.
11. Dees EC, Carey LA. Improving endocrine therapy for breast cancer: it's not that simple. J Clin 
Oncol 2013;31(2):171-3.
12. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent 
kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as 
first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer 
(PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 2015;16(1):25-35.
13. Pritchard KI. Endocrine therapy: is the first generation of targeted drugs the last? J Intern Med 
2013;274(2):144-52.
14. Adelson K, Germain D, Raptis G, Biran N. Hormonal modulation in the treatment of breast 
cancer. Endocrinol Metab Clin North Am;40(3):519-32.
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15. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med 
2011;62:233-47.
16. Jessen K, et al. INK128 Is a Potent and Selective TORC1/2 Inhibitor With Broad Oral 
Antitumor Activity. Mol Cancer Therapy 2009;8(12):Abstract B148.
17. Kessler L, Wang S, Xin G, Kucharski J, Staunton J, Lan L, et al. INK128, an orally active 
TORC1/2 kinase inhibitor, shows broad antitumor activity and enhances efficacy of cytotoxic 
as well as targeted agents. Cancer Res 2010;70(8; Supplement 1 Abstract 4496).
18. Hassan B, Akcakanat A, Takafumi S, Evans K, Adkins F, Meric-Bernstam F. Inhibitor 
MLN0128 Has Antitumor Efficacy In Cell Lines With Intrinsic And Acquired 
Rapamycin-Resistance. Academic Surgical Congress 2013(Abstract ASC20130420).
19. Voss M, Gordon MS, Mita M, Rini B, Makker V, Macarulla T, et al. Phase I study of 
investigational oral mTORC1/2 inhibitor TAK-228 (formerly MLN0128): expansion phase in 
patients with renal, endometrial, or bladder cancer. 2015.
20. Ghobrial IM, Siegel D, Vij R, Wolf JL, Berdeja JG, Matous JV, et al. MLN0128 (INK128), an 
Investigational Oral Dual TORC1/2 Inhibitor, in Patients (pts) with Relapsed or Refractory 
Multiple Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), or Waldenstrom 
Macroglobulinemia (WM): Preliminary Results From a Phase 1 Dose-Escalation Study. ASH 
Annual Meeting Abstracts 2012;120(21):4038.
21. Lonning PE. Additive endocrine therapy for advanced breast cancer - back to the future. Acta 
Oncol 2009;48(8):1092-101.
22. Bertelli G, Garrone O, Merlano M, Occelli M, Bertolotti L, Castiglione F, et al. Sequential 
treatment with exemestane and non-steroidal aromatase inhibitors in advanced breast cancer. 
Oncology 2005;69(6):471-7.
23. Van Tine BA, Crowder RJ, Ellis MJ. ER and PI3K independently modulate endocrine 
resistance in ER-positive breast cancer. Cancer Discovery 2011;1(4):287-8.
24. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, et al. Double-blind, 
randomized placebo controlled trial of fulvestrant compared with exemestane after prior 
nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone 
receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol 
2008;26(10):1664-70.
25. Zagouri F, Sergentanis TN, Chrysikos D, Filipits M, Bartsch R. mTOR inhibitors in breast 
cancer: a systematic review. Gynecol Oncol 2012;127(3):662-72.
26. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, et al. 
Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence 
in estrogen receptor-positive human breast cancer. J Clin Invest 2010;120(7):2406-13.
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27. Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, et al. Preclinical modeling 
of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen 
receptor-positive breast cancer. Breast Cancer Res 2011;13(2):R21.
28. Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, et al. Everolimus in 
postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 
2012;366(6):520-9.
29. Wolff AC, Lazar AA, Bondarenko I, Garin AM, Brincat S, Chow L, et al. Randomized phase 
III placebo-controlled trial of letrozole plus oral temsirolimus as first-line endocrine therapy in 
postmenopausal women with locally advanced or metastatic breast cancer. J Clin Oncol 
2013;31(2):195-202.
30. Massarweh S, Romond E, Black EP, Van Meter E, Shelton B, Kadamyan-Melkumian V, et al. 
A phase II study of combined fulvestrant and everolimus in patients with metastatic estrogen 
receptor (ER)-positive breast cancer after aromatase inhibitor (AI) failure. Breast Cancer Res 
Treat 2014;143(2):325-32.
31. Boulay A, Rudloff J, Ye J, Zumstein-Mecker S, O'Reilly T, Evans DB, et al. Dual inhibition of 
mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. 
Clin Cancer Res 2005;11(14):5319-28.
32. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. Department 
of Health and Human Services National Cancer Institute. 14 June 2010.
33. Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. 
Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: 
American Society of Clinical Oncology/College of American Pathologists Clinical Practice 
Guideline Update. Arch Pathol Lab Med 2013.
34. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. J Natl Cancer Inst 1993;85(5):365-76.
35. Nguyen J, Popovic M, Chow E, Cella D, Beaumont JL, Chu D, et al. EORTC QLQ-BR23 and 
FACT-B for the assessment of quality of life in patients with breast cancer: a literature review. 
J Comp Eff Res 2015;4(2):157-66.
36. Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, et al. Palbociclib in 
Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med 2015;373(3):209-19.
37. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982;5(6):649-55.
38. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
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39. The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & Co; 
1994.
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Appendix A
Schedule of Events
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Schedule of Events
Screening (a)
Treatment
PC 
EOT 
(b)
EOT 
(c)
PFS/OS 
Follow-up
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 and 
Beyond
D -28 to D -1
D1
D15
D1
D15
D1
D1
D1
Informed consent
X
X
Inclusion/exclusion criteria
X
X
Demographics
X
Medical history
X
Height
X
Weight
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
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
X
X
12-lead ECG (single) (e)
X
X
X
X
X
X
X
X
Radiographic tumor evaluation (f)
X
Every other cycle, starting with Cycle 2 (f)
X
X
X (g)
Bone scan (h)
X
As necessary to monitor representative areas, at the investigator’s discretion.
Subsequent cancer therapy
X
X (g)
Follow-up phone calls (OS)
X (g)
HRQL assessments (i)
X
X
X
X
X
X
Monitoring of concomitant 
medications and procedures
Recorded from first dose of study drug through 30 days after the last dose of study 
drug
AE reporting
Recorded from first dose of study drug through 30 days after the last dose of 
study drug
SAEs (j) will be reported from signing of the informed consent form through 30 days after the last 
dose of study drug.
Footnotes are on last table page.
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Schedule of Events (continued)
Screening (a)
Treatment
PC 
EOT 
(b)
EOT 
(c)
PFS/OS 
Follow-up
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 and 
Beyond
D -28 to D -1
D1
D15
D1
D15
D1
D1
D1
MLN0128 administration 
(Combination arms only) (k)
According to treatment arm assignment: daily (Arm B)
or weekly (Arm C; ie, Days 1, 8, 15, and 22 of each 28-day cycle)
Fulvestrant administration 
(All treatment arms) (k)
Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1,
and then once every 4 weeks
Patient dosing diary 
instructions/review
X
X
X
X
X
X
Samples/Laboratory Assessments
Hematology and chemistry (l)
X
X
X
X
X
X
X
X
X
X
Coagulation (PT/INR, aPTT)
X
X
X
X
X
X
X
X
Fasting lipid profile
X
X
X
X
X
X
X
HbA1c
X
X
Q3C (m)
X
Urinalysis (l)
X (n)
X (n)
Fasting serum glucose (o)
X
X
X
X
X
In-home FBG monitoring (p)
For patients in Arms B and C, daily from Cycle 1 Day 2 through last dose 
of study drug (may be decreased to once a week after the first 2 months, as 
detailed in Section 10.4.15). In-home glucose monitoring is not required 
on days when fasting glucose is measured in the clinic.
Footnotes are on last table page.
CCI
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page.
Non-Commercial Use Only and Subject to the Applicable Terms of Use
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Schedule of Events (continued)
Screening (a)
Treatment
PC 
EOT 
(b)
EOT 
(c)
PFS/OS 
Follow-up
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5 and 
Beyond
D -28 to D -1
D1
D15
D1
D15
D1
D1
D1
Blood sample for plasma PK (t)
X
X
X
AE=adverse event, aPTT=activated partial thromboplastin time, CT=computed tomography, CTC=circulating tumor cell, ctDNA=circulating tumor DNA, D=day, 
DNA=deoxyribonucleic acid, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, EOT=End-of-Treatment visit, FBG=fasting blood glucose, 
HbA1c=glycosylated hemoglobin, HRQL=health-related quality of life, INR=international normalized ratio, MRI=magnetic resonance scan, OS=overall survival, 
PC EOT=Precrossover End-of-Treatment visit, PT=prothrombin time, PFS=progression-free survival, PK=pharmacokinetic(s), PTE=pretreatment event, 
SAE=serious adverse event.
Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days) for holidays, vacations, and other administrative reasons, 
starting after the completion of Cycle 2 Day 1. 
(a) Screening assessments are performed within 28 days before administration of the first dose of study drug. Screening assessments performed no more than 3 days 
before the first dose will qualify as baseline (Cycle 1 Day 1) assessments and need not be repeated, unless otherwise specified.
(b) Patients randomized to the single-agent fulvestrant arm who progress on study may be eligible for crossover treatment. It is recommended that crossover 
treatment begin within 28 days (+10 days) after documented disease progression (imaging date of PD), with the goal of maintaining the ongoing schedule of 
fulvestrant therapy (ie, dosing every 28 days). Whenever possible, MLN0128 should be initiated at the next scheduled dose of fulvestrant, but only when the patient 
has completed the precrossover screening requirements and is eligible to continue. If the crossover treatment cannot begin within 28 days (+10 days) after 
documented PD, contact the medical monitor.
CCI
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Property of Takeda: For Non-Commercial Use Only and Su
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(c) Patients will attend an EOT Visit 30 to 40 days after receiving their last dose of study drug, or at the start of subsequent anticancer therapy (including crossover 
treatment as described in Section 7.1), at which time patients will enter posttreatment follow-up. If subsequent anticancer therapy is required before 30 days after the 
last dose, the EOT Visit should be conducted before the initiation of subsequent anticancer therapy.
(d) Perform vital signs measurement prior to study drug administration. Vital sign measurements include blood pressure (diastolic and systolic), heart rate, and 
temperature.
(e) A single, 12-lead ECG will be performed predose on Day 1 of every cycle, and during the EOT Visit. When the timing of an ECG coincides with blood samples, 
the ECG should be completed first. Additional ECGs may be obtained as clinically indicated.
(f) Baseline CT scan (with contrast) or MRI of the chest, abdomen, and pelvis must be obtained within 21 days before the first dose of study drug. Starting at 
Cycle 2, CT scan (with contrast) or MRI will be performed at the end of every other cycle, within 7 days before Day 1 of the next cycle; for example, the Cycle 2 
evaluation must be done within 7 days before Cycle 3 Day 1, the Cycle 4 evaluation must be done within 7 days before Cycle 5 Day 1, etc. For those patients who 
have documented radiographic PD, CT scan (with contrast) or MRI are not required at the EOT Visit. The same imaging modality (CT scan [with contrast] or MRI) 
will be used throughout the study.
(g) Patients who discontinue study treatment for reasons other than PD will continue to have PFS follow-up visits every 2 months (±1 week) for the first 6 months 
after the EOT Visit and then every 3 months (±1 week), until PD or start of another anticancer therapy, whichever occurs first. After PD or start of another 
anticancer therapy (including crossover treatment as described in Section 7.1), all patients will be followed only for survival every 6 months (±1 week).
(h) A bone scan will be required for all patients within 21 days before the first dose of study drug), and thereafter at the discretion of the investigator to monitor 
representative areas.
(i) HRQL instruments to be used are the EORTC QLQ-C30 and the EORTC QLQ-BR23, and must be completed before other assessments are performed or study 
drug is administered.
(j) Including serious PTEs; see Section 11.0.
(k) The first dose of study drug must be administered within 5 days after randomization on study. In Arm B, daily MLN0128 will be administered on an empty 
stomach; in Arm C, weekly MLN0128 will be administered with a light meal (see Section 9.1).
(l) Refer to Section 10.4.14 for a list of the required clinical laboratory assessments. Laboratory assessments may be performed within 24 hours before the required 
study visit. Safety laboratory results must be available and reviewed by the investigator before study drug administration. Electrolyte levels should be corrected as 
needed before study drug administration. Preassessment fasting is not required for on Cycle 1 Day 15 or Cycle 2 Day 15.
(m) Starting at Cycle 6, HbA1c and urinalysis will be assessed every 3 cycles (Cycle 6, Cycle 9, Cycle 12, etc).
(n) For Screening, creatinine clearance must be ≥40 mL/min based either on Cockroft-Gault estimate or based on a 12- or 24-hour urine collection.
(o) Fasting serum glucose will be measured in the clinic. Patients are required to fast overnight (nothing except water and/or medications after midnight or for a 
minimum of 8 hours before the assessment) for each of these measurements. For patients receiving single-agent fulvestrant in Arm A or fulvestrant+MLN0128 QW 
in Arm C, the fasting serum glucose may be assessed as part of the predose chemistry panel. After fasted sampling is complete, patients receiving 
fulvestrant+MLN0128 QW in Arm C should consume a light meal prior to dosing (Section 9.1). For patients receiving fulvestrant+MLN0128 QD in Arm B, a 
separate sample must be taken approximately 2 hours after study drug administration, with patients continuing to fast until that sample is taken. The collection of the 
2-hour postdose sample is not expected on the nondosing days. In-home glucose monitoring is not required on days when fasting glucose is measured in the clinic.
(p) Patients in the combination fulvestrant+MLN0128 treatment arms (Arm B and Arm C) will be given a glucometer to monitor daily fasting glucose levels at 
home and will be instructed to notify the study clinician any time the fasting glucose is abnormal (ie, ≥150 mg/dL). See Section 10.4.15 for further instructions.
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(q) 
.
(r) 
(s)
 
 
 
(t) PK samples will be collected only from patients receiving MLN0128, including patients receiving crossover treatment, but not from patients randomized to 
single-agent fulvestrant. Samples will be collected at the times specified in the Treatment Arm B Sparse PK Sample Breakdown and Treatment Arm C Sparse PK
Sample Breakdown. For all PK samples, the date and time of MLN0128 dosing and the date and time of PK sampling will need to be recorded.
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Treatment Arm B Sparse PK Sample Breakdown
MLN0128 Sparse PK Sampling (Plasma)
Cycle 1 Day 1 (a)
Cycle 1 Day 15 (b)
Cycle 2 Day 1 (c)
At time of clinic visit (anytime postdose)
X1
X1
Approximately 1 hour after prior PK sample collection
X1
X1
1 to 2 hours postdose (±15 min)
X1
PK=pharmacokinetic(s), X#=the number of samples required (eg, 2 samples=X2).
This PK sampling schedule applies to subjects initially randomized to Arm B and those receiving crossover treatment in Arm B.
(a) The exact date and time of MLN0128 dosing on Cycle 1 Day 1 and the date/time of PK sampling must be recorded. Over the course of the study, a distribution 
of sampling times within the specified sampling windows is encouraged.
(b) On Cycle 1 Day 15, subjects will take their regularly scheduled doses of MLN0128 at home and will record the exact date/time of dose administration in their 
subject diaries. Subjects will then report to the clinic for the scheduled visit, during which they will provide PK samples. Over the course of the study, a distribution 
of clinic visit/sampling times (eg, morning through late afternoon) for this visit is encouraged.
(c) On Cycle 2 Day 1, subjects will take their regularly scheduled doses of MLN0128 in the clinic after completion of fasting serum glucose sampling. The exact 
date/time of dose administration and the date/time of PK sampling must be recorded. Over the course of the study, a distribution of clinic visit/sampling times (eg, 
morning through late afternoon) for this visit is encouraged.
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Treatment Arm C Sparse PK Sample Breakdown
MLN0128 Sparse PK Sampling (Plasma)
Cycle 1 Day 1 (a)
Cycle 1 Day 15 (b)
Cycle 2 Day 1 (c)
At time of clinic visit (anytime postdose)
X1
X1
Approximately 1 hour after prior PK sample collection
X1
X1
1 to 2 hours postdose (±15 min)
X1
3 to 6 hours postdose (±30 min)
X2 (d)
PK=pharmacokinetic(s), X#=the number of samples required (eg, 2 samples=X2).
This PK sampling schedule applies to subjects initially randomized to Arm C and those receiving crossover treatment in Arm C.
(a) Subjects should bring a light meal with them to this visit. Subjects will begin consuming the meal within 30 min prior to dosing, after which they will take their 
doses of MLN0128. The exact date/time of meal consumption, MLN0128 dosing, and PK sampling must be recorded. Over the course of the study, a distribution of 
sampling times within the specified sampling windows is encouraged.
(b) Subjects will take their regularly scheduled doses of MLN0128 at home with a light meal and will record the exact date/time of meal consumption and dose 
administration in their subject diaries. Subjects will then report to the clinic for the scheduled visit, during which they will provide PK samples. The date/time of PK 
sampling must be recorded. Over the course of the study, a distribution of clinic visit/sampling times (eg, morning through late afternoon) for this visit is 
encouraged.
(c) Subjects should bring a light meal with them to this visit. After completion of fasting serum glucose sampling, subjects will begin consuming the meal within 
30 min prior to dosing, after which they will take their regularly scheduled doses of MLN0128. The exact date/time of meal consumption, MLN0128 dosing, and 
PK sampling must be recorded. Over the course of the study, a distribution of clinic visit/sampling times (eg, morning through late afternoon) for this visit is 
encouraged.
(d) Two samples will be taken no less than 1 hour apart within the specified window.
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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 Form FDA 1572:

Conduct the study in accordance with the protocol.

Personally conduct or supervise the staff who will assist in the protocol.

Ensure that study-related procedures, including study specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, prior to the receipt of written 
approval from relevant governing bodies/authorities.

Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.

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.

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.

Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.

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.

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.
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MLN0128 (TAK-228)
Study No. C31006
Page 92 of 105
Protocol Incorporating Amendment No. 3
02 October 2017

Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.

Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.

Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.

If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should ensure that this individual 
or party is qualified to perform those trial-related duties and functions and should implement 
procedures to ensure the integrity of the trial-related duties and functions performed and any 
data generated.
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MLN0128 (TAK-228)
Study No. C31006
Page 93 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Appendix C
Investigator Consent to Use of Personal Information 
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details, and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


MLN0128 (TAK-228)
Study No. C31006
Page 94 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Appendix D
ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
ECOG=Eastern Cooperative Oncology Group.
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 [37].
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MLN0128 (TAK-228)
Study No. C31006
Page 95 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Appendix E
Cockcroft-Gault Equation
For women:
Creatinine Clearance =
0.85 (140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
Creatinine Clearance =
0.85 (140-age [years])weight [kg]
0.81(serum creatinine [µmol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. [38]
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MLN0128 (TAK-228)
Study No. C31006
Page 96 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Appendix F
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of physical 
activity. They are comfortable at rest. Ordinary physical activity 
results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels. Ninth Ed. Boston, MA: Little, Brown & Co; 1994:253-256. [39]
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MLN0128 (TAK-228)
Study No. C31006
Page 97 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Appendix G
List of Relevant Cytochrome P450 Inhibitors and Inducers
Moderate CYP1A2 Inhibitors
Cimetidine
Methoxsalen 
Strong CYP1A2 Inhibitors
Fluvoxamine
Ciprofloxacin
Clinically Significant Enzyme Inducers
Carbamazepine
Rifabutin
St. John’s Wort
Phenobarbital
Rifampin
Phenytoin
T=Rifapentine 
Source: fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm.
Note that these lists are not exhaustive.
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MLN0128 (TAK-228)
Study No. C31006
Page 98 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Appendix H
EORTC QLQ-C30 Version 3
:
Please go on to the next page
EORTC QLQ-C30 (version 3)
We are interested in some things about you and your health. Please answer all of the questions
yourself by circling the number that best applies to you. There are no "right" or "wrong"
answers. The information that you provide will remain strictly confidential.
Please fill in your initials:
Your birthdate (Day, Month, Year):
Today's date (Day, Month, Year): 
Not at
A
Quite Very
all
little
a bit much
1.
Do you have any trouble doing strenuous activities,
like carrying a heavy shopping bag or a suitcase?
1
2
3
4
2.
Do you have any trouble taking a long walk?
1
2
3
4
3.
Do you have any trouble taking a shortwalk outside
of the house?
1
2
3
4
4.
Do you need to stay in bed or a chair during the day?
1
2
3
4
5. Do you need help with eating, dressing, washing
yourself or using the toilet?
1
2
3
4
During the past week:
Not at
A
Quite Very
All
little
a bit much
6. Were you limited in doing either your work or other
daily activities?
1
2
3
4
7. Were you limited in pursuing your hobbies or other
leisure time activities?
1
2
3
4
8. Were you short of breath?
1
2
3
4
9. Have you had pain?
1
2
3
4
10. Did you need to rest?
1
2
3
4
11. Have you had trouble sleeping?
1
2
3
4
12. Have you felt weak?
1
2
3
4
13. Have you lacked appetite?
1
2
3
4
14. Have you felt nauseated?
1
2
3
4
15. Have you vomited?
1
2
3
4
16. Have you been constipated?
1
2
3
4
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MLN0128 (TAK-228)
Study No. C31006
Page 99 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
© Copyright 1995 EORTC Quality of Life Study Group.  All rights reserved.  Version 3.0
During the past week:
Not at
A
Quite Very
all
little
a bit
much
17. Have you had diarrhea?
1
2
3
4
18. Were you tired?
1
2
3
4
19. Did pain interfere with your daily activities?
1
2
3
4
20. Have you had difficulty in concentrating on things,
like reading a newspaper or watching television?
1
2
3
4
21. Did you feel tense?
1
2
3
4
22. Did you worry?
1
2
3
4
23. Did you feel irritable?
1
2
3
4
24. Did you feel depressed?
1
2
3
4
25. Have you had difficulty remembering things?
1
2
3
4
26. Has your physical condition or medical treatment
interfered with your family life?
1
2
3
4
27. Has your physical condition or medical treatment
interfered with your social activities?
1
2
3
4
28. Has your physical condition or medical treatment
caused you financial difficulties?
1
2
3
4
For the following questions please circle the number between 1 and 7 that
best applies to you
29. How would you rate your overall health during the past week?
1
2
3
4
5
6
7
 Very poor
         Excellent
30. How would you rate your overall quality of life during the past week?
1
2
3
4
5
6
7
 Very poor
         Excellent
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MLN0128 (TAK-228)
Study No. C31006
Page 100 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Appendix I
EORTC QLQ-BR23
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MLN0128 (TAK-228)
Study No. C31006
Page 101 of 105
Protocol Incorporating Amendment No. 3
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MLN0128 (TAK-228)
Study No. C31006
Page 102 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Appendix J
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 3 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Remove the exclusion criterion relating to treatment with strong CYP inhibitors or 
inducers.
The primary change occurs in Section 8.2 Exclusion Criteria:
Deleted text: 11. Treatment with strong cytochrome P450 (CYP) 3A4, CYP2C9, and/or CYP2C19
inhibitors and/or inducers within 1 week before the first dose of study drug (see 
Appendix G).
Rationale for Change:
This change, which removes enrollment restrictions for patients taking CYP3A4, CYP2C9, or 
CYP2C19 inhibitors and/or inducers in this study, was made due to updated data on MLN0128 
metabolism by specific CYP isoforms.
Change 2: Update the list of concomitant medications prohibited during the study.
The primary change occurs in Section 9.5.2 Excluded Concomitant Medications and Procedures 
for Combination MLN0128 Plus Fulvestrant Treatment Arms (Arm B and Arm C):
Initial 
wording:

Strong CYP3A4 and CYP2C19 inducers and/or inhibitors and moderate 
inhibitors of CYP2C9 (see Appendix G) should be administered only with 
caution and at the discretion of the investigator. Alternative treatments, if 
available, should be considered.
…

[…] Examples of histamine H2 receptor antagonists include ranitidine, 
famotidine, nizatidine, and cimetidine.
Amended or 
new 
wording:

Strong CYP3A4 and CYP2C19 inducers and/or cytochrome P450 (CYP) 1A2 
inhibitors and CYP inducers should be administered with caution and at the 
discretion of the investigator (see Appendix G for a list of these agents).
Alternative treatments, if available, should be considered. (Refer to Appendix G
for a list of strong inhibitors and strong inducers of CYP2C9, CYP2C19, and 
CYP3A4.)
…

[…] Examples of histamine H2 receptor antagonists include ranitidine, 
famotidine,and nizatidine, and c. Cimetidine, a moderate CYP1A2 inhibitor, 
is not recommended as a first choice H2 receptor antagonist (seeAppendix 
G).
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MLN0128 (TAK-228)
Study No. C31006
Page 103 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Rationale for Change:
This change was made to update the recommendations on concomicant medication use during the 
study based on updated data on MLN0128 metabolism by specific CYP isoforms.
Change 3: Update the list of relevant CYP inhibitors and inducers.
The primary change occurs in Appendix G List of Relevant Cytochrome P450 Inhibitors and 
Inducers:
Description 
of the 
change:
The list of relevant CYP inhibitors and inducers was updated to remove sections 
listing strong CYP2C19 inhibitors and strong and moderate CYP3A4 inhibitors, to 
add a section listing strong and moderate CYP1A2 inhibitors, and to update the 
section listing clinically significant enzyme inducers.
Rationale for Change:
This change was made for consistency with updated data on MLN0128 metabolism by specific 
CYP isoforms.
Change 4: Remove dietary restrictions related to CYP inhibitors and inducers.
The primary change occurs in Section 9.5.2 Excluded Concomitant Medications and Procedures 
for Combination MLN0128 Plus Fulvestrant Treatment Arms (Arm B and Arm C):
Deleted text: In addition to the above medications, consumption of grapefruit or grapefruit juice is 
not permitted during the study. Patients should not consume food or beverages 
containing the fruit or juice of grapefruits or Seville oranges within 7 days before the 
first dose of study drug and throughout the study (see Appendix G) 
Rationale for Change:
This change was made for consistency with new data that removes the necessity for restrictions 
concerning CYP2C9 and 2C19.
The following sections also contain this change:

Section 9.7 Precautions and Restrictions.

Appendix G List of Relevant Cytochrome P450 Inhibitors and Inducers.
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MLN0128 (TAK-228)
Study No. C31006
Page 104 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Change 5: Update the number of study sites.
The primary change occurs in Section 7.2 Number of Patients:
Initial 
wording:
Approximately 153 patients (51 patients per treatment arm) will be enrolled in this 
study from approximately 55 study centers in North America and Europe. A patient is 
considered to be enrolled in the study when she has been randomized into a treatment 
arm.
Amended or 
new 
wording:
Approximately 153 patients (51 patients per treatment arm) will be enrolled in this 
study from approximately 55 65 study centers in North America and Europe. A 
patient is considered to be enrolled in the study when she has been randomized into a 
treatment arm.
Rationale for Change:
This change was made to ensure that enrollment was achieved within the timelines.
Section 2.0 STUDY SUMMARY also contains this change.
Change 6: Update the recommendations for initiation of crossover treatment.
The primary change occurs in Section 7.1.4 Potential for Crossover Treatment:
Initial 
wording:
Crossover treatment must begin within 28 days after documented PD. The ongoing 
schedule of fulvestrant therapy should be maintained (ie, dosing every 28 days), and 
MLN0128 should be initiated at the next scheduled dose of fulvestrant. This will be 
Cycle 1 Day 1 of the crossover treatment.
Amended or 
new 
wording:
It is recommended that Ccrossover treatment must begin within 28 days (+10 days) 
days after documented disease progression (imaging date of PD), with the goal of 
maintaining Tthe ongoing schedule of fulvestrant therapy should be maintained (ie, 
dosing every 28 days), and. Whenever possible, MLN0128 should be initiated at the 
next scheduled dose of fulvestrant, but only when the patient has completed the 
precrossover screening requirements and is eligible to continue. If the crossover 
treatment cannot begin within 28 days (+10 days) after documented PD, contact 
the medical monitor. This will be Cycle 1 Day 1 of the crossover treatment.
Rationale for Change:
This change was made to reflect updated dosing recommendations.

Appendix A Schedule of Events also contains this change.
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MLN0128 (TAK-228)
Study No. C31006
Page 105 of 105
Protocol Incorporating Amendment No. 3
02 October 2017
Change 7: Update guidance for fasting serum glucose post-dose collection on non-dosing days.
The primary change occurs in Appendix A Schedule of Events:
Description 
of the 
change
A sentence was added to footnote (o) to clarify that collection of the 2 hour post-dose 
sample is not expected on non-dosing days.
Rationale for Change:
This change was made to increase the ease and accuracy of recording data at the site level.
The following sections also contain this change:

Appendix A Schedule of Events.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: An Open-Label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With 
Fulvestrant in Women With ER-Positive/HER2-Negative Advanced or Metastatic Breast 
Cancer That Has Progressed During or After Aromatase Inhibitor Therapy
MLN0128 in Combination With Fulvestrant in Women With Advanced or Metastatic Breast 
Cancer After Aromatase Inhibitor Therapy
NCT Number: NCT02756364
SAP Approve Date: 04 December 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C31006
An Open-Label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With 
Fulvestrant in Women With ER-Positive/HER2-Negative Advanced or Metastatic Breast Cancer 
That Has Progressed During or After Aromatase Inhibitor Therapy
PHASE 2
Version: Final
Date: 04 December 2018
Prepared by:
Based on:
Protocol Version: Amendment 3
Protocol Date: 02 October 2017
PPD
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
bitor) in
bitor) 
anced or
anced o
ase Inhi
se Inh
on: : Fina
Fin
4 Decem
Dece
l Versi
Vers
l
tocol D
ocol 
Commerc
oper


C31006
Page 2 of 31
Statistical Analysis Plan Final
04 December 2018
1.0
TABLE OF CONTENTS
1.0
TABLE OF CONTENTS.................................................................................................2
2.0
LIST OF ABBREVIATIONS..........................................................................................4
3.0
OBJECTIVES .................................................................................................................6
3.1
Primary Objectives ....................................................................................................6
3.2
Secondary Objectives.................................................................................................6
3.3
Additional Objectives ................................................................................................6
3.4
Exploratory Objectives ..............................................................................................6
3.5
Study Design .............................................................................................................7
3.5.1
Enrollment and Randomization............................................................................7
3.5.2
Weekly MLN0128 Dose Confirmation (Arm C)...................................................8
3.5.3
Study Evaluations ................................................................................................9
3.5.4
Potential for Crossover Treatment........................................................................9
3.5.5
Potential for Single-Agent MLN0128 Dosing.....................................................10
4.0
ANALYSIS ENDPOINTS.............................................................................................11
4.1
Primary Endpoint.....................................................................................................11
4.2
Secondary Endpoints ...............................................................................................11
4.3
Health-Related Quality of Life Endpoints ................................................................11
4.4
Exploratory Endpoints .............................................................................................11
5.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
6.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
6.1
General Principles....................................................................................................13
6.1.1
Methods for Handling Missing Data...................................................................13
6.1.2
Definitions of Baseline Values...........................................................................13
6.1.3
Definition of Study Days....................................................................................13
6.2
Analysis Sets ...........................................................................................................14
6.3
Disposition of Subjects ............................................................................................14
6.4
Demographic and Other Baseline Characteristics.....................................................15
6.5
Medical History and Concurrent Medical Conditions...............................................15
6.6
Medication History and Concomitant Medications...................................................16
6.6.1
Prior Therapies...................................................................................................16
6.6.2
Follow-up Anti-Cancer Therapy.........................................................................16
6.7
Study Drug Exposure and Compliance.....................................................................16
6.8
Efficacy Analysis.....................................................................................................17
6.8.1
Primary Efficacy Endpoint(s).............................................................................17
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6.8.2
Subgroup Analyses ............................................................................................19
6.8.3
Secondary Efficacy Endpoint(s).........................................................................20
6.8.4
Additional Efficacy Endpoint(s).........................................................................22
6.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................22
6.9.1
Pharmacokinetic Analysis ..................................................................................22
6.9.2
Pharmacodynamic Analysis ...............................................................................23
6.10
Patient Reported Outcomes......................................................................................23
6.10.1 EORTC QLQ-C30 and EORTC QLQ-BR23 Score ............................................23
6.11
Safety Analysis........................................................................................................24
6.11.1 Adverse Events ..................................................................................................24
6.11.2 Clinical Laboratory Evaluations .........................................................................26
6.11.3 Vital Signs .........................................................................................................26
6.11.4 12-Lead ECGs ...................................................................................................26
6.11.5 Other Observations Related to Safety.................................................................27
6.12
Crossover Treatment................................................................................................27
6.13
Interim Analysis ......................................................................................................27
6.14
Changes in the Statistical Analysis Plan...................................................................27
7.0
REFERENCES..............................................................................................................28
8.0
APPENDIX...................................................................................................................29
LIST OF IN-TEXT FIGURES
Figure 3.a
C31006 Study Design ..........................................................................................8
LIST OF IN-TEXT APPENDICES
Appendix A
By-Subject Listings............................................................................................29
Appendix B
Date Imputation Rules........................................................................................30
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2.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
CBR
clinical benefit rate
CR
complete response
CDK
cyclin-dependent kinase
CT
computed tomography
ctDNA
circulating tumor DNA
ECG
electrocardiogram
ECOG 
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
End-of-Treatment (visit)
EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-
Core 30
EORTC QLQ-
BR23 
European Organization for Research and Treatment of Cancer Breast Cancer-Specific Quality 
of Life Questionnaire
ER
estrogen receptor
HbA1c
glycosylated hemoglobin, hemoglobin A1c
HER2 
human epidermal growth factor receptor-2
HR
hazard ratio
IV
intravenous; intravenously
IRT
interactive response technology 
MedDRA
Medical Dictionary for Regulatory Activities
MLN0128
also known as TAK-228
MRI
magnetic resonance imaging
mTOR
mechanistic (or mammalian) target of rapamycin
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
objective response rate
OS
overall survival
PP
per protocol
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcomes
PTEN
phosphatase and tensin homolog
QD
quaque die; each day; once daily
QOL
quality of life
QW
every week
QTc
rate-corrected QT interval (msec) 
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RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SD
stable disease
TAK-228
MLN0128
TEAE
treatment-emergent adverse event
TTP
time-to-progression
ULN
upper limit of normal (range)
US
United States
USPI
United States Prescribing Information
WHO
World Health Organization
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3.0
OBJECTIVES
3.1
Primary Objectives
The primary objectives are:
!
To compare the PFS of patients treated with the combination of fulvestrant+daily MLN0128 
versus patients treated with single-agent fulvestrant.
!
To compare the PFS of patients treated with the combination of fulvestrant+weekly 
MLN0128 versus patients treated with single-agent fulvestrant.
3.2
Secondary Objectives
The secondary objectives are:
!
To compare secondary efficacy endpoints in patients treated with the combination of 
fulvestrant+daily MLN0128 versus patients treated with single-agent fulvestrant.
!
To compare secondary efficacy endpoints in patients treated with the combination of 
fulvestrant+weekly MLN0128 versus patients treated with single-agent fulvestrant.
!
To assess the safety and tolerability of the combination of fulvestrant+MLN0128.
!
To collect plasma concentration-time data with sparse PK sampling (combination 
fulvestrant+MLN0128 treatment arms [Arm B and Arm C] only), to contribute to future 
population PK analysis.
3.3
Additional Objectives
The health-related quality of life (HRQL) objective is:
To assess the HRQL and symptoms, as measured by the European Organization for Research 
and Treatment of Cancer QLQ Questionnaire, version 3.0 (EORTC QLQ-C30) and the EORTC 
QLQ Breast Cancer-Specific Questionnaire (EORTC QLQ-BR23), among the 3 treatment arms.
3.4
Exploratory Objectives
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3.5
Study Design
3.5.1
Enrollment and Randomization
This is an open-label, randomized, 3-arm, multicenter, phase 2 study of the efficacy and safety of 
the combination of fulvestrant+daily MLN0128 compared with single-agent fulvestrant, and the 
combination of fulvestrant+weekly MLN0128 compared with single-agent fulvestrant, in the 
treatment of postmenopausal women with advanced or metastatic ER-positive/HER2-negative 
breast cancer that has progressed during or after AI therapy. Patients who provide written 
informed consent and meet all eligibility criteria will be randomized 1:1:1 to 1 of 3 treatment 
arms via the interactive response technology (IRT):

Arm A, single-agent fulvestrant: fulvestrant, 500 mg intramuscularly (IM), on Cycle 1 Days 
1 and 15 (loading regimen), and then on Day 1 of each subsequent 28-day cycle.

Arm B, combination of fulvestrant+daily MLN0128: fulvestrant as above and MLN0128, 
4 mg PO QD continuously.

Arm C, combination of fulvestrant+weekly MLN0128: fulvestrant as above and MLN0128, 
30 mg PO QW continuously.
Patients will be stratified at randomization according to the presence or absence of visceral 
metastasis, previous sensitivity to hormonal therapy, and previous exposure to CDK 4/6 
inhibitors. Visceral metastasis is defined as all lesions not included in the following list: breast, 
skin, subcutaneous tissue, lymph node or bone. Previous sensitivity to hormonal therapy is 
defined as at least 24 months of endocrine therapy before recurrence in the adjuvant setting (ie, 
in patients who have not received previous endocrine therapy in the metastatic setting) or a 
response or stabilization for at least 24 weeks of the most recent endocrine therapy for 
advanced/metastatic disease.
Enrollment will be managed via the IRT to ensure that approximately 40% of enrolled patients 
have previously received a CDK4/6 inhibitor in combination with an AI. Enrollment of non-
CDK4/6 pretreated patients may be stopped in the case that 60% or greater of enrollment has 
occurred with only non-CDK4/6 pretreated patients.
Enrollment is defined as being randomized to a treatment arm. The first dose of study drug must 
be administered within 5 days after randomization on study. Patients will receive study 
medication(s) in 28-day cycles. The study design is displayed in Figure 3.a.
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Figure 3.a
C31006 Study Design
DC=discontinuation, EOT=End-of-Treatment, OS=overall survival, PFS=progression-free survival, 
RAND=randomization.
(a) The weekly dose of 30 mg MLN0128 will be tested in a safety lead-in of 6 patients in this study (as detailed in 
Section 3.5.2) to ensure safety and tolerability of the combination with fulvestrant.
3.5.2
Weekly MLN0128 Dose Confirmation (Arm C)
This will be the first study in which weekly MLN0128 will be combined with fulvestrant. 
Therefore, a safety and tolerability assessment will be performed for patients treated with 
fulvestrant+weekly MLN0128 (30 mg) after the first 6 DLT-evaluable patients have completed 
1 cycle (ie, Cycle 1 Day 28). Patients will be considered evaluable for DLT assessment if they 
have completed all scheduled study visits during the first cycle and have received at least 3 
(75%) of the 4 planned doses of MLN0128 in combination with fulvestrant in Cycle 1. The 
30 mg starting dose for weekly MLN0128 will be confirmed or adjusted based on the DLTs 
observed:

If ≤1 DLT occurs, the MLN0128 dose for this treatment arm will remain the same (ie, 30 mg 
weekly MLN0128, in combination with fulvestrant).

If ≥2 DLTs occur, all patients subsequently randomized to this treatment arm will receive a 
starting dose of 20 mg weekly MLN0128, in combination with fulvestrant. The starting dose 
reduction will be documented in formal written communication to all study sites.
DLTs will be assessed and collected in the database for the first 6 evaluable patients in Arm C 
only (fulvestrant+weekly MLN0128). DLTs are not applicable to patients in Arm A or Arm B at 
any time in the study, or to patients in Arm C who are not included in the safety and tolerability 
assessment, or to cross-over patients. Enrollment of patients into the study will continue while 
this safety and tolerability assessment is conducted. For any patients initially assigned to the 
DC for disease 
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Fulvestrant 
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OS 
Follow-up
PFS 
Follow-up
EOT
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DC for    
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OS 
Follow-up
PFS 
Follow-up
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30 mg QW starting dose, the MLN0128 dose may be decreased if necessary per the dose 
modification criteria outlined in the protocol.
3.5.3
Study Evaluations
Safety assessments (including AEs, SAEs, laboratory assessments, vital signs, 
electrocardiograms (ECGs), Eastern Cooperative Oncology Group [ECOG] performance status, 
and weight) will be performed throughout the treatment period, including the End-of-Treatment 
(EOT) Visit, to evaluate the safety and tolerability of MLN0128. Toxicity will be evaluated 
according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI 
CTCAE), Version 4.03, effective date 14 June 2010.
HRQL will be assessed via the EORTC QLQ-C30 and EORTC QLQ-BR23 instruments 
throughout the treatment period, including the EOT Visit.
Radiological tumor evaluations (computed tomography [CT] scan with intravenous [IV] contrast 
or magnetic resonance imaging [MRI] as clinically indicated) of the chest, abdomen, and pelvis 
will be used to evaluate disease response according to RECIST guidelines (Version 1.1). 
Radiographic tumor evaluations will be performed by the investigator at the time points specified 
in the Schedule of Events.
Blood samples will be collected (from patients in the combination fulvestrant+MLN0128 
treatment arms [Arm B and Arm C] only) to contribute data to an overall population plasma PK 
analysis, in combination with data from the other clinical studies of MLN0128.
Patients will receive study medication(s) until PD, unacceptable toxicity, or withdrawal of 
consent. Patients who discontinue study medication will complete an EOT Visit 30 to 40 days 
after the last dose of study drug. The EOT Visit should be conducted before the initiation of 
subsequent anticancer therapy, even if it occurs sooner than 30 days after the last dose of study 
drug. Patients who discontinue study treatment for reasons other than PD will continue to have 
PFS follow-up visits every 2 months (±1 week) for the first 6 months after the EOT Visit and 
then every 3 months (±1 week), until PD or start of another anticancer therapy, whichever occurs 
first. After PD or start of another anticancer therapy, patients will be followed for survival every 
6 months (±1 week).
3.5.4
Potential for Crossover Treatment
Patients in the single-agent fulvestrant arm (Arm A) who have radiographically confirmed PD 
may be allowed to receive crossover treatment with the combination of fulvestrant+MLN0128). 
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Once documented PD has been confirmed, patients referred for crossover will complete the 
Precrossover EOT Visit as soon as possible. Patients must meet all applicable study eligibility 
criteria at the time of crossover (eg, the exclusion for prior fulvestrant therapy would not apply), 
and eligibility for crossover will be confirmed by the sponsor’s project clinician (or designee). 
Eligible patients will then be randomized via the IRT in a 1:1 ratio to either fulvestrant+daily 
MLN0128 or fulvestrant+weekly MLN0128.
It is recommended that crossover treatment begin within 28 days (+10 days) after documented
disease progression (imaging date of PD), with the goal of maintaining the ongoing schedule of 
fulvestrant therapy (ie, dosing every 28 days). Whenever possible, MLN0128 should be initiated 
at the next scheduled dose of fulvestrant but only when the patient has completed the 
precrossover screening requirements and is eligible to continue. If the crossover treatment cannot 
begin within 28 days (+10 days) after documented PD, contact the medical monitor.
Patients may receive crossover treatment until they experience PD on crossover treatment, 
unacceptable toxicity, they withdraw consent, or they are no longer considered by the 
investigator to be deriving clinical benefit from the crossover treatment.
Only the data collected during the study treatment in the initial single-agent fulvestrant arm will 
be included in the planned efficacy and safety analyses for the study. After crossover treatment 
begins, safety and efficacy data will be collected (as detailed in the Schedule of Events) and 
presented separately.
3.5.5
Potential for Single-Agent MLN0128 Dosing
If fulvestrant is discontinued for a patient in either combination arm (Arm B or Arm C), the 
patient may continue receiving MLN0128 at their current dose if, after discussion between the 
investigator and sponsor, it is determined that the patient would derive benefit from continued 
treatment with single-agent MLN0128 and there are no safety concerns.
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4.0
ANALYSIS ENDPOINTS
4.1
Primary Endpoint
The primary endpoint is:
!
PFS.
4.2
Secondary Endpoints
The secondary endpoints are:
!
Overall survival (OS).
!
TTP.
!
Objective response rate (ORR); defined as CR∀PR per Response Evaluation Criteria in Solid 
Tumors (RECIST) Version 1.1.
!
CBR; defined as CR∀PR∀SD with SD of any duration, and CBR with SD duration of at least 
6 months. 
!
The number and percentage of patients with TEAEs.
4.3
Health-Related Quality of Life Endpoints
The HRQL endpoints are:
!
Changes from Baseline in functional and symptom scores, and global health status and 
quality of life score from the EORTC QLQ-C30 questionnaire.
!
Changes from Baseline in functional and symptom scales from the EORTC QLQ-BR23 
questionnaire.
4.4
Exploratory Endpoints
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5.0
DETERMINATION OF SAMPLE SIZE
The primary efficacy endpoint is PFS. Assuming that the median PFS is 4 months for fulvestrant 
[1] and that the combination of fulvestrant and MLN0128 (administered either QD or QW) can 
improve the median PFS to 8 months (HR of 0.5), then a total of 72 PFS events are needed for 
each pair-wise comparison. Each treatment arm will require 51 patients. The calculations are 
based on a power of 90%, 2-sided alpha of 10%, and a dropout rate of 10% due to either lost to 
follow-up or withdrawal of consent.
The accrual duration will be approximately 14 months. The final analysis for the pair-wise 
comparisons of PFS between fulvestrant+MLN0128 QD and fulvestrant, and between 
fulvestrant+MLN0128 QW and fulvestrant, is estimated to occur approximately 20 months after 
the first patient is randomized.
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6.0
METHODS OF ANALYSIS AND PRESENTATION
6.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.3.
Continuous data will be summarized using descriptive statistics (number of observations, mean, 
standard deviation, median, 25th and 75th percentiles (where specified), minimum, and 
maximum). Frequencies and percentages will be used for summarizing categorical (discrete) 
data. For summaries of categorical variables percentages are based on the number of subjects 
with non-missing values unless otherwise specified (e.g. objective response rate, clinical benefit 
rate).
Confidence intervals, when presented, will generally be constructed at the 95% level. For 
binomial variables, the normal approximation methods will be employed unless otherwise 
specified.
All statistical tests and resulting P-values will be reported as 2-sided and will be assessed at 
α=0.05 significance level unless otherwise stated. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate. Percentages will be presented to 1 decimal place.
A month is operationally defined to be 30.4375 days. 
Where specified, there will be two pair-wise comparisons: fulvestrant vs. fulvestrant + 
MLN0128 QD and fulvestrant vs. fulvestrant + MLN0128 QW.
6.1.1
Methods for Handling Missing Data
For efficacy and safety data, no imputation of values for missing data will be performed. For 
patient reported outcomes, handling of missing data is discussed in section 6.10. Data imputation 
rules for incomplete dates are described in Appendix B.
6.1.2
Definitions of Baseline Values
In general, for efficacy endpoints the last observed measurement prior to randomization will be 
considered the baseline measurement. For safety endpoints, the last observation before first dose 
of study drug will be considered the baseline measurement. For patient-reported outcomes the 
last observed measurement on or before the date of first dose of study drug will be considered 
the baseline measurement.
6.1.3
Definition of Study Days
For the purposes of efficacy data summary, Day 1 is defined as the date of randomization. For 
visits (or events) that occur on or after randomization, Day is defined as (date of visit [event] –
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date of randomization + 1). For visits (or events) that occur prior to randomization, Day is 
defined as (date of visit [event] – date of randomization). There is no Day 0.
For the purposes of safety data summary or calculations of time since baseline, Study Day 1 is 
defined as the date on which a subject is administered their first dose of study drug. For visits (or 
events) that occur on or after the first dose of study drug, study day is defined as (date of visit 
[event] – date of first dose of study drug + 1). For visits (or events) that occur prior to Study Day 
1, study day is defined as (date of visit [event] – date of first dose of study drug). There is no 
Study Day 0.
6.2
Analysis Sets

Full analysis set: all randomized patients. Patients will be analyzed according to the 
randomization assignment. The ITT population will be used for the primary efficacy analysis 
of PFS, and secondary efficacy endpoints including OS and TTP.

Safety analysis set: patients who receive at least 1 dose of study drug. Patients will be 
analyzed according to the treatment arm actually received. The safety population will be 
used for all safety analyses. In addition, the safety population will be used for a sensitivity 
analysis of secondary efficacy endpoints ORR, CBR, CBR with SD duration at least 6 
months and the best overall response and patients will be analyzed according to the 
randomization assignment.

Response-evaluable analysis set: patients who receive at least 1 dose of study drug, have 
measurable disease or bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of 
measurable disease at Baseline, and have 1 post-Baseline disease assessment. Patients will be 
analyzed according to the randomization assignment. The response-evaluable population will 
be used for the primary analysis of secondary efficacy endpoints of ORR, CBR, CBR with 
SD duration at least 6 months and the best overall response.
The number and percentage of patients in each population will be summarized.
6.3
Disposition of Subjects
Study information including the date first subject signed ICF, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary endpoint of 
PFS, MedDRA version, WHO Drug version and SAS Version will be generated in a summary 
table. The date of last procedure for PFS is the date of progressive disease or death, otherwise 
use the date of the last response assessment.
The disposition of patients includes the number and percentage of patients for the following 
categories: randomized and not treated, discontinued study drug, primary reason to discontinue 
study drug, ongoing (if applicable at the time of database lock), discontinued from the study, and 
primary reason to discontinue from the study. All percentages will be based on the number of 
patients in the full analysis set.
In addition, the number and percentage of patients in the fulvestrant arm who crossed over to 
receive fulvestrant + MLN0128 QD or fulvestrant + MLN0128 QW will be summarized.
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6.4
Demographic and Other Baseline Characteristics
Summaries of demographics, baseline characteristics and stratification factors will be presented 
for subjects in the full analysis set.
The demographic characteristics consist of:

Age (continuous).

Age category.
–
Adults (18-64 years).
–
From 65 to 84 years.
–
85 years and over.

Height (cm).

Weight (kg) – screening if available otherwise C1D1.

Ethnicity.

Race.

Country/Site (Spain, United States, Canada).
Baseline characteristics consist of:

Time since first diagnosis (years) [(date of first dose – date of initial diagnosis)/365.25)].

Time since diagnosis of M1 or locoregional recurrence (years).

Sites of metastatic disease (visceral, bone-only, other).

Number of metastatic sites (1, 2, ≥3).

ECOG Performance Status.
Stratification factors consist of:

Presence or absence of visceral metastasis.

Previous sensitivity to hormonal therapy.

Previous exposure to cyclin-dependent kinase (CDK) 4/6 inhibitors.
There will be separate summaries for stratification for the original IRT values and corrected IRT
values.
6.5
Medical History and Concurrent Medical Conditions
Medical history will be summarized by MedDRA System Organ Class and preferred term (full 
analysis set).
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6.6
Medication History and Concomitant Medications
The number and percentage of patients taking concomitant medications will be tabulated by 
WHO standardized medication name based on the safety analysis set. Concomitant medications 
are medications ongoing at the time of the first dose of study drug or medications that started 
after the first dose and within 30 days of the last dose of study drug.
6.6.1
Prior Therapies
The following will be summarized for the full analysis set:

Prior lines of chemotherapy (none, 1, 2)

Number of prior endocrine therapies (1, 2, >3)

Prior (neo)adjuvant chemotherapy

Prior metastatic chemotherapy
The number and percent of patients receiving prior therapies in each category and the prior 
therapies (WHO drug standardized medication name) within each category will be summarized 
(full analysis set):

previous chemotherapy

previous hormonal therapy

previous targeted therapy
6.6.2
Follow-up Anti-Cancer Therapy
The number and percentage of patients receiving any anti-cancer therapy, and type of anti-cancer 
therapy will be summarized based on the full analysis set.
6.7
Study Drug Exposure and Compliance
Summaries and descriptive statistics of duration of treatment in weeks [(date of last dose – date 
of first dose + 1)/7], total number of cycles administered, average daily dose for MLN0128 QD, 
cumulative dose for each study drug, planned cumulative dose for each study drug and relative 
dose intensity will be summarized for patients in the safety analysis set. 
Number of cycles administered = A treated cycle is defined as a cycle in which the patient 
received any amount of study drug. 
Cumulative dose (mg) = Sum of all doses (mg) administered to a subject during the treatment 
period.
Relative dose intensity = (cumulative dose / planned dose) * 100.
Fulvestrant (500 mg intramuscularly on Cycle 1 Days 1 and 15 (loading regimen), and then on 
Day 1 of each subsequent 28-day cycle):
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
Planned dose (adjusted for delays in the start of a cycle):
[ (number of cycles*500 mg/cycle + 500 mg (C1D15 loading dose)] * [ (number of cycles 
*28 days/cycle) / (date of first dose in last cycle + 28 days – date of first dose)]
MLN0128 4 mg QD:

Average daily dose (mg/day): Cumulative dose / duration of treatment in days.

Planned dose: (Date of first dose in last cycle + 28 days – date of first dose) * 4 mg/day.
MLN0128 30 mg QW:

Planned dose: [(Date of first dose in last cycle + 28 days – date of first dose) / 7] * 30 
mg/week
Action on Study Drug
The reason for dose modification (omission, delay, reduction) of each study drug will be 
summarized by cycle (Cycles 1-8), greater than 8 cycles and overall based on the safety analysis 
set.
6.8
Efficacy Analysis
The analysis of PFS, OS and TTP will be based on the full analysis set. The analysis of ORR, 
CBR and CBR with SD duration at least 6 months will be based on both safety and response-
evaluable analysis set. All efficacy analyses are based on the investigator response assessment 
per RECIST 1.1 criteria.
6.8.1
Primary Efficacy Endpoint(s)
The primary endpoint is PFS, defined as the time from the date of randomization to the date of 
first documentation of progression or death due to any cause, whichever occurs first. Progression 
is based on the investigator response assessment per RECIST 1.1 criteria. PFS in months is 
defined as:
PFS (months) = (earliest date of progression or death – date of randomization + 1)/30.4375
The date of progression is defined as the earliest date of progression or new lesions among target 
lesions, non-target and new lesion dates at that particular visit. For a patient whose disease has 
not progressed and is last known to be alive, PFS will be censored at the last response assessment 
that is SD or better.
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The approach for handling of missing response assessments and censoring is presented below:
Situation
Date of Progression/Censoring
Outcome
No baseline tumor assessment
Randomization
Censored
No post baseline tumor 
assessment and no death
Randomization
Censored
Disease progression documented 
between scheduled visits
Date of first documented disease 
progression
Progressed
Disease progression documented 
subsequent to missing 2 or more 
adequate tumor assessments
Date of first documented disease 
progression
Progressed
No documented disease 
progression or no death
Date of last adequate assessment
Censored
Alternate subsequent therapy 
started prior to disease 
progression
Date of last adequate assessment 
prior to the start of subsequent 
therapy
Censored
Death without progression and 
without subsequent anti-cancer 
therapy
Date of death
Progressed
Adequate Assessments: Investigator response assessment of CR, PR, SD or PD (excluding 
inevaluable or missing assessments)
PFS Analysis
The primary efficacy analysis will be based on the full analysis set. The Kaplan-Meier method 
will be used to analyze the distribution of PFS for each treatment arm. Kaplan-Meier survival 
curves, the 25th, 50th (median), and 75th percentiles, along with associated 2-sided 95% 
confidence intervals (CIs) based on Brookmeyer and Crowley, and Kaplan-Meier estimates with 
95% CIs at 3, 6, 9, and 12 months will be presented. The primary hypothesis is to be tested at the 
0.10 significance level (2-sided). The p-values from a stratified log-rank test and hazard ratios 
(HR) (and 95% CI) estimated from a stratified Cox regression model with treatment arm and 
stratification factors as covariates will be presented for the pairwise comparison of fulvestrant to 
fulvestrant + MLN0128 QD and fulvestrant to fulvestrant + MLN0128 QW. The original IRT 
stratification factors will be used in models. 
The source of progression (death or progressive disease) will be summarized by treatment group.
The reasons for censoring in the PFS Kaplan-Meier analysis will be tabulated for each treatment 
group:

Received subsequent anti-cancer therapy.
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
No baseline or no post baseline response assessment.

Death or progression after more than 1 missed visit.

Withdrawal of consent.

Lost to follow-up.

No documented death or disease progression.
6.8.1.1
Sensitivity Analyses of the Primary Efficacy Endpoint (PFS)
Sensitivity analyses will be performed to explore the robustness of the results of the primary 
analysis.
PFS Sensitivity Analysis 1: discrepancy between original stratification in IRT system and 
corrected stratification in IRT system
The p-values from a stratified log rank test and the hazard ratio along with its 95% confidence 
interval will be estimated using a stratified Cox regression model with treatment arm and 
stratification factors as covariates. PFS will be compared between treatment groups using the 
corrected IRT strata. This analysis will be performed if at least one stratification variable 
between the original IRT and the corrected IRT disagrees for at least 10% of the randomized 
subjects.
PFS Sensitivity Analysis 2: account for missing tumor assessment prior to PFS event 
(progression or death). 
This analysis will be performed only if at least 20% of events of disease progression were 
documented subsequent to missing 2 or more adequate tumor assessments. 

Subjects who miss 2 or more consecutive adequate scheduled tumor assessments 
immediately followed by an event of disease progression will be censored on the date of their 
most-recent adequate tumor assessment prior to the missing/inadequate assessments.

If 2 or more consecutive missing adequate assessments are immediately followed by an 
adequate assessment with an overall response assignment of SD, PR, or CR, this will deemed 
sufficient clinical evidence that progression did not occur during the period of missing data 
and the missing evaluations will be ignored.
6.8.2
Subgroup Analyses
The focus of the subgroup analyses is to assess the consistency of treatment effects across 
subgroups for the 2 comparisons: fulvestrant vs. fulvestrant + MLN0128 QD and fulvestrant vs. 
fulvestrant + MLN0128 QW. 
The 25th, 50th (median), and 75th percentiles, along with associated 2-sided 95% Cis will be 
presented by subgroup and treatment arm. Forest plots (including the number of events/number 
of patients in each arm, hazard ratio (HR) and 95% CI within each subgroup for the 2 treatment 
comparisons) and individual Kaplan-Meier survival curves for each subgroup will be presented.
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The analysis of PFS will be repeated in each of the following subgroups.

Age (< 65 years, ≥65 years).

Race (white, non-white) [Not Reported will be excluded].

Region (North America, Europe).
Stratification factors per IRT (original):

Presence or absence of visceral metastasis.

Previous sensitivity to hormonal therapy.

Previous exposure to CDK 4/6 inhibitors.
6.8.3
Secondary Efficacy Endpoint(s)
Secondary efficacy endpoints include OS, ORR, TTP, CBR with SD of any duration and CBR 
with SD duration of at least 6 months. The analyses of OS and TTP will be done for the full 
analysis set. The analyses of ORR, CBR, and CBR with SD duration at least 6 months will be 
done for both the safety and response evaluable set.
In the event of response (i.e. overall response is PR or better), the date used for the start of 
response is defined as the latest of all dates among target lesions or non-target lesions dates at 
that particular visit.
Overall survival (OS)
Overall survival in months is defined as the time from the date of randomization to the date of 
death [date of death (OS (months) = (date of death – date of randomization + 1)/30.4375)]. 
Patients without documentation of death at the time of analysis will be censored at the date last 
known to be alive. The Kaplan-Meier method will be used to analyze the distribution of OS for 
each treatment arm. Kaplan-Meier survival curves, the 25th, 50th (median), and 75th percentiles, 
along with associated 2-sided 95% confidence intervals (CIs), and Kaplan-Meier estimates with 
95% CIs at 3, 6, 9, and 12 months will be presented. A stratified log-rank test and hazard ratios 
(and 95% CI) estimated from a stratified Cox regression model with treatment arm and 
stratification factors as covariates will be presented for the comparison of fulvestrant vs.
fulvestrant + MLN0128 QD and fulvestrant vs. fulvestrant + MLN0128 QW. The original IRT 
stratification factors will be used in models. 
Best Overall Response
Best overall response is defined as the best response recorded after the first dose of study drug 
until subsequent therapy. This will be the best response reported by the investigator; ordered 
from best to worst: Complete Response, Partial Response, Stable Disease, Progressive Disease. 
The best response can also be Not Evaluable (NE) or No assessment performed if this is the only 
investigator assessment of objective response available for the patient.
Overall response rate (ORR) is defined as the proportion of patients among response evaluable 
analysis set who achieve a best overall response of CR or PR based on investigators assessment 
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of response following RECIST 1.1. A stratified Cochran-Mantel-Haenszel (CMH) test based on 
stratification factors will be used to compare ORR between treatment arms based on the original 
IRT (fulvestrant vs. fulvestrant + MLN0128 QD and fulvestrant vs. fulvestrant + MLN0128
QW). The Mantel-Haenszel estimate of the odds ratio and the associated 95% CIs will be 
presented for each comparison specified above based on original IRT.
Clinical Benefit Rate (CBR)
CBR is defined as the proportion of patients who achieve a best response of CR, PR, or SD of 
any duration. A stratified Cochran-Mantel-Haenszel (CMH) test based on stratification factors 
will be used to compare CBR between treatment arms (fulvestrant vs. fulvestrant + MLN0128 
QD and fulvestrant vs. fulvestrant + MLN0128 QW). The Mantel-Haenszel estimate of the odds 
ratio and the associated 95% CIs will be presented for each comparison specified above.
Clinical Benefit Rate with SD duration of at least 6 months 
CBR with SD duration of at least 6 months (CBR-16) is defined as the proportion of patients 
who achieve CR or PR of any duration or have SD with duration of at least 6 months (see 
below). A stratified Cochran-Mantel-Haenszel (CMH) test based on stratification factors will be 
used to compare the CBR with SD duration at least 6 months between treatment arms 
(fulvestrant vs. fulvestrant + MLN0128 QD and fulvestrant vs. fulvestrant + MLN0128 QW). 
The Mantel-Haenszel estimate of the odds ratio and the associated 95% CIs will be presented for 
each comparison specified above.
SD with a duration of at least 6 months is defined as the number of patients who achieve CR or 
PR at any time or have SD at the end of Cycle 2, at the end of Cycle 4, and at the end of Cycle 6.
In addition, to account for unscheduled visits or PFS follow up visits (for those who discontinued 
for reasons other than progressive disease prior to alternative therapy or cross-over), SD for at 
least 6 months will include cases where at least three post baseline scans have SD and the 
duration of stable disease is greater than 180 days.
The proportion of patients with the following best response will be summarized by treatment 
group: CR, PR, SD, SD at least 6 months, overall response (ORR), CBR and CBR with SD 
duration at least 6 months.
Time to Tumor Progression (TTP)
TTP in months is defined as the time from the date of randomization to the date of first 
documentation of progression (TTP (months) = (date of first documentation of progression –
date of randomization + 1)/30.4375). For a patient whose disease has not progressed, TTP will be
censored at the last response assessment that is SD or better. 
The Kaplan-Meier method will be used to analyze the distribution of TTP for each treatment 
arm. Kaplan-Meier survival curves, the 25th, 50th (median), and 75th percentiles, along with 
associated 2-sided 95% confidence intervals (CIs), and Kaplan-Meier estimates with 95% CIs at 
3, 6, 9, and 12 months will be presented. A stratified log-rank test and hazard ratios (and 95% 
CI) estimated from a stratified Cox regression model with treatment arm and stratification factors 
as covariates will be presented for the comparison of fulvestrant vs. fulvestrant + MLN0128 QD 
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and fulvestrant vs. fulvestrant + MLN0128 QW. The original IRT stratification factors will be 
used in models.
6.9
Pharmacokinetic/Pharmacodynamic Analysis
6.9.1
Pharmacokinetic Analysis
Sparse PK data for MLN0128 are being collected to contribute to a future population PK 
analysis. These data may be combined with data from other studies in which the PK of 
MLN0128 is characterized for population PK analysis. The results of the population PK analysis 
will be presented in a separate report.
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6.9.2
Pharmacodynamic Analysis
6.10
Patient Reported Outcomes
Patient-reported outcome (PRO) assessments will be collected through 2 different instruments: 
EORTC QLQ-C30 and QLQ-BR23. The full analysis set will be used to present patient-reported 
outcome analysis. For each treatment group and at each assessment point and overall, the number 
and percentage of compliance for the EORTC QLQ-C30 and QLQ-BR23 questionnaires will be 
summarized. Compliance is defined as the number of questionnaires completed (answered at 
least one question) as a proportion of the number of expected questionnaires per the schedule of 
events (Day 1 of each cycle and End of Treatment). Patients who died will not be included in the 
expected count.
Patient with missing baseline scores are not assessable for baseline description or change from 
baseline and time to deterioration analyses. Patients with baseline scores, but with no follow-up 
scores, are not assessable for change from baseline. For time to deterioration they will be 
censored at Day 1. Published manuals/guidance for EORTC QLQ-C30 and QLQ-BR23 will be 
used for scoring and handling missing data. In the case where there is no guidance for handling 
missing data, missing items will be considered missing, they will not be imputed.
6.10.1 EORTC QLQ-C30 and EORTC QLQ-BR23 Score
Descriptive statistics including the 95% CI around mean for actual values and the change from 
baseline (post – baseline) will be tabulated at each scheduled time point and the EOT visit for 
each of the functional and symptom scores from the EORTC QLQ-C30 and QLQ-BR23
questionnaires, the global health status/QOL score and summary score from the EORTC QLQ-
C30 questionnaire up to 12 cycles. In addition, the mean and mean change from baseline of the 
EORTC QLQ-C30 subscales, the global health status/QOL score, summary score and the 
EORTC QLQ-BR23 subscales will also be presented over time by treatment group in figures up 
to 12 cycles (including 95% CI around mean). 
The change from baseline of EORTC QLQ-C30 subscales, global health status/QOL, summary 
score, QLQ-BR23 subscales, and summary score will be analyzed using linear mixed models, 
including treatment group, visit, the interaction between treatment group and visit, baseline score 
(and other covariates i.e. stratification factors as per original IRT) as covariates. Random-
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intercept only model with the appropriate covariance structure will be used based on the 
unstructured and AR(1). The first covariance structure that has all the parameter estimates 
converged for all the subscales will be used. The estimated means with 95% CIs will be provided 
at each time point up to 12 cycles for each treatment arm. The mean difference in each score and 
95% CIs and p values for the pairwise comparison of fulvestrant to fulvestrant + MLN0128 QD 
and fulvestrant to fulvestrant + MLN0128 QW will be presented at each time point up to 12 
cycles.
6.11
Safety Analysis
All safety analyses will be performed using the Safety analysis set.
6.11.1 Adverse Events
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.
Treatment-emergent AEs 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.
Treatment emergent adverse events will be summarized based on the number and percentage of 
patients experiencing events by MedDRA system organ class and preferred term. Tabular 
summaries by MedDRA system organ class and preferred term will be provided for the 
following: 

Treatment-emergent adverse events.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

Most commonly reported TEAEs (at least 10% in any arm, sorted by preferred term).

Serious adverse events.

Most frequent non-serious TEAEs (>5% in any arm) [for disclosure reporting]
Patients reporting the same event more than once will have that event counted only once within 
each body system, and once within each preferred term.
Adverse events of interest will be tabulated for the following:
Adverse event of 
interest
MedDRA Preferred Term
Asthenic Conditions 
Asthenia, Decreased activity, Fatigue, Malaise, Sluggishness 
(modified HLT)
Mucosal Inflammation
Enanthema
Allergic stomatitis
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Adverse event of 
interest
MedDRA Preferred Term
Mucosa vesicle
Aphthous ulcer
Mucosal atrophy
Lip erosion
Mucosal discolouration
Lip ulceration
Mucosal dryness
Mouth ulceration
Mucosal erosion
Oral mucosa erosion
Mucosal exfoliation
Palatal ulcer
Mucosal haemorrhage
Stomatitis
Mucosal hyperaemia
Stomatitis haemorrhagic
Mucosal hypertrophy
Stomatitis necrotising
Mucosal induration
Oedema mucosal
Mucosal inflammation
Mucosal infection
Mucosal membrane 
hyperplasia
Mucosal excoriation
Mucosal necrosis
Erythroplasia
Mucosal pain
Burning sensation mucosal
Mucosal pigmentation
Paraesthesia mucosal
Mucosal roughness
Leukoplakia
Mucosal toxicity
Drug eruption
Mucosal ulceration
Fixed eruption
Mucous membrane disorder
Mucocutaneous haemorrhage
Rash
Mucocutaneous rash, Nodular rash, Rash, Rash erythematous, 
Rash generalized, Rash macular, Rash maculo-papular, Rash 
maculovesicular, Rash morbilliform, Rash popular, Rash 
rubelliform, Rash scarlatiniform, Rash vesicular
6.11.1.1 Deaths
All-cause mortality will be tabulated, which includes death of all causes, and deaths related to 
breast cancer. On-study deaths (from first dose to 30 days after last dose) will be tabulated 
including deaths related to breast cancer, deaths due to study treatment, and deaths within 30 and 
60 days of first dose.
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6.11.2 Clinical Laboratory Evaluations
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
version 4.03. The number and proportion of patients with shifts in NCI CTCAE toxicity grades 
relative to the baseline toxicity grade will be summarized for the following laboratory tests:

Hematology: Hemoglobin increased, Activated partial thromboplastin time (aPTT) 
prolonged, INR increased, Lymphocyte count decreased, Lymphocyte count increased, 
Neutrophil count decreased, Platelet count decreased, White blood cell count decreased

Chemistry: Alanine aminotransferase (ALT) increased, Alkaline phosphatase increased, 
Aspartate aminotransferase (AST) increased, Bilirubin (total) increased, Cholesterol high, 
Creatinine increased, Gamma glutamyl transferase (GGT) increased, Corrected Calcium -
decreased, Corrected Calcium – increased, Glucose – decreased, Glucose – increased, 
Potassium – decreased, potassium – increased, magnesium – decreased, magnesium –
increased, sodium – decreased, sodium – increased, triglycerides – increased, albumin –
decreased, phosphate – decreased, amylase – increased
The shift from baseline to worst post baseline will include scheduled and unscheduled visits.
For fasting glucose, the shifts from baseline to the worst post baseline (2 hours only) will be 
summarized for the fulvestrant and fulvestrant + MLN0128 QD arms, and for the fulvestrant + 
MLN0128 QW patients enrolled prior to protocol amendment no 3. Similarly, the changes from 
pre-dose to 2 hours post dose for fasting glucose values will be presented.
The actual values (in SI units) and change from baseline in clinical laboratory parameters will be 
summarized by treatment group for Neutrophils (ANC), Aspartate aminotransferase (AST), 
Alanine aminotransferase (ALT), Glucose, Hemoglobin A1c, Cholesterol (total), Triglycerides, 
High-density lipoprotein cholesterol (HDL-C) and Low-density lipoprotein cholesterol (LDL-C) 
at each scheduled visit up to and including 12 cycles. Figures of mean actual values over time 
will also be generated for these clinical laboratory parameters (in SI units).
6.11.3 Vital Signs
The actual values and change from baseline of vital sign parameters including temperature, heart
rate, systolic and diastolic blood pressure, and weight, will be summarized by treatment group at 
each scheduled visit up to and including 6 cycles. In addition, the minimum post-baseline value, 
change to minimum post-baseline value, maximum post-baseline value, and change to maximum 
post-baseline value will be summarized.
6.11.4 12-Lead ECGs
The actual values and change from baseline for ECG results (QT, QTcF, PR interval, QRS 
interval, Ventricular Rate) will be summarized over time for each treatment group up to 6 cycles. 
The number and percent of patients with increases >30 ms and >60 ms from pre-dose in QTcF
will also be summarized over time up to 6 cycles. In addition, the minimum post-baseline value, 
change to minimum post-baseline value, maximum post-baseline value, and change to maximum 
post-baseline value will be summarized.
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6.11.5 Other Observations Related to Safety
For ECOG performance status shifts from baseline to the worst post-baseline on study score will 
be tabulated by treatment arm.
6.12
Crossover Treatment
Data collected after crossover treatment begins will not be included in the planned efficacy and 
safety analyses for the study. 
The following information will be provided in a listing for crossover patients from the fulvestrant
arm (presented by crossover treatment):
!
Best overall response prior to/after crossover
!
Duration of treatment (weeks) prior to/after crossover
!
Reason for discontinuing fulvestrant/reason for discontinuing crossover treatment
6.13
Interim Analysis
6.14
Changes in the Statistical Analysis Plan 
!
For PFS analysis, patients who started alternate subsequent therapy prior to disease 
progression will be censored at the date of last adequate assessment prior to the start of 
subsequent therapy. The protocol did not explicitly state this condition.
!
In addition to Kaplan-Meier method that will be used to analyze distribution of PFS, OS and 
TTP for each treatment arm and the p-values from a stratified log-rank test, the HRs and 95% 
CIs from a stratified Cox regression model with treatment arm and stratification factors as 
covariates will also be presented for comparison of fulvestrant vs. fulvestrant + MLN0128 
QD and fulvestrant vs. fulvestrant + MLN0128 QW. The protocol did not explicitly state the 
model for estimating the HRs.
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7.0
REFERENCES
1. Turner NC, Ro J, Andre F, Loi S, Verma S, Iwata H, et al. Palbociclib in Hormone-Receptor-
Positive Advanced Breast Cancer. New England Journal of Medicine 2015;373(3):209-19.
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8.0
APPENDIX
Appendix A
By-Subject Listings
In addition to the analysis outputs outlined above in the main text, separate by-patient listings 
will also be generated:

Disposition of subjects (including crossover treatment, if applicable).

Demographic and other baseline characteristics.

Stratification Factors.

Significant protocol deviations.

Concomitant medications.

Follow-up anti-cancer therapy.

TEAEs resulting in discontinuation of study drug.

TEAEs resulting in discontinuation of crossover treatment.

SAEs.

SAEs for crossover patients.

Deaths and cause of death.

Deaths and cause of death for crossover patients.

Sparse PK data.

RECIST response assessment and best overall response based on investigator assessment.

RECIST response assessment and best overall response based on investigator assessment
– Crossover Patients.
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Appendix B
Date Imputation Rules
Incomplete Dates in the Screening Period
1. If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug. Otherwise, the fifteenth will 
be used.
2. If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the first of January will be used.
3. If only the year is present, and it is not the same as the year of the first dose of study drug, the 
fifteenth of June will be used. 
Incomplete Adverse Event Onset Date
Assumption: For on-study Adverse Events.
If year is missing (or completely missing): set to the date of first dose.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
If year = year of first dose: set the date to the first dose date.
If year < year of first dose: set month and day to December 31st.
If year > year of first dose: set month and day to January 1st.
If month and year are present and day is missing:
If year = year of first dose, and:
If month = month of first dose: set day to day of first dose.
If month < month of first dose: set day to last day of month.
If month > month of first dose: set day to 1st day of month.
If year < year of first dose: set day to last day of month.
If year > year of first dose: set day to 1st day of month.
For all other cases: set to date of first dose.
Incomplete Concomitant Medication Start Date
If year is missing (or completely missing): do not impute.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
Set month and day to January 1st.
If year and month are present and day is missing:
Set day to 1st day of month.
Incomplete Concomitant Medication End Date
If year is missing (or completely missing): do not impute.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
Set month and day to December 31st.
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If year and month are present and day is missing:
Set day to last day of the month.
Incomplete Subsequent Anti-Cancer Therapy Start Date
If year is missing (or completely missing): set to date of last dose of study treatment + 1
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
If year > year of the last dose: Set month and day to January 1st.
If year = year of the last dose: Set month and day to date of last dose of study 
treatment +1
If year and month are present and day is missing:
Set day to 1st day of month if the resulting imputed date is greater than date of last 
dose.
Otherwise set the imputed date to date of last dose + 1
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