Conditions: Clear-cell Metastatic Renal Cell Carcinoma
Keywords: Drug therapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 96
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of single-agent MLN0128 and the combination of MLN0128 + MLN1117 compared with everolimus in the treatment of participants with metastatic clear-cell renal cell carcinoma (mccRCC) that have progressed on vascular endothelial growth factor (VEGF)-targeted therapy.

Detailed description:
The drugs being tested in this study are called MLN0128 and MLN1117. MLN0128 and MLN1117 are being tested to treat people who have mccRCC. This study will assess the efficacy and safety of MLN0128 and MLN1117 as well as how it is processed by the body in participants with advanced or mccRCC.

The study will enroll approximately 96 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the three treatment groups:

* Everolimus 10 mg once daily
* MLN0128 30 mg once weekly
* MLN0128 4 mg once daily for 3 days per week + MLN1117 200 mg once daily for 3 days per week

All participants will be asked to take the study drug at the same time on each scheduled day.

This multi-center trial will be conducted worldwide. The overall time to participate in this study is 2 years after last participant is randomized, or when the last participant discontinues study treatment (approximately 3 years). Participants will make multiple visits to the clinic including a follow-up visit 30 to 40 days after receiving their last dose of study drug or prior to start of subsequent anticancer therapy for safety assessment. Participants will then be followed for Progression Free and Overall Survival.

Arms:
arm 1: Everolimus 10 mg capsules, orally, once daily in a 28-day treatment cycle until disease progression, consent withdrawal, death, or transfer to the Post-trial Access (PTA) program (Median duration of treatment was 15.43 weeks up to end of study). arm 2: MLN0128 30 mg capsules, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.64 weeks up to end of study). arm 3: MLN0128 4 mg and MLN1117 200 mg capsules, orally, both once daily for 3 days per week (QD X 3) on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle until disease progression, unacceptable toxicity, consent withdrawal, death, or transfer to the PTA program (Median duration of treatment was 9.43 weeks up to end of study).

Interventions: intervention 1: Everolimus intervention 2: MLN0128 intervention 3: MLN1117
Intervention descriptions: intervention 1: Everolimus capsules. intervention 2: MLN0128 capsules. intervention 3: MLN1117 capsules.

Protocol document:
Prot_000.pdf: 



Title: A Phase 2, Open-label Study to Evaluate the Efficacy and Safety of Single-Agent MLN0128 and 
the Combination of MLN0128+MLN1117 Compared With Everolimus in the Treatment of Adult 
Patients With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma That Has Progressed on 
Vascular Endothelial Growth Factor-Targeted Therapy
NCT Number: NCT02724020
Protocol Approve Date: 03-December-2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from view 
with a black/blue bar) to protect either personally identifiable information (PPD) or company confidential 
information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


1
PROTOCOL
A Phase 2, Open-label Study to Evaluate the Efficacy and Safety of Single-Agent MLN0128 
and the Combination of MLN0128+MLN1117 Compared With Everolimus in the 
Treatment of Adult Patients With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma 
That Has Progressed on Vascular Endothelial Growth Factor-Targeted 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:
C31005
IND Number:
126,347
EudraCT Number:
2015-002133-22
Compound:
MLN0128, MLN1117
Date:
03-December-2018
Amendment Number:
10 (France)
Amendment History
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
22 May 2015
Initial Protocol
Not applicable
Global
09 February 2016
01
Nonsubstantial
Global
15 September 2016
02
Nonsubstantial
France
01 December 2016
03
Substantial
France
17 April 2017
04
Substantial
Global
17 April 2017
05
Substantial
France
03 October 2017
06
Substantial
Global
02 October 2017
07
Substantial
France
26-October-2017
08
Substantial
Hungary
03-December-2018
09
Substantial
Global
03 December-2018
10
Substantial
France
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1.0
ADMINISTRATIVE
1.1
Contacts
A separate contact information list will be provided to each site.
Serious adverse event and pregnancy reporting information is presented in Section 11.0, as is 
information on reporting product complaints.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
North America
Europe
Serious adverse event and pregnancy reporting
See Section 11.0
See Section 11.0
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES 
The signature of the responsible Takeda medical officer (and other signatories, 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
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wing:
olidated
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privac
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and Subje
: For Non-Commercial Use Only an


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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
inserts, and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 11.0 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/Provence)
Location of Facility (Country)
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1.3
Protocol Amendment 10 Summary of Changes
Rationale for Amendment 10
This document describes the changes in reference to the protocol incorporating 
Amendment No. 10. The primary purpose of this amendment is to define study closure, remove 
long-term follow-up, remove the option for cross-over treatment, and add the option of a 
Post-Trial Access (PTA) program. 
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Appendix L. 
Changes in Amendment 10
1. Removed long-term follow-up, the option for cross-over treatment from Arm A to Arm B or 
Arm C, and added the option for patients to transfer to a Post-Trial Access (PTA) program.
2. Study closure was defined as when the last patient discontinues treatment. 
3. A new section was added (10.10) detailing the PTA program.
4. Modified the exclusion criterion relating to proton-pump inhibitors (PPIs). 
5. Revised the restrictions on concomitant use of PPIs. 
6. Physical examinations after Screening were changed to symptom-directed physical 
examinations.
7. The requirement for a confirmatory scan 4 weeks from the previous scan for patients with a 
complete response (CR) or partial response (PR) was removed.
8. A recommendation was added for radiographic assessment every 6 months after 12 cycles of 
treatment.
9. The requirement for weight to be measured at Day 15 of Cycles 1 and 2 was removed.
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 10 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
RCC...................................................................................................................19
4.1.2
Study Drugs MLN0128 and MLN1117 ..............................................................21
4.2
Rationale for the Proposed Study.............................................................................23
4.2.1
Rationale for the Doses and Schedule in Arm B .................................................23
4.2.2
Rationale for the Doses and Schedule in Arm C .................................................24
4.3
Potential Risks and Benefits.....................................................................................25
5.0
STUDY OBJECTIVES .................................................................................................26
5.1
Primary Objectives ..................................................................................................26
5.2
Secondary Objectives...............................................................................................26
5.3
Quality of Life Objective .........................................................................................26
6.0
STUDY ENDPOINTS...................................................................................................27
6.1
Primary Endpoint.....................................................................................................27
6.2
Secondary Endpoints ...............................................................................................27
6.3
QOL Endpoints........................................................................................................27
7.0
STUDY DESIGN..........................................................................................................28
7.1
Overview of Study Design.......................................................................................28
7.2
Number of Patients ..................................................................................................30
7.3
Duration of Study ....................................................................................................30
8.0
STUDY POPULATION................................................................................................31
8.1
Inclusion Criteria .....................................................................................................31
8.2
Exclusion Criteria ....................................................................................................32
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9.0
STUDY DRUG .............................................................................................................35
9.1
Study Drug Administration......................................................................................35
9.2
Reference/Control Therapy......................................................................................36
9.3
Dose Modification Guidelines..................................................................................36
9.3.1
Intrapatient Dose Escalation...............................................................................36
9.3.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................36
9.3.3
Criteria for Dose Interruption During a Cycle.....................................................36
9.3.4
Criteria for Dose Reduction................................................................................37
9.3.5
Criteria for Discontinuation of Study Drug.........................................................38
9.4
Excluded Concomitant Medications and Procedures ................................................38
9.4.1
Excluded Concomitant Medications and Procedures for Arm A .........................38
9.4.2
Excluded Concomitant Medications and Procedures for Arms B and C..............39
9.4.3
Potential for Drug-Drug Interactions with MLN0128 and/or MLN1117.............39
9.5
Permitted Concomitant Medications and Procedures................................................40
9.6
Precautions and Restrictions ....................................................................................40
9.7
Management of Clinical Events ...............................................................................41
9.7.1
Management of Hyperglycemia .........................................................................42
9.7.2
Management of Hyperlipidemia .........................................................................43
9.7.3
Management of Oral Mucositis ..........................................................................44
9.7.4
Management of Rash .........................................................................................45
9.7.5
Management of Nausea/Vomiting ......................................................................46
9.7.6
Management of Cardiac Abnormalities ..............................................................47
9.7.7
Management of Other Nonhematologic Toxicities .............................................48
9.7.8
Management of AST/ALT Elevations ................................................................49
9.7.9
Management of Noninfectious Pneumonitis .......................................................50
9.7.10 Management of Opportunistic Infections............................................................51
9.7.11 Blinding and Unblinding....................................................................................51
9.8
Description of Investigational Agents ......................................................................52
9.9
Preparation, Reconstitution, and Dispensation..........................................................52
9.10
Packaging and Labeling...........................................................................................52
9.11
Storage, Handling, and Accountability.....................................................................53
9.12
Other Protocol-Specified Materials ..........................................................................53
10.0
STUDY CONDUCT......................................................................................................54
10.1
Study Personnel and Organizations..........................................................................54
10.2
Arrangements for Recruitment of Patients................................................................54
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10.3
Treatment Group Assignments.................................................................................54
10.4
Study Procedures.....................................................................................................54
10.4.1 Informed Consent...............................................................................................55
10.4.2 Patient Demographics ........................................................................................55
10.4.3 Medical History .................................................................................................55
10.4.4 Physical Examination.........................................................................................55
10.4.5 Patient Height and Weight .................................................................................55
10.4.6 Vital Signs .........................................................................................................55
10.4.7 Pregnancy Test...................................................................................................55
10.4.8 Concomitant Medications and Procedures..........................................................56
10.4.9 AEs....................................................................................................................56
10.4.10
Enrollment....................................................................................................56
10.4.11
ECG..............................................................................................................56
10.4.12
Clinical Laboratory Evaluations....................................................................56
10.4.13
Fasting Serum Glucose .................................................................................57
10.4.14
In-Home Daily Fasting Glucose Monitoring..................................................58
10.4.15
Disease Assessment ......................................................................................58
10.4.16
PK Measurements.........................................................................................59
10.4.17
Pharmacodynamic Measurements .................................................................59
10.4.18
DNA Measurements......................................................................................59
10.4.19
Banked Tumor Specimen Measurements; Tumor Biopsies............................60
10.4.20
QOL and Symptom Assessments ..................................................................60
10.5
Completion of Treatment .........................................................................................61
10.6
Completion of Study................................................................................................61
10.7
Discontinuation of Treatment With Study Drug and Patient Replacement................61
10.8
Withdrawal of Patients From Study .........................................................................61
10.9
Study Compliance....................................................................................................62
10.10 Post-Trial Access Program.......................................................................................62
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
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11.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........65
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
eCRFs......................................................................................................................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
14.1.4 PK Analysis .......................................................................................................71
14.1.5 Pharmacodynamic Analysis ...............................................................................71
14.1.6 Other Analyses...................................................................................................71
14.1.7 Safety Analysis ..................................................................................................71
14.2
Interim Analysis and Criteria for Early Termination ................................................72
14.3
Determination of Sample Size..................................................................................72
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........................................................................76
16.1
IRB and/or IEC Approval ........................................................................................76
16.2
Subject Information, Informed Consent, and Subject Authorization .........................77
16.3
Subject Confidentiality ............................................................................................78
16.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................78
16.4.1 Publication and Disclosure.................................................................................78
16.4.2 Clinical Trial Registration..................................................................................79
16.4.3 Clinical Trial Results Disclosure ........................................................................79
16.5
Insurance and Compensation for Injury....................................................................79
17.0
REFERENCES..............................................................................................................80
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LIST OF IN-TEXT TABLES
Table 4.a
DLT Observed With Weekly MLN0128 in Study MLN0128-1004 ....................23
Table 4.b
DLT Observed With MLN0128 Plus MLN1117 (3 Days Per Week) in Study 
C32001 ..............................................................................................................24
Table 9.a
Examples of a Light Meal ..................................................................................35
Table 9.b
Dose Modifications for Single-Agent MLN0128................................................37
Table 9.c
Dose Modifications for MLN0128 in Combination with MLN1117 ...................38
Table 9.d
Management of Hyperglycemia .........................................................................43
Table 9.e
Management of Hyperlipidemia .........................................................................44
Table 9.f
Management of Oral Mucositis ..........................................................................45
Table 9.g
Management of Rash .........................................................................................46
Table 9.h
Management of Nausea/Vomiting ......................................................................47
Table 9.i
Management of Left Ventricular Dysfunction ....................................................48
Table 9.j
Management of QTc Interval Prolongation.........................................................48
Table 9.k
Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue)......................................................................................49
Table 9.l
Management of AST/ALT Elevations ................................................................50
Table 9.m
Management of Noninfectious Pneumonitis .......................................................51
Table 10.a
Clinical Chemistry, Hematology, and Coagulation Tests....................................57
Table 10.b
Clinical Urinalysis Tests ....................................................................................57
Table 10.c
Fasting Lipid Profile ..........................................................................................57
LIST OF IN-TEXT FIGURES
Figure 7.a
Study Design......................................................................................................29
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................83
Appendix B
Responsibilities of the Investigator.....................................................................89
Appendix C
Investigator Consent to Use of Personal Information..........................................91
Appendix D
Karnofsky Performance Status ...........................................................................92
Appendix E
Methods of Contraception Considered to be Effective........................................93
Appendix F
Cockcroft-Gault Equation ..................................................................................94
Appendix G
New York Heart Association Classification of Cardiac Disease..........................95
Appendix H
List of Relevant Cytochrome P450 Inhibitors and Inducers ................................96
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Appendix I
List of BCRP, OCT1, and OCT2 Substrates.......................................................97
Appendix J
EORTC QLQ-C30 Version 3 .............................................................................98
Appendix K
Functional Assessment of Cancer Therapy Kidney Symptom 
Index-Disease-Related Symptoms....................................................................100
Appendix L
Detailed Description of Amendments to Text...................................................101
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Millennium Pharmaceuticals, Inc
Compound:
MLN0128, MLN1117
Title of Protocol: A Phase 2, Open-label Study to Evaluate 
the Efficacy and Safety of Single-Agent MLN0128 and the 
Combination of MLN0128+MLN1117 Compared With 
Everolimus in the Treatment of Adult Patients With 
Advanced or Metastatic Clear-Cell Renal Cell Carcinoma 
That Has Progressed on Vascular Endothelial Growth 
Factor-Targeted Therapy
IND No.: 126,347
EudraCT No.:
2015-002133-22
Study Number: C31005
Phase: 2
Study Design:
This phase 2, open-label, randomized, 3-arm study is designed to evaluate the efficacy and safety of single-agent 
MLN0128 and the combination of MLN0128 and MLN1117 compared with single-agent everolimus in the treatment 
of patients with metastatic clear-cell renal cell carcinoma (mccRCC) that has progressed on vascular endothelial 
growth factor (VEGF)-targeted therapy. Patients who meet the eligibility criteria will be stratified according to the 
number of prior lines of therapy (1, >1 prior line) and the International Metastatic Renal Cell Carcinoma Database 
Consortium risk category (favorable, intermediate, or poor) and will be randomized at a ratio of 1:1:1 to one of 
3 treatment groups:

Arm A: single-agent everolimus.

Arm B: single-agent MLN0128.

Arm C: combination of MLN0128+MLN1117.
Safety assessments (which include vital signs, hematology, serum chemistry, and urinalysis) will be performed every 
2 weeks for the first two 28-day cycles and then at the beginning of each subsequent cycle thereafter. 
Primary Objectives:

To compare the efficacy of single-agent MLN0128 versus single-agent everolimus in patients with mccRCC. 

To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent everolimus in patients 
with mccRCC. 
Secondary Objectives:

To assess the safety and tolerability of MLN0128 and MLN0128+MLN1117.

To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent MLN0128 in patients 
with mccRCC.

To evaluate the efficacy (endpoints other than progression-free survival [PFS]; ie, overall survival [OS], 
time-to-progression [TTP], objective response rate [ORR], and clinical benefit rate [CBR]) among the 3 treatment 
groups.

To collect plasma concentration-time data with sparse pharmacokinetic (PK) sampling to contribute to future 
population PK analysis.
Quality of Life Objective:

To assess the health-related quality of life and symptoms as measured by the European Organization for Research 
and Treatment of Cancer Quality of Life Questionnaire-Core 30 and the Functional Assessment of Cancer 
Therapy-Kidney Symptom Index-Disease-Related Symptoms questionnaire among the 3 treatment groups.
Subject Population: Patients aged ≥18 years with mccRCC that has progressed on VEGF-targeted therapy
Number of Subjects: Approximately 189 patients

Arm A: everolimus; n=approximately 63.
Number of Sites:
Approximately 60-70 sites in North America and 
Europe
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
Arm B: MLN0128; n=approximately 63.

Arm C: MLN0128+MLN1117; n=approximately 63.
Dose Level(s):

Arm A: everolimus, 10 mg once daily (QD; every day 
of a 28-day treatment cycle).

Arm B: MLN0128, 30 mg every week on Days 1, 8, 15, 
and 22 of a 28-day treatment cycle.

Arm C: MLN0128 4 mg+MLN1117 200 mg, both 
QD3 days per week (on Days 1-3, 8-10, 15-17, and 
22-24 of a 28-day treatment cycle).
Route of Administration:

MLN0128: oral.

MLN1117: oral.

Everolimus: oral.
Duration of Treatment:
Patients will receive MLN0128, MLN0128+MLN1117, or 
everolimus until they experience disease progression or 
unacceptable toxicity, withdraw consent, die, or transfer to 
the Post-Trial Access (PTA) program. The maximum 
duration of treatment will be 24 months. 
Period of Evaluation:
The study will be closed when the last patient 
discontinues study treatment. 
Main Criteria for Inclusion:
Adult patients with histologically confirmed renal cell carcinoma with a clear-cell component, measurable disease per 
RECIST version 1.1, adequate bone marrow reserve and renal and hepatic function based on minimum laboratory 
criteria, Karnofsky performance status of 70% or higher, and life expectancy of at least 3 months. Eligible patients 
must have received at least one prior line of VEGF-targeted therapy and must have had radiographic evidence of 
progressive disease either on or within 6 months of stopping their most recent systemic therapy for advanced 
mccRCC, and may have received up to 4 total prior lines of therapy.
Main Criteria for Exclusion:
Patients who have central nervous system metastases, uncontrolled comorbidities such as pulmonary disease or 
infection that might compromise the patient’s participation in the study, and women who are either breast-feeding or 
pregnant, will be excluded.
Main Criteria for Evaluation and Analyses:
The primary endpoint of the study is PFS. The secondary endpoints are the incidence of treatment-emergent adverse 
events, OS, TTP, ORR (complete response [CR]+partial response [PR] per RECIST version 1.1), CBR (defined as 
CR+PR+stable disease[SD]) with SD of any duration, and CBR with SD duration of at least 4 months.
Statistical Considerations:
The primary endpoint of the study is PFS, defined as the time from the date of randomization to the date of first 
documentation of disease 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, 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% CIs; hazard ratio 
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 0.15 significance level (2-sided). The p-values from a stratified log-rank test and 
hazard ratios and will be presented for each pair-wise comparison.
Secondary efficacy endpoints include OS, ORR, TTP, CBR (CR+PR+SD of any duration), and CBR with SD duration 
of at least 4 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 in the full analysis set.
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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. CBR will also be presented for a best response of 
CR, PR, and SD of at least 4 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.
Sample Size Justification: 
Approximately 189 patients will be enrolled in the 3 treatment arms.
The primary efficacy endpoint is PFS. Assuming that the median PFS is 5 months for everolimus and that MLN0128 
(either as a single agent or in combination with MLN1117) can improve the median PFS to 8 months (hazard ratio of 
0.625), then a total of 95 PFS events are needed for each pair-wise comparison, and approximately 63 patients are 
required for each treatment arm. The calculations are based on a power of 80%, 2-sided alpha of 15%, 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 total accrual will be approximately 14 months, where 10% of the patients 
are enrolled within the first 3 months and 40% are enrolled at the end of 7 months. The final analysis for the pair-wise 
comparisons of PFS between single-agent MLN0128 and everolimus and between the combination of 
MLN0128+MLN1117 and everolimus will occur approximately 9 months after the last 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. The identified vendors in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator or Investigators 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
4E-BP1
eukaryotic translation initiation factor 4E-binding protein 1
AE
adverse event
AKT
serine/threonine-specific protein kinase (also known as protein kinase B)
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BCRP
breast cancer resistance protein
CBR
clinical benefit rate
CFR
Code of Federal Regulations
CNS
central nervous system
CR
complete response
CRO
contract research organization 
CT
computed tomography
CYP
cytochrome P450
DLT
dose-limiting toxicity
ECG
electrocardiogram
eCRF
electronic case report form
EOT
End-of-Treatment (visit)
FBG
fasting blood glucose
FDA
Food and Drug Administration
EORTC QLQ-C30 European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire-Core 30
FKSI-DRS
Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms
GCP
Good Clinical Practice
GI
gastrointestinal
HbA1c
glycosylated hemoglobin, hemoglobin A1c
HDPE
high-density polypropylene
HIF
hypoxia-inducible factor
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous; intravenously
IXRS
interactive voice and/or web response system 
mccRCC
metastatic clear-cell renal cell carcinoma
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc and its affiliates
MLN0128
also known as TAK-228
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MLN1117
also known as TAK-117
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTOR
mechanistic (or mammalian) target of rapamycin
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OCT1
organic cation transporter protein 1
OCT2
organic cation transporter protein 2
ORR
objective response rate
OS
overall survival
p-
phosphorylated
PCP
Pneumocystis carinii pneumonia
PDGF
platelet-derived growth factor
PFS
progression-free survival
PI3K
phosphoinositide 3-kinase
PI3Kα
phosphoinositide 3-kinase alpha subunit
PIK3CA
phosphoinositide-3-kinase, catalytic alpha polypeptide
PJP
Pneumocystis jiroveci pneumonia
PK
pharmacokinetic(s)
PPI
proton pump inhibitor 
PR
partial response
PRO
patient-reported outcomes
PTA
Post-Trial Access
PTE
pretreatment event
PTEN
phosphatase and tensin homolog
QD
quaque die; each day; once daily
QD3 QW
once daily for 3 days each week
QOL
quality of life
QW
every week
QTc
rate-corrected QT interval (msec) 
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
S473
serine 473
S6K
ribosomal protein S6 kinase
SAE
serious adverse event
SD
stable disease
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
TAK-117
MLN01117
TAK-228
MLN0128
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TEAE
treatment-emergent adverse event
TORC1
mammalian (or mechanistic) target of rapamycin complex 1
TORC2
mammalian (or mechanistic) target of rapamycin complex 2
TTP
time-to-progression
ULN
upper limit of normal (range)
US
United States
USPI
United States Prescribing Information
VEGF
vascular endothelial growth factor 
VHL
von Hippel-Lindau
WHO
World Health Organization
3.4
Corporate Identification 
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical 
Company Limited
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Americas
Takeda Development Center Americas, Inc
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
Millennium Pharmaceuticals, Inc, TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as
applicable
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4.0
INTRODUCTION
4.1
Background
Kidney cancer is the twelfth most common cancer world-wide, with an estimated 338,000 new 
cases based on 2012 global data [1]. The incidence of kidney cancer is higher in men than in 
women, with 214,000 new cases in men and 124,000 new cases in women. Geographically, the 
highest incidence rates are in Northern and Eastern Europe, North America, and Australia [1,2]. 
However, the overall incidence rates have been increasing over the last 3 decades [3]. More than 
90% of kidney cancers are renal cell carcinoma (RCC), of which 80% have a clear-cell 
morphology [4].
4.1.1
RCC
RCC is a highly vascularized tumor that is refractory to chemotherapy and can be treated with 
molecularly targeted antiangiogenic compounds, including tyrosine kinase inhibitors that act on 
the vascular endothelial growth factor (VEGF) receptor (such as sunitinib, sorafenib, axitinib, and 
pazopanib), anti-VEGF antibody (bevacizumab), and rapalogs (temsirolimus and everolimus).
Approximately 80% to 90% of clear-cell carcinomas have either biallelic mutation or inactivation 
of the von Hippel-Lindau (VHL) gene, which regulates hypoxia-inducible factor (HIF)-1α and 
HIF-2α transcription factors that are involved in the hypoxia response [5-8]. As part of the hypoxic 
response, the HIF-1α and HIF-2α transcription factors lead to an increase in the expression of 
angiogenic growth factors, such as VEGF, platelet-derived growth factor-β (PDGF-β), 
transforming growth factor-α, and angiopoietin-1 [5,7,8].
When oxygen is restored, the VHL protein forms a multiprotein complex that is involved in the 
ubiquitination and subsequent proteasomal degradation of the HIF transcription factors. When 
VHL is absent, the angiogenic growth factors are expressed constitutively in the absence of 
hypoxia.
Therapy has focused on the growth factor (eg, VEGF, PDGF) and mechanistic (or mammalian) 
target of rapamycin (mTOR) signaling pathways. Tyrosine kinase inhibitors that inhibit 
angiogenic growth factor receptors, such as VEGF and PDGF receptors, and anti-VEGF antibody 
(bevacizumab) are approved for first-line therapy in RCC; however, development of resistance to 
VEGF-targeted therapy occurs almost invariably.
The mTOR Pathway as a Therapeutic Target in RCC
The mTOR pathway is another therapeutic target in RCC. The mTOR serine/threonine kinase has 
a central role in regulating cellular growth and metabolism in response to external environmental 
factors [9,10]. The mTOR kinase binds with other proteins to form 2 distinct multiprotein 
complexes, mTOR complex 1 (TORC1) and mTOR complex 2 (TORC2). The TORC1 complex is 
stimulated by growth factors and amino acids, and regulates cell growth by controlling the activity 
of the ribosomal protein S6 kinase (S6K) and eukaryotic translation initiation factor 4E-binding 
protein 1 (4E-BP1) [11]. The TORC2 complex is activated by growth factors, and promotes cell 
survival, proliferation, and actin cytoskeleton organization by phosphorylating and activating 
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kinases, such as serine/threonine-specific protein kinase (AKT, also known as protein kinase B), 
which is a regulator of apoptosis [12,13].
Two major classes of mTOR inhibitors are under development: allosteric inhibitors and adenosine 
triphosphate (ATP)-competitive inhibitors. The first-generation, or allosteric, inhibitors include 
rapamycin and the related analogs or rapalogs temsirolimus, everolimus, and ridaforolimus. The 
rapalogs effectively inhibit phosphorylation of S6K, but only partially inhibit the phosphorylation 
of 4E-BP1, which regulates cap-dependent translation of transcripts for cell survival, proliferation, 
and angiogenesis [9,10]. Thus, rapamycin and the rapalogs are only partial inhibitors of TORC1 
[9,10].
The ATP-competitive inhibitors (also known as mTOR kinase inhibitors or TORKinibs), such as 
MLN0128, bind to the catalytic domain of mTOR. Thus, these agents inhibit both TORC1 and 
TORC2 complexes, including the rapamycin-insensitive or -resistant actions of TORC1, such as 
phosphorylation of 4E-BP1 [14-17].
Resistance to Rapalogs
The rapalogs temsirolimus and everolimus have been approved by the United States (US) Food 
and Drug Administration (FDA) as monotherapy for patients with advanced RCC. However, 
resistance to single-agent rapalog therapy occurs frequently and may be related to either 
incomplete inhibition of the targeted pathway (such as phosphorylation of 4E-BP1) or the loss of 
S6K-mediated feedback inhibition of growth-factor receptor signaling, leading to paradoxic 
hyperactive signaling. The normal feedback loop involves activated S6K, which phosphorylates 
and inactivates insulin-receptor substrate-1 and inhibits signaling through the phosphoinositide 
3-kinase (PI3K) pathway [13,18]. In the presence of rapalogs, the feedback loop is abrogated, 
leading to continued PI3K signaling, TORC2 activation, and subsequent phosphorylation of AKT 
at threonine 308 and serine 473 (S473), which markedly enhances the activity of AKT 
[9,10,13,18]. This leads to continued signaling from the receptor through the PI3K pathway, 
TORC2, and AKT, leading to cell survival and proliferation.
The loss of feedback inhibition by rapalogs has been demonstrated in clinical trials. In an analysis 
of either paired fresh tumor samples or skin biopsies obtained from 55 patients who received 
different doses of everolimus, either daily or weekly in a phase 1 trial, everolimus inhibited 
TORC1 in a dose- and schedule-dependent manner, with near complete inhibition of S6K [19]. 
Half of the paired tumor samples had a posttreatment increase in the phosphorylation of AKT at 
S473 [19]. These results provide direct evidence that loss of S6K feedback and subsequent 
PI3K/TORC2-induced activation of AKT occurs commonly in patients with nonhematologic 
tumors receiving single-agent everolimus. 
The rapalog everolimus is an allosteric inhibitor of TORC1. In a phase 3 study of single-agent 
everolimus in patients whose VEGF-targeted therapy had failed, single-agent everolimus 
prolonged median progression-free survival (PFS) by approximately 3 months compared with 
patients who received placebo and best supportive care (median PFS 4.9 months vs 1.9 months) 
[20]. The less-than-expected anticancer activity of single-agent rapalogs may be due to incomplete 
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inhibition of TORC1 actions, such as 4E-BP1, or the loss of feedback inhibition of the signaling 
pathway mediated by S6 kinase following pharmacologic inhibition of TORC1.
4.1.2
Study Drugs MLN0128 and MLN1117
MLN0128
MLN0128 (also known as TAK-228) is a potent and selective catalytic mTOR (TORC1/2) 
inhibitor that has the potential to improve upon everolimus treatment response in metastatic 
clear-cell RCC (mccRCC) through a more complete inhibition of TORC1 signaling (S6 and 
4E-BP1) and through inhibition of TORC2 substrates, such as AKT. This could lead to a more 
profound block of the angiogenic growth and survival signaling than that achieved with rapalogs.
Clinical Experience With MLN0128
Single-agent MLN0128 is in clinical development with 3 phase 1 studies in patients with advanced 
non-hematologic tumors (Studies INK128-001, MLN0128-1004, and C31002). In addition, 
MLN0128 is being investigated in combination with paclitaxel, with or without trastuzumab, in a 
phase 1 study in patients with advanced solid tumors (INK128-003).
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) and in 
a phase 1/2 study in patients with advanced estrogen receptor-positive, human epidermal growth 
factor receptor-2 negative breast cancer (Study C31001).
The most common treatment-emergent adverse events (TEAEs) observed with MLN0128 are 
consistent with the pharmacodynamic mechanism of mTOR inhibition that is also seen with 
rapalogs (TORC1 inhibition) or other dual mTORC1/2 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.
MLN0128 has been shown to have antitumor activity against RCC in a murine xenograft model. In 
addition, preliminary clinical data from a tumor-specific expansion cohort in Study INK128-001 
suggests that MLN0128 has antitumor activity in patients with RCC.
Further details are presented in the current edition of the MLN0128 Investigator’s Brochure (IB).
MLN1117 in Combination With MLN0128
MLN1117 (also known as TAK-117) is a potent and highly selective small-molecule inhibitor of 
the class I PI3K alpha subunit (PI3K) isoform. PI3Kis activated by upstream receptor tyrosine 
kinases such as epidermal growth factor receptors, human epidermal growth factor receptor-2, 
insulin-like growth factor-1 receptor, and insulin receptors, and possibly by activated Ras. 
The addition of the PI3Kα inhibitor MLN1117 to MLN0128 should counteract the reactivation of 
this pathway and enhance MLN0128 activity. This is supported by indirect evidence from 
nonclinical studies with NVP-BEZ235, a dual PI3K/mTOR inhibitor, and rapamycin in RCC cell 
lines and murine xenograft models. In these investigations, NVP-BEZ235 was associated with 
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more profound reduction in tumor size and more complete inhibition of phosphorylation of 
TORC1/2 and PI3K substrates, including AKT, eukaryotic translation initiation factor 4E, and 
4E-BP1, than rapamycin [21]. Thus, the combination of MLN0128 and milled MLN1117 has the 
potential to improve MLN0128 treatment response in mccRCC through a more complete and 
prolonged inhibition of this signaling pathway.
Clinical Experience of MLN1117 in Combination With MLN0128
MLN1117 is in clinical development for the treatment of advanced non-hematologic tumors, as a 
single agent (Study INK1117-001) and in combination (Study C32001). These studies have been 
designed to investigate the safety, pharmacokinetics (PK), pharmacodynamics, and preliminary 
efficacy of MLN1117, either as a single agent or in combination with MLN0128.
Potential overlapping toxicities associated with MLN0128 and MLN1117, and the identified and 
potential risks of both drugs, including data from nonclinical and clinical studies for each product, 
have been reviewed. More detailed information on the identified and potential risks of both drugs 
is included in the individual, single-agent IBs. Class effects of mTOR inhibitors (for MLN0128) 
and PI3K inhibitors (for MLN1117) have also been considered. Potential overlapping toxicities for 
both agents include:

Dermatologic disorders (pruritus, rash).

Gastrointestinal (GI) disorders (diarrhea, mucosal inflammation, nausea, stomatitis, vomiting).

Generalized disorders (anorexia, asthenia, decreased appetite, fatigue).

Hematologic disorders (lymphoid, bone marrow depletion).

Metabolic disorders (decreased blood chloride, hypercholesterolemia, hyperglycemia).
On the basis of current clinical experience, and the previous list of potential overlapping toxicities, 
hyperglycemia, diarrhea, nausea, vomiting, fatigue, and rash are the most anticipated adverse 
events (AEs) associated with the MLN0128+MLN1117 combination regimen. These events are 
expected to be manageable.
Further details are presented in the current edition of the MLN0128, MLN0128+MLN1117, and 
MLN1117 IBs.
Preliminary PK of MLN0128
The PK parameters measured for unmilled MLN0128 active pharmaceutical ingredient in the 
phase 1 clinical studies have been generally consistent across a range of doses and multiple 
schedules. MLN0128 has shown linear PK and fast oral absorption with first time of occurrence of 
maximum (peak) concentration occurring between 1 and 4 hours after a single dose. The mean 
half-life of MLN0128 is approximately 8 hours, and no accumulation has been observed in plasma 
after repeat daily dosing.
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4.2
Rationale for the Proposed Study
A TORC1/2 inhibitor would be expected to provide more complete inhibition of the mTOR 
pathway than a rapalog, and the combination of a PI3Kα inhibitor with a TORC1/2 inhibitor would 
be expected to provide more robust inhibition of the mTOR and growth factor signaling pathways 
than either agent alone. This randomized, open-label, 3-arm investigation of MLN0128, 
MLN0128+MLN1117, and everolimus will test the hypothesis that TORC1/2 inhibition, either 
with or without additional PI3Kα inhibition, will provide better efficacy compared with 
single-agent rapalog inhibition of TORC1 in patients with mccRCC and progressive disease after 
VEGF-targeted therapy.
4.2.1
Rationale for the Doses and Schedule in Arm B
The selected dose and schedule for Arm B of 30 mg MLN0128 every week (QW) is based on the 
findings from 2 studies: Study INK128-001 and Study MLN0128-1004. 
Study INK128-001was the first-in-human study of MLN0128. Study INK128-001 was an 
open-label study designed to determine the maximum tolerated dose (MTD) and to identify 
dose-limiting toxicities (DLTs) 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 (2-40 mg via 4 dosing schedules) in the dose escalation phase.
Doses of 40 mg QW, 30 mg QW, and 5 mg once daily (QD) were further evaluated in an additional 
82 patients in the expansion phase.
Improved tolerability, including a reduced frequency of TEAEs leading to dose interruptions and 
modifications, respectively (5 mg QD [26% and 67%] vs 30 mg QW [24% and 41%] vs 40 mg QW 
[19% and 77%] as of a data cut on 09 December 2015), and longer duration of clinical benefit 
favored 30 mg QW dosing as a recommended phase 2 dose (RP2D) and schedule for further 
development.
With the introduction of milled MLN0128, the recommended dose to be used in Arm B 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
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 the 
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PK of MLN0128 were noted between the unmilled MLN0128 (Study INK128-001) and milled 
MLN0128 (Study MLN0128-1004) when given QW. 
4.2.2
Rationale for the Doses and Schedule in Arm C 
The dose and schedule selected for Arm C of 4 mg MLN0128 plus 200 mg of MLN1117 (both 
once daily for 3 days each week [QD3 QW]) are based on the results of Study C32001 conducted 
under IND 117,524. Study C32001 is an ongoing, open-label study designed to determine the 
MTD and DLTs for oral administration of milled MLN0128 given in combination with MLN1117 
and was designed to characterize the safety and tolerability of escalating doses of MLN0128 
and/or MLN1117 in patients with advanced solid tumors. The study featured a dose-escalation 
phase evaluating 3 dosing schedules. A favorable tolerability profile was observed when 
increasing doses of MLN0128 (3 to 8 mg) were administered with a fixed dose of MLN1117 (both 
given QD3 QW). The MTD for MLN0128 in combination with MLN1117 both given QD3 QW 
was 6 mg MLN0128+200 mg MLN1117 (Table 4.b). 
Table 4.b
DLT Observed With MLN0128 Plus MLN1117 (3 Days Per Week) in Study 
C32001
Dose of Milled 
MLN0128+MLN1117
Number of Evaluable 
Patients
DLTs Observed in Cycle 1
6 mg+200 mg QD3 QW
6
1 patient experienced DLT of aspartate aminotransferase/ 
alanine aminotransferase elevation)
4 mg+200 mg QD3 QW
8
None
While both combination dose levels were considered safe on the basis of 3+3 rules, the lower dose 
level of 4 mg+200 mg QD3 QW was chosen as the RP2D for milled MLN0128+MLN1117 for 
further development.
The mechanistic justification for comparing the effectiveness of either single-agent MLN0128 or 
the combination of MLN0128 and MLN1117 with that of everolimus in patients with RCC is 
outlined in detail in Section 7.0.
Briefly, a TORC1/2 inhibitor like MLN0128 would be expected to provide more complete 
inhibition of the mTOR pathway than a rapalog (eg, everolimus as an allosteric TORC1 inhibitor), 
and the combination of a PI3Kα inhibitor (MLN1117) with a TORC1/2 inhibitor (MLN0128) 
would be expected to provide more robust/sustained inhibition of the mTOR and growth factor 
signaling pathways than either agent alone. This randomized, open-label, 3-arm investigation of 
MLN0128, MLN0128+MLN1117, and everolimus will test the hypothesis that TORC1/2 
inhibition, either with or without additional PI3Kα inhibition, will provide better efficacy 
compared with single-agent rapalog inhibition of TORC1 in patients with mccRCC and 
progressive disease after VEGF-targeted therapy.
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4.3
Potential Risks and Benefits
The most common TEAEs observed with MLN0128 are consistent with the pharmacodynamic 
mechanism of mTOR inhibition that is also seen with rapalogs (TORC1 inhibition) or other dual 
mTORC1/2 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. 
Potential overlapping toxicities associated with MLN0128 and MLN1117 and the identified and
potential risks of both drugs, including data from nonclinical and clinical studies for each product, 
have been reviewed. More detailed information on the identified and potential risks of both drugs 
is included in the individual single-agent IBs. Class effects of mTOR inhibitors (for MLN0128) 
and PI3K inhibitors (for MLN1117) have also been considered. Potential overlapping toxicities for 
both agents include:

Dermatologic disorders (pruritus, rash).

GI disorders (diarrhea, mucosal inflammation, nausea, stomatitis, vomiting).

Generalized disorders (anorexia, asthenia, decreased appetite, fatigue).

Hematologic disorders (lymphoid, bone marrow depletion).

Metabolic disorders (decreased blood chloride, hypercholesterolemia, hyperglycemia).
On the basis of current clinical experience and the previous list of potential overlapping toxicities, 
hyperglycemia, diarrhea, nausea, vomiting, fatigue, and rash are the most anticipated TEAEs 
associated with the MLN0128+MLN1117 combination regimen. These events are expected to be 
manageable.
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 management and prophylaxis of potential toxicities, criteria for dose modification, 
and regular monitoring of TEAEs and serious adverse events (SAEs) by the sponsor. 
The benefits of MLN0128 and MLN0128+MLN1117 are discussed in Section 4.1.2.
Further details are presented in the current editions of the MLN0128, MLN0128+MLN1117, and 
MLN1117 IBs.
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5.0
STUDY OBJECTIVES
5.1
Primary Objectives
The primary objectives of the study are:

To compare the efficacy of single-agent MLN0128 versus single-agent everolimus in patients 
with mccRCC.

To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent 
everolimus in patients with mccRCC. 
5.2
Secondary Objectives
The secondary objectives of the study are:

To assess the safety and tolerability of MLN0128 and MLN0128+MLN1117.

To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent 
MLN0128 in patients with mccRCC. 

To evaluate the efficacy (endpoints other than PFS; ie, overall survival [OS], 
time-to-progression [TTP], objective response rate [ORR], and clinical benefit rate [CBR]) 
among the 3 treatment groups.

To collect plasma concentration-time data with sparse PK sampling to contribute to future 
population PK analysis.
5.3
Quality of Life Objective
The health-related quality of life (QOL) objective is:

To assess the health-related QOL and symptoms as measured by the European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 
(EORTC-QLQ-C30) and the Functional Assessment of Cancer Therapy Kidney Symptom 
Index-Disease-Related Symptoms (FKSI-DRS) questionnaire among the 3 treatment groups.
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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:

The number and percentage of patients with TEAEs.

OS.

TTP.

ORR (defined as complete response [CR]+partial response [PR] per Response Evaluation 
Criteria in Solid Tumors [RECIST] version 1.1).

CBR (defined as CR+PR+stable disease [SD]) with SD of any duration, and CBR with SD 
duration of at least 4 months.
6.3
QOL Endpoints
The health-related QOL endpoints are:

Changes from Baseline in functional and symptom scores, and global health status and QOL 
score from the EORTC QLQ-C30 and symptom scales from the FKSI-DRS questionnaire.
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7.0
STUDY DESIGN
7.1
Overview of Study Design
This is a phase 2, open-label study of the safety and efficacy of MLN0128, as a single agent and in 
combination with MLN1117, in adult patients with advanced or mccRCC that has progressed on 
VEGF-targeted therapy. Eligibility will be determined during the Screening period, which may 
last for up to 28 days before the Cycle 1 Day 1 visit. Patients who meet all eligibility criteria and 
provide written informed consent will be enrolled in this study. Approximately 189 patients who 
meet the eligibility criteria will be stratified according to the number of prior lines of therapy 
(1, >1 prior line) and the International Metastatic Renal Cell Carcinoma Database Consortium risk 
category (favorable, intermediate, or poor) [22], and will be randomized at a ratio of 1:1:1 to one of 
3 treatment arms:

Arm A: single-agent everolimus.

Arm B: single-agent MLN0128.

Arm C: combination of MLN0128+MLN1117.
Patients will receive study drug(s) (ie, MLN0128, MLN1117, and everolimus) in 28-day cycles. 
Patients in Arm A will receive everolimus 10 mg QD according to current prescribing information 
in either the United States Prescribing Information (USPI) [23] or Summary of Product 
Characteristics (SmPC) [24] for everolimus. Patients in Arm B will receive MLN0128 30 mg 
orally once weekly (on Days 1, 8, 15, and 22 of a 28-day treatment cycle). Patients in Arm C will 
receive MLN0128 4 mg and MLN1117 200 mg orally both QD3 days per week (on Days 1-3, 
8-10, 15-17, and 22-24 of a 28-day treatment cycle). Patients will receive MLN0128, 
MLN0128+MLN1117, or everolimus until they experience disease progression or unacceptable 
toxicity, withdraw consent, die, or transfer to the Post-Trial Access (PTA) program. The study 
design is displayed in Figure 7.a.
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Figure 7.a
Study Design
The rationale for the planned doses for Arm B and Arm C are described in Section 4.2.1. 
Radiographic tumor evaluations will be performed by contrast-enhanced computed tomography 
(CT) scan with intravenous (IV) contrast or magnetic resonance imaging (MRI) with IV contrast, 
unless contraindicated. CT of the chest, and CT or MRI of the abdomen and pelvis, will be used to 
evaluate disease response according to RECIST version 1.1 [25]. Supplemental x-ray and/or bone 
scanning may be performed, but these methods are not suitable for lesion measurement. 
Radiographic tumor evaluations will be performed at the time points specified in Appendix A
Schedule of Events.
Study data will be reviewed after the first 30 patients in each arm have received 2 cycles of study 
drug. If at the end of Cycle 2, 50% or more patients in a treatment arm (ie, Arm B [single agent 
MLN0128] or Arm C [MLN0128+MLN1117]) have either progressive disease or have died, or 
have discontinued study treatment due to treatment-related AEs, then that study arm may be 
closed. If both Arms B and C meet these criteria, then the study may be closed.
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Throughout the study, toxicity will be evaluated according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03, effective date 
14 June 2010 [26]. Dose modification guidelines are in Section 9.3.
AEs will be assessed, and clinical laboratory values, vital signs, and electrocardiograms (ECGs) 
will be obtained to evaluate the safety and tolerability of single-agent MLN0128 and 
MLN0128+MLN1117 in combination.
Sparse PK samples will be collected in Cycle 1 from all patients enrolled in Arms B and C for 
plasma PK analysis of MLN0128 (Arms B and C) and MLN1117 (Arm C). Blood samples for all 
PK analyses will be collected at the time points specified in the Treatment Arm B Sparse 
Pharmacokinetic Sample Breakdown and Treatment Arm C Sparse Pharmacokinetic Sample 
Breakdown.
Data generated in this study may be combined with data from other studies, in which the PK of 
MLN0128 or MLN1117 is characterized for a future population PK analysis.
7.2
Number of Patients
The study planned to enroll approximately 189 patients with mccRCC from approximately 60 to 
70 study centers in North America and Europe. A patient is considered to be enrolled in the study 
when he or she has been randomized into a treatment arm.
7.3
Duration of Study
Patients will receive study medication(s) until disease progression, unacceptable toxicity, 
withdrawal of consent, or study closure. 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 less than 30 days after the 
last dose of study drug.
A final analysis of PFS will be performed after the required number of events has been observed, 
which is expected approximately 9 months after the last patient has been randomized. 
The study will be closed 2 years after the last 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. Male or female patients aged 18 years or older.
2. Histologically confirmed RCC with a clear-cell component.
3. Evidence that the RCC is advanced or metastatic.
4. Radiologic evidence of progressive disease (according to RECIST version 1.1) either during or 
within 6 months after stopping their most recent systemic therapy for RCC before enrollment 
into this study.
5. At least 2 prior lines of systemic therapy for advanced metastatic ccRCC, including at least 1 
prior line of VEGF-targeted therapy, but not more than 4 total prior lines of systemic therapy. 
Exposure to more than 1 line of VEGF-targeted therapy is acceptable. Patients may also have 
received prior therapies with interferon, IL-2, anti-PD1 antibodies, cabozantinib, or other 
experimental agents, but not prior therapy with any agent that targets PI3K, AKT, or mTOR. 
6. Karnofsky performance status ≥70% (refer to Appendix D).
7. Life expectancy of ≥3 months.
8. Female patients who:

Are postmenopausal for at least 1 year before the Screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method (See Appendix E), at the same 
time, from the time of signing the informed consent through 90 days (or longer, as 
mandated by local labeling [eg, USPI, SmPC, etc]) after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice highly effective barrier contraception during the entire study treatment 
period and through 120 days after the last dose of study drug (or longer, as mandated by 
local labeling [eg, USPI, SmPC, etc]), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea 
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are not acceptable methods of contraception. Female and male condoms should not be used 
together.)

Agree not to donate sperm during the course of this study or within 120 days after receiving 
their last dose of study drug.
9. Suitable venous access for the study-required blood sampling.
10. Screening clinical laboratory values as specified below: 

Absolute neutrophil count (ANC) 2000/L and platelet count 100,000/L.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 times the 
upper limit of the normal range (ULN).

Total bilirubin 1.5ULN.

Estimated creatinine clearance by Cockcroft-Gault ≥40 mL/min/1.73m2 (see Appendix F).

Glycosylated hemoglobin(HbA1c) <7.0%, fasting serum glucose 130 mg/dL, and fasting 
triglycerides 300 mg/dL.
11. At least 14 days since the end of prior systemic VEGF-targeted treatment (ie, sunitinib, 
pazopanib, axitinib, or sorafenib), radiotherapy, or surgical procedure with resolution of all 
treatment-related toxicity (except alopecia and hypothyroidism) either to Grade 0 or 1 
(NCI CTCAE version 4.03) or to Baseline.
12. At least 21 days since the last dose of bevacizumab, other antibody, or interferon.
13. Voluntary written consent must be given before performance of any study-related procedure 
not part of standard medical care, with the understanding that consent may be withdrawn by 
the patient at any time without prejudice to future medical care.
8.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Central nervous system (CNS) metastasis.
2. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active 
CNS disease, active infection, or any other condition that might compromise the patient’s 
participation in the study.
3. Known human immunodeficiency virus infection.
4. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C 
infection.
5. Manifestations of malabsorption due to prior GI surgery, GI disease, or for an unknown reason 
that may alter the absorption of everolimus, MLN0128, or MLN1117. In addition, patients 
with enteric stomata are excluded.
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6. Women who are either breast feeding or pregnant.
7. History of any of the following within the last 6 months before administration of 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 G).

Pulmonary embolism.
8. Significant active cardiovascular or pulmonary disease including:

Uncontrolled hypertension (ie, either systolic blood pressure >160 mm Hg or diastolic 
blood pressure >95 mm Hg). Use of antihypertensive agents to control hypertension before 
Cycle 1 Day 1 is allowed.

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 the rate-corrected QT interval (QTc; eg, repeated demonstration 
of QTc interval >480 msec, or history of congenital, long-QT syndrome, or torsades de 
pointes).
9. Diagnosed or treated for another malignancy within 2 years before administration of the first 
dose of study drug, or previously diagnosed with another malignancy and have any evidence of 
residual disease. Patients with nonmelanoma skin cancer, superficial bladder cancer, very low 
risk prostate on observation, or carcinoma in situ of any type are not excluded if they have 
undergone complete resection.
10. Prior therapy with agents that target PI3K, AKT, or mTOR. Patients with known 
hypersensitivity to everolimus or rapamycin derivatives are also excluded.
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11. Any serious medical or psychiatric illness that could, in the investigator’s opinion, potentially 
interfere with the completion of treatment according to this protocol.
12. Patients who have taken a PPI within 3 days before receiving the first dose of study drug.
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9.0
STUDY DRUG
9.1
Study Drug Administration
All protocol-specific criteria for administration of MLN0128 or MLN1117 must be met and 
documented before study drug administration. Study drug will be administered only to eligible 
patients under the supervision of the investigator or identified subinvestigator(s).
For Arm B, 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 orally with approximately (at least) 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
For Arm C, MLN0128 and MLN1117 will be administered on an empty stomach. 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. Each dose of MLN0128 and MLN1117 will be given 
orally with approximately (at least) 8 ounces (240 mL) of water.
Cycles consist of 28 days for all treatment arms. In Treatment Arm A, everolimus will be 
administered QD (every day of a 28-day treatment cycle). In Treatment Arm B, MLN0128 will be 
administered once weekly (on Days 1, 8, 15, and 22 of a 28-day treatment cycle) and should be 
taken on the same day of each week. In Treatment Arm C, MLN0128 and MLN1117 will be 
administered together, 3 consecutive days per week (on Days 1-3, 8-10, 15-17, and 22-24 of a 
28-day treatment cycle), and should be taken on the same days of each week. 
Patients should be instructed to take their study medication at approximately the same time on each 
scheduled dosing day and not to take more than the prescribed dose at any time. MLN0128 and 
MLN1117 should always be taken together, at the same time, when dosed on the same day. 
Patients should swallow the study medication whole and not chew it, open it, or manipulate it in 
any way before swallowing. If a patient does not take their MLN0128 and/or MLN1117 doses 
within 12 hours after the scheduled dosing time (for patients in Arm A or C) or within 24 hours 
after the scheduled dosing time (for patients in Arm B), then the dose should be skipped and 
considered a missed dose. Patients should record any missed doses in their diary (see the Study 
Manual) and resume drug administration at the next scheduled time with the prescribed dosage.
If severe emesis or mucositis prevents the patient from taking scheduled doses, that dose will be 
skipped. If emesis occurs after study medication ingestion, the dose will not be readministered, and 
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patients should resume dosing at the next scheduled time with the prescribed dosage. Patients 
should record the occurrence of the emesis in their dosing diaries (see the Study Manual). Under 
no circumstance should a patient repeat a dose or double-up doses.
9.2
Reference/Control Therapy 
Everolimus can be taken either with or without food according to either the USPI [23] or SmPC 
[24]. Patients should be instructed to take their study medication at approximately the same time 
on each scheduled dosing day and not to take more than the prescribed dose at any time. 
9.3
Dose Modification Guidelines
This section describes dose modification guidelines for study drugs MLN0128 and MLN1117. 
Any dose modifications for everolimus should follow the guidelines provided in the current USPI 
[23] or SmPC [24] for everolimus. Refer to Section 9.7 for dose adjustment guidelines related to 
the management of clinical events. 
9.3.1
Intrapatient Dose Escalation
Intrapatient dose escalation is not allowed. 
9.3.2
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
MLN0128 and MLN1117 should be administered in continuous cycles, which should continue 
unless the patient has a Grade 3 or greater MLN0128- and/or MLN1117-related event. Guidelines 
for dose interruption are in Section 9.3.3 and for dose reduction are in Section 9.3.4. 
9.3.3
Criteria for Dose Interruption During a Cycle
Administration of MLN0128 and the combination of MLN0128+MLN1117 should be withheld 
for treatment-related toxicities that are Grade 3 or higher despite supportive treatment per standard 
clinical practice. 
The following nonhematologic toxicities attributed to either MLN0128 or MLN1117 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-HT3 antagonist and a corticosteroid given in standard doses and according to standard 
schedules.)

Grade 3 or higher diarrhea that occurs in the absence of optimal supportive therapy.

Grade 3 fatigue.
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9.3.4
Criteria for Dose Reduction
9.3.4.1
Single-Agent MLN0128 Once Weekly (Arm B)
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 
Grade 2 for hyperglycemia or rash, as detailed in Sections 9.7.1 and 9.7.4, respectively) 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 10 mg, then the 
investigator and the project clinician should discuss whether the patient would benefit from a 
further dose reduction.
Table 9.b
Dose Modifications for Single-Agent MLN0128
Dose Level
Dose Regimen 
MLN0128 Capsules: Number and Strength
0
30 mg QW
Six 5-mg capsules 
1
20 mg QW
Four 5-mg capsules 
2
15 mg QW
Three 5-mg capsule 
3
10 mg QW
Two 5-mg capsules 
9.3.4.2
MLN0128+MLN1117 (Arm C)
The primary principle for dose reduction in Arm C is to maintain the 200 mg dose of MLN1117, 
which is considered the minimum efficacious dose when combined with MLN0128. Thus, the 
dose of MLN0128 will be reduced, if necessary, while the dose and schedule of MLN1117 is 
maintained when study drug administration is resumed (Table 9.c).
If the Grade 3 or higher event that led to dose interruption resolves to Grade 1 (or Grade 2 for 
hyperglycemia or rash, as detailed in Sections 9.7.1 and 9.7.4, respectively) or baseline value 
within 3 weeks of interrupting treatment, then the patient may resume combination study treatment 
provided that treatment with study drug is thought to be beneficial for the patient by the 
investigator and with the sponsor’s approval. In this case, the patient may resume study treatment 
with MLN1117 at 200 mg QD×3 days and MLN0128 reduced by 1 dose level; for interruptions 
due to Grade 3 elevations of ALT or AST, study treatment may be resumed at the prior dose 
without dose reduction (Section 9.7.8).
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Table 9.c
Dose Modifications for MLN0128 in Combination with MLN1117
Dose Level
Dose QD×3 days per week
MLN0128 Capsules: Number and Strength 
MLN0128
MLN1117 
0
4 mg
200 mg
One 3 mg capsule and one 1 mg capsule
1
3 mg
200 mg
One 3 mg capsule
2
2 mg
200 mg
Two 1 mg capsules
3
1 mg
200 mg
One 1 mg capsule
9.3.5
Criteria for Discontinuation of Study Drug
For patients in Arm A, everolimus should be discontinued according to the current guidance 
provided in either the USPI [23] or SmPC [24] for everolimus.
If study drug administration (in Arm B or Arm C) 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, then study 
drug treatment should be stopped. However, if the patient has evidence of clinical benefit and is 
considered to possibly benefit from continued protocol treatment, the patient may continue 
protocol treatment with further dose reductions, upon review and approval by the project clinician, 
or participate in the PTA program if available. 
For all patients, the EOT visit should be completed within 30 to 40 days after the last dose of study 
drug. 
9.4
Excluded Concomitant Medications and Procedures
9.4.1
Excluded Concomitant Medications and Procedures for Arm A 
The current USPI [23] and SmPC [24] for everolimus list the excluded medications for patients 
receiving everolimus in Arm A of the study. 
In addition, these specific exclusions also apply to Arm A:

Other investigational agents including mTOR, PI3K, 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). Palliative therapy for target lesions is not allowed.

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.
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9.4.2
Excluded Concomitant Medications and Procedures for Arms B and C 
All prescription and over-the-counter medications, including influenza vaccines, taken by a patient 
as of the first administration of study drug through 30 days following the last dose will be recorded 
on the designated electronic case report form (eCRF).
The following medications, therapies, and procedures are prohibited during the study:

Other investigational agents including mTOR, PI3K, 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, excluding inhalers), unless necessary for 
treatment of a study drug-related AE (eg, rash).

Strong cytochrome P450 (CYP) 1A2 inhibitors and CYP inducers should be administered only 
with caution and at the discretion of the investigator (see Appendix H for a list of these agents). 
Alternative treatments, if available, should be considered.

Concomitant administration of any PPI is prohibited only for patients randomized to 
MLN0128 + MLN1117. Patients receiving PPI therapy before enrollment must stop using the 
PPI 3 days before their first dose of study drugs. 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 and within 6 hours after MLN0128 
or MLN0128+MLN1117 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 H).

Administration of neutralizing antacids and calcium preparations is permitted except from 
4 hours before until 2 hours after MLN0128 or MLN0128+MLN1117 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.
9.4.3
Potential for Drug-Drug Interactions with MLN0128 and/or MLN1117
On the basis of in vitro drug metabolism studies, MLN1117 is primarily metabolized by CYP3A4 
(72%), with minor contributions from CYPs 1A2 (12%), 2C9 (9%), and 2C8 (6%). Recently 
completed in vitro metabolism experiments in human hepatocytes using 14C-labeled MLN0128 
suggest that MLN0128 is metabolized primarily via CYP1A2 (approximately 31%-40%), with a 
minor contribution from CYP3A4 (approximately 11%-22%). These data suggest that MLN0128 
is also metabolized by direct glucuronidation (approximately 22%) and an unidentified nonuridine 
diphosphate glucuronosyltransferase pathway (approximately 18%). The new data differ from the 
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previous in vitro CYP phenotyping data obtained using recombinant CYP enzymes, which 
suggested the involvement of CYP2C9 (approximately 35%), CYP2C19 (approximately 28%), 
and CYP3A4 (approximately 28%) in MLN0128 metabolism. Neither MLN1117 nor MLN0128 
inhibits or induces any of the major CYP enzymes. On the basis of this information, the risk of a 
drug-drug interaction between MLN1117 and MLN0128 is considered to be low. In addition, 
physiologically based PK modeling and simulation using the new metabolism data for MLN0128 
suggest that the risk for a metabolism-based drug-drug interaction with MLN0128 appears to be 
low. Therefore, strong CYP1A2 inhibitors and CYP inducers should be administered with caution 
and at the discretion of the investigator during the study (see Appendix H).
There is potential for MLN1117 to affect the PK of breast cancer resistance protein (BCRP) 
substrates (eg, methotrexate, imatinib, topotecan, lapatinib, rosuvastatin, etc) and organic cation 
transporter protein 1 (OCT1) or organic cation transporter protein 2 (OCT2) substrates 
(eg, metformin, cimetidine, amantadine, famotidine, pindolol, etc; see Appendix I). If patients 
require treatment with medications that are known substrates of these transporters, then these 
agents should be administered with caution or alternative treatment options should be considered. 
It is recommended that patients requiring metformin for treatment of hyperglycemia resulting 
from MLN0128+MLN1117 administration that treatment should begin with the lowest effective 
dose of metformin, and patients should have their blood or serum glucose monitored closely. 
9.5
Permitted Concomitant Medications and Procedures 
Prophylactic use of antiemetic, antinausea, and antidiarrheal medications is encouraged, and these 
may be administered before the first dose and subsequent doses of study drug, as needed 
throughout the study, and as clinically indicated per standard practice. 
Other medications considered necessary for the safety and wellbeing of the patient may be 
administered at the discretion of the investigator. Any concomitant medications added or 
discontinued during the study should be recorded on the eCRF.
9.6
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 are intranasal influenza, 
measles, mumps, rubella, oral polio, Bacille Calmette-Guerin, yellow fever, varicella, and TY21a 
typhoid vaccines.
No dietary restrictions will be imposed on study patients other than fasting for glucose monitoring 
(refer to Sections 9.7.1, 10.4.13, and 10.4.14). Patients receiving MLN0128 and MLN1117 in Arm 
C should refrain from eating or drinking for 2 hours before and 1 hour after each dose (per 
Section 9.1).
Patients who show evidence of hyperglycemia during the study should be encouraged to follow a 
low-carbohydrate diet.
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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.
It is not known what effects either MLN0128 or MLN1117 has on human pregnancy or 
development of the embryo or fetus. Therefore, female patients participating in this study should 
avoid becoming pregnant, and male patients should avoid impregnating a female partner. 
Nonsterilized female patients of reproductive age group and male patients should use effective 
methods of contraception through defined periods and after study treatment as specified below. 
Female patients must meet one of the following:

Postmenopausal for at least 1 year before the Screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method (See Appendix E), at the same time, 
from the time of signing of the informed consent through 90 days (or longer, as mandated by 
local labeling [eg, USPI, SmPC, etc]) after the last dose of study drug, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.) 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to one of the 
following:

Agree to practice highly effective barrier contraception during the entire study treatment
period and through 120 days after the last dose of study drug (or longer, as mandated by local 
labeling [eg, USPI, SmPC, etc]), OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)

Agree not to donate sperm during the course of this study or within 120 days after receiving 
their last dose of study drug.
9.7
Management of Clinical Events 
For current guidance on the management of clinical events for patients receiving everolimus in 
Arm A, refer to either the USPI [23] or SmPC [24] for everolimus. 
For patients being treated with single-agent MLN0128 QW (Arm B), 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 Grade 2 for 
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hyperglycemia or rash, as detailed in Sections 9.7.1 and 9.7.4, respectively) 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).
For patients being treated with MLN0128+MLN1117 (Arm C), the primary principle for dose 
reduction is to maintain the 200 mg dose of MLN1117, which is considered the minimum 
efficacious dose when combined with MLN0128. Thus, the dose of MLN0128 will be reduced, if 
necessary, while the dose and schedule of MLN1117 is maintained when study drug 
administration is resumed (Table 9.c).
If the Grade 3 or higher event that led to dose interruption resolves to Grade 1 (or Grade 2 for 
hyperglycemia or rash, as detailed in Sections 9.7.1 and 9.7.4, respectively) or baseline value 
within 3 weeks of interrupting treatment, then the patient may resume combination study treatment 
with MLN1117 at 200 mg QD×3 days and MLN0128 reduced by 1 dose level.
9.7.1
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, 
consider initiating treatment with an oral hypoglycemic agent, such as metformin. All patients 
with ≥Grade 2 hyperglycemia (fasting glucose >160 mg/dL) must be treated aggressively with oral 
hypoglycemic agents and/or insulin as clinically indicated. The investigator should consult an 
endocrinologist, if needed, to aid in optimizing the patient’s hyperglycemia treatment plan.
It is recommended that patients be initially treated with a fast-acting insulin sensitizer such as 
metformin at 500 mg orally QD, and titrate up to a maximum of 1000 mg orally twice daily as 
needed. Concurrent addition to metformin of dipeptidyl peptidase-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.d) are 
provided to aid the investigator in initiating antiglycemic therapies.
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Table 9.d
Management of Hyperglycemia
Grade
Description
Treatment
Dose Modification
1
Fasting blood sugar 
>ULN to 160 mg/dL

Continue close monitoring of blood 
sugar.

Initiate oral hypoglycemic agent.
None
2
>160 to 250 mg/dL

Initiate oral hypoglycemic agent and/or 
insulin if not well controlled on oral 
agent.
None
≥3
>250 mg/dL

Initiate oral hypoglycemic agent and/or 
insulin.
Hold study drug(s) until ≤Grade 2. 
(a)
Resume study drug based on timing 
of recovery after maximal 
treatment: 

≤1 week: resume study drug at 
same dose and schedule.

>1 but ≤2 weeks: reduce the 
dose of MLN0128 by 1 dose 
level (See Section 9.3.4). (b)

>2 weeks: stop study drug(s).
Prevention/Prophylaxis:

Follow fasting 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 or 2 hyperglycemia respond quickly to oral metformin. Early initiation of therapy at the 
lowest therapeutic dose is recommended to prevent higher-grade hyperglycemia.

Fasting blood glucose levels ≥150 mg/dL by glucometer should be followed by closer monitoring of serum 
glucose and possible intervention. 
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held.
(b) As described in Section 9.3.4 and Section 9.7, dose reduction applies only to MLN0128 treatment. The dose of 
MLN1117 should be maintained at 200 mg when resuming treatment after an interruption of study drug or dose 
modification of MLN0128.
9.7.2
Management of Hyperlipidemia
Guidance on study drug dose modification for patients with hyperlipidemia is provided in 
Table 9.e.
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Table 9.e
Management of Hyperlipidemia
Grade
Description
Treatment
Dose Modification
1
Cholesterol:
>ULN-300 mg/dL
Triglycerides:
>150-300 mg/dL
None
None
2
Cholesterol:
>300-400 mg/dL
Triglycerides:
>300-500 mg/dL 
Treat hyperlipidemia according 
to standard guidelines.
Triglycerides ≥500 mg/dL 
should be treated urgently, 
due to risk of pancreatitis.
Maintain dose, if tolerable.
If toxicity becomes intolerable, 
interrupt study drug(s) until 
recovery to ≤Grade 1. Re-initiate 
study drug(s) at the same dose 
level. (a)
3
Cholesterol:
>400-500 mg/dL
Triglycerides:
>500-1000 mg/dL
Same as for Grade 2.
Hold study drug(s) until recovery 
to ≤Grade 1, then reinitiate study 
drug(s) with the dose of 
MLN0128 reduced by 1 level 
(Section 9.3.4). (a) (b)
4
Cholesterol:
>500 mg/dL
Triglycerides:
>1000 mg/dL
Same as for Grade 2.
Same as for Grade 3.
Prevention/Prophylaxis:

Recommend lifestyle modifications, as appropriate (balanced diet, limit alcohol consumption, increase physical 
activity).
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held.
(b) As described in Section 9.3.4 and Section 9.7, dose reduction applies only to MLN0128 treatment. The dose of 
MLN1117 should be maintained at 200 mg when resuming treatment after an interruption of study drug or dose 
modification of MLN0128.
9.7.3
Management of Oral Mucositis
Guidance on study drug dose modification for patients with oral mucositis is provided in Table 9.f.
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Table 9.f
Management of Oral Mucositis
Grade
Description
Treatment
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 study drug(s) dose if 
tolerable. (a)

Hold study drug(s) if 
intolerable until recovery to 
≤Grade 1, then restart at same 
dose.
3
Severe pain, interfering with 
oral intake.

Same as for Grade 2.

Consider intralesional 
corticosteroids.

Hold study drug(s) until 
recovery to ≤Grade 1, then 
restart study drug(s) with the 
dose of MLN0128 reduced by 
1 level (Section 9.3.4). (a) (b)
4
Life-threatening 
consequences.

Same as for Grade 2

Consider intralesional 
corticosteroids

Stop study drug(s). (a)
Prevention/Prophylaxis:

Initiation of a nonalcoholic mouth wash, or 0.9% salt water rinses 4 to 6 times daily is strongly recommended at 
the 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) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held. 
(b) As described in Section 9.3.4 and Section 9.7, dose reduction applies only to MLN0128 treatment. The dose of 
MLN1117 should be maintained at 200 mg when resuming treatment after an interruption of study drug or dose 
modification of MLN0128.
9.7.4
Management of Rash
Patients who develop Grade 4 rash should permanently discontinue study treatment, unless they 
derive clinical benefit, in which case they may be retreated at a reduced dose level after recovery to 
Grade 1 severity. Grade 4 rash is defined as rash acneiform/papulopustular with papules and/or 
pustules covering any percentage of body surface area, which may or may not be associated with 
symptoms of pruritus or tenderness, and are associated with extensive superinfection, with IV 
antibiotics indicated; life-threatening consequences (NCI CTCAE version 4.03, effective date 
14 June 2010 [26]). 
Guidance on study drug dose modification for patients with rash is provided in Table 9.g.
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Table 9.g
Management of Rash
Grade
Description
Treatment
Dose Modification
≤2
Macules/papules covering 
≤30% body surface area with 
or without symptoms.
Consider treatment with topical 
steroid cream/ointment and/or oral 
antihistamines or antibiotics.
None
3
Macules/papules covering 
30% body surface area with 
or without symptoms.
Consider treatment with topical 
steroid cream/ointment, oral 
antihistamines, oral antibiotics, 
and/or pulsed steroids.
Hold study drug(s) until ≤Grade 2. (a)
Resume study drug(s) based on timing 
of recovery:

≤3 weeks: reduce the dose of 
MLN0128 by 1 dose level 
(Section 9.3.4). (a) (b)

>3 weeks: stop study drug(s). (a)
Patients who develop Grade 4 rash should permanently discontinue study treatment, unless they derive clinical 
benefit, in which case they may be retreated at a reduced dose level after recovery to Grade 1 severity. Grade 4 rash 
is defined as rash acneiform/papulopustular with papules and/or pustules covering any percentage of body surface 
area, which may or may not be associated with symptoms of pruritus or tenderness, and are associated with extensive 
superinfection, with IV antibiotics indicated; life threatening consequences.
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.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held. 
(b) As described in Section 9.3.4 and Section 9.7, dose reduction applies only to MLN0128 treatment. The dose of 
MLN1117 should be maintained at 200 mg when resuming treatment after an interruption of study drug or dose 
modification of MLN0128.
9.7.5
Management of Nausea/Vomiting
Guidance for patients with nausea and/or vomiting is provided in Table 9.h.
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Table 9.h
Management of Nausea/Vomiting
Grade
Description
Treatment
Dose Modification
≤2
Loss of appetite with or without 
decreased oral intake; 
1 to 5 episodes of vomiting within 
24 hours.

Maximize antiemetic 
therapy.

Consider IV fluid 
hydration.
None
≥3
Inadequate oral intake; 
≥6 episodes of vomiting within 
24 hours.

Maximize antiemetic 
therapy.

Initiate tube feeding, IV
fluids, 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 study drug(s) 
until ≤Grade 1, then resume treatment 
with the dose of MLN0128 reduced 
by 1 level. (a) (b)
Prevention/Prophylaxis:
Prophylactic use of antiemetic, antinausea, and antidiarrheal medications are encouraged and may be used before each 
MLN0128+MLN1117 dosing as needed throughout the study.
IVF=intravenous fluids, TPN=total parental nutrition.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held. 
(b) As described in Section 9.3.4 and Section 9.7, dose reduction applies only to MLN0128 treatment. The dose of 
MLN1117 should be maintained at 200 mg when resuming treatment after an interruption of study drug or dose 
modification of MLN0128.
9.7.6
Management of Cardiac Abnormalities
Management of Patients With Possible Cardiac Instability
For patients showing signs of cardiac instability after MLN0128+MLN1117 administration, 
additional monitoring onsite before clinic discharge should be considered.
Management of Patients With Left Ventricular Dysfunction
Guidance for MLN0128+MLN1117 dose adjustment for patients with left ventricular dysfunction 
is provided in Table 9.i.
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Table 9.i
Management of Left Ventricular Dysfunction
Grade
Description
Dose Modification
1
Asymptomatic decline in:
LVEF >15% from baseline values, OR
LVEF >10% to 15% from baseline values and is 
below institution’s LLN.
No change; continue study drug(s) at the same dose 
and schedule. (a)
2
Symptomatic cardiac dysfunction/congestive heart 
failure.
Stop study drug(s). (a)
LLN=lower limit of normal, LVEF=left ventricular ejection fraction.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held.
Management of Patients with QTc Interval Prolongation
Patients who experience persistent symptomatic Grade 3 or Grade 4 QTc prolongation without 
another cause should permanently discontinue study treatment.
Guidance for MLN0128+MLN1117 dose adjustment for patients exhibiting a prolonged QTc 
interval is provided in Table 9.j.
Table 9.j
Management of QTc Interval Prolongation
Grade
Description
Treatment
Dose Modification
2
480 msec QTc 
501 msec
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication, etc).
None; continue study drug(s) at the same 
dose and schedule. (a)
3
QTc 501 msec
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication).(a)
Consider a formal consult by a cardiologist;
Notify the sponsor’s project clinician;
Additional ECGs may be performed at 
intervals that the treating physician deems 
clinically appropriate until repeated QTc 
measurements fall or are below the 
threshold interval that triggered the repeat 
measurement.
Hold study drug(s). (b)
Patients who experience persistent 
symptomatic Grade 3 or Grade 4 QTc 
prolongation without another cause should 
permanently discontinue study treatment.
(a) A list of medications known to prolong the QTc interval can be found at 
https://www.crediblemeds.org/new-drug-list/ 
(b) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held.
9.7.7
Management of Other Nonhematologic Toxicities
Guidance on dose adjustment for patients with other nonhematologic toxicities is provided in 
Table 9.k. 
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Patients who develop Grade 4 nonhematological toxicities (with the exception of isolated 
non-clinically significant laboratory values) should permanently discontinue study treatment, 
unless they derive clinical benefit, in which case they may be retreated at a reduced dose level after 
recovery to Grade 1 severity. 
Table 9.k
Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue)
Grade
Description
Treatment
Dose Modification
1
Mild; asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention 
not indicated.
Initiate appropriate medical 
therapy and monitor.
If tolerable, then no adjustment is 
required.
2
Moderate; minimal, local or 
noninvasive intervention 
indicated.
Initiate appropriate medical 
therapy and monitor.

If tolerable, no adjustment 
required.

If toxicity becomes intolerable, 
hold study drug(s) until recovery 
to ≤Grade 1, then reinitiate at 
same dose. 
≥3
Severe or medically significant 
but not immediately 
life-threatening; hospitalization or 
prolongation of hospitalization 
indicated
Hold study drug(s) until recovery to 
≤Grade 1. Reinitiate study drug(s) 
with the dose of MLN0128 reduced 
by 1 level (Section 9.3.4) (a) (b)
Patients who develop Grade 4 
nonhematological toxicities (with the 
exception of isolated non-clinically 
significant laboratory values) should 
permanently discontinue study 
treatment, unless they derive clinical 
benefit, in which case they may be 
retreated at a reduced dose level after 
recovery to Grade 1 severity.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held. 
(b) As described in Section 9.3.4 and Section 9.7, dose reduction applies only to MLN0128 treatment. The dose of 
MLN1117 should be maintained at 200 mg when resuming treatment after an interruption of study drug or dose 
modification of MLN0128.
9.7.8
Management of AST/ALT Elevations
Patients who develop Grade 3 or Grade 4 AST/ALT elevation in combination with Grade 2 total 
bilirubin elevation when alternative causes cannot be identified (ie, Hy’s Law) should permanently 
discontinue study treatment.
Guidance on dose adjustment for patients with AST/ALT elevations is provided in Table 9.l.
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Table 9.l
Management of AST/ALT Elevations
Grade
Description
Treatment
Dose Modification
1
>ULN to 3ULN
None
None
2
Asymptomatic with levels 3 to 
5ULN; >3ULN with the 
appearance of worsening fatigue, 
nausea, vomiting, right upper 
quadrant pain or tenderness, 
fever, rash, or eosinophilia.

Closely monitor LFTs at least 
weekly or more frequently as 
indicated.

Assess patient for other causes 
of transaminitis (eg, past 
medical history, concomitant 
medications).
None
3
>5 to 20ULN; >5ULN 
for >2 weeks
Same as for Grade 2. 
Hold study drug(s) until ≤Grade 1; 
Restart MLN0128 and MLN1117 at 
the same doses. (a)
Permanently discontinue study 
treatment if in combination with 
Grade 2 total bilirubin elevation 
when alternative causes cannot be 
identified.
4
>20ULN
Same as for Grade 2. 
Stop study drug(s). (a)
Prevention/Prophylaxis:
Ensure proper screening of patients for study participation.
LFTs=liver function tests.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held.
9.7.9
Management of Noninfectious Pneumonitis
Guidance for the management of pneumonitis is provided in Table 9.m.
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Table 9.m
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.
Interrupt study drug(s) 

When symptoms ≤Grade 1, 
reinitiate study drug(s) with 
the dose of MLN0128 
reduced by 1 level (Section 
9.3.4). 

If no recovery within 4 weeks, 
then discontinue study 
drug(s). (a,b)
3
Symptomatic:
Interfering with activities of daily living;
Requires administration of oxygen.
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1.
Interrupt study drug(s) until 
symptoms resolve to ≤Grade 1. (a)

Consider reinitiating study 
drug(s) with the dose of 
MLN0128 reduced by 1 level 
(Section 9.3.4). (b)

If toxicity recurs at Grade 3, 
discontinue study drug(s).
4
Life-threatening:
Ventilatory support indicated.
Rule out infection and 
consider treatment with 
corticosteroids.
Stop study drug(s). (a)
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117, then both 
agents should be held. 
(b) As described in Section 9.3.4 and Section 9.7, dose reduction applies only to MLN0128 treatment. The dose of 
MLN1117 should be maintained at 200 mg when resuming treatment after an interruption of study drug or dose 
modification of MLN0128.
9.7.10
Management of Opportunistic Infections
Opportunistic infections, such as Pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), are a 
known risk for patients receiving everolimus treatment; and prophylaxis for PJP/PCP should be 
considered when concomitant use of corticosteroids or other immunosuppressive agents is 
required (refer to Section 9.4 and Section 9.5 for guidance regarding concomitant medication use). 
Although opportunistic infections, including PCP, have not been observed in patients receiving 
MLN0128 or MLN1117 treatment, opportunistic infections should be considered during 
diagnostic evaluation of symptomatic patients.
9.7.11
Blinding and Unblinding
Not applicable. This is an open-label study.
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9.8
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), each containing 1, 3, and 5 mg of MLN0128, respectively, in addition to 
the following inactive ingredients: microcrystalline cellulose (solid filler/diluents), magnesium 
stearate (lubricant), and hard gelatin capsule.
All 3 dose strengths are formulated into size-2 capsules, and each dose strength is differentiated by 
color, as listed below:

1 mg MLN0128 capsules: white opaque.

3 mg MLN0128 capsules: Swedish orange opaque.

5 mg MLN0128 capsules: gray opaque.
MLN1117 will be supplied as 100 mg capsules for oral administration. Each 100 mg capsule 
contains 100 mg of MLN1117 and the following inactive ingredients: hard gelatin capsule and 
small amount of colloidal silicon dioxide. See the MLN0128, MLN1117, and 
MLN0128+MLN1117 IBs for full details. 
Everolimus is commercially available and will be supplied by Millennium as 10 mg, 5 mg, and 
2.5 mg tablets for oral administration.
9.9
Preparation, Reconstitution, and Dispensation
MLN0128 and MLN1117 dosage forms will be provided in labeled bottles in accordance with all 
applicable regulations. Materials provided by the sponsor should be dispensed to patients with 
clear administration instructions from the investigator.
MLN0128 and MLN1117 are anticancer drugs and, as with other potentially toxic compounds, 
caution should be exercised when handling MLN0128 and MLN1117 capsules.
9.10
Packaging and Labeling
MLN0128 and MLN1117 will be provided by Millennium and will be handled at the investigative 
site as open-label material.
MLN0128 will be provided in 30-ct, 60-cc high-density polyethylene (HDPE) bottles with 
polypropylene, child-resistant caps and induction seal. MLN1117 will be provided in 14-ct, 30-cc 
HDPE bottles with child-resistant caps and induction seal. 
MLN0128 and MLN1117 are packaged and labeled in accordance with all applicable regulations.
Everolimus will be supplied by Millennium to all participating sites. Everolimus will be provided 
as blister packs and will be labeled per all requirements specified by governing regulations.
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9.11
Storage, Handling, and Accountability
Upon receipt at the investigative site, MLN0128 and MLN1117 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 and MLN1117 supplies should be used 
before the retest expiry date. 
Everolimus should be stored according to instructions provided in the USPI [23] or SmPC [24].
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 and MLN1117 are an investigational agents, they 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 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 and 
MLN1117.
Patients will be instructed to return any unused study drug in the original packaging along with 
their completed diary cards at the appropriate visits.
Please refer to the Study Manual for additional instructions.
9.12
Other Protocol-Specified Materials
Not applicable.
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10.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
10.1
Study Personnel and Organizations
The contact information for the Millennium project clinician for this study, the central laboratory 
and any additional clinical laboratories, the coordinating investigator for each member 
state/country (where applicable), the Interactive Web Response System provider, and the contract 
research organization (CRO) team may be found in the Study Manual. A full list of investigators is 
available in the sponsor’s investigator database.
10.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).
10.3
Treatment Group Assignments
A centralized randomization procedure IXRS will be used for treatment group assignment. 
Patients who meet the eligibility criteria will be stratified according to the number of prior lines of 
therapy (1, >1 prior line) and the International Metastatic Renal Cell Carcinoma Database 
Consortium risk category (favorable, intermediate, or poor) [22], and will be randomized at a ratio 
of 1:1:1 to one of 3 treatment arms:

Arm A: single-agent everolimus, 10 mg QD (every day of a 28-day treatment cycle).

Arm B: single-agent MLN0128, 30 mg QW (on Days 1, 8, 15, and 22 of a 28-day treatment 
cycle).

Arm C: combination of MLN0128 4 mg+MLN1117 200 mg, both QD3 days per week (on 
Days 1-3, 8-10, 15-17, and 22-24 of a 28-day treatment cycle).
The first dose of study drug must be administered within 5 days after randomization on study.
10.4
Study Procedures
Patients will be evaluated at scheduled visits over the following study periods: Screening, 
Treatment, and EOT. Evaluations during the Screening period are to be conducted within 28 days 
before administration of the first dose of study drug. Unless otherwise noted, evaluations during 
the Treatment period must occur before study drug administration. 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. The 
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timing of PK assessments is specified in the Treatment Arm B Sparse Pharmacokinetic Sample 
Breakdown and Treatment Arm C Sparse Pharmacokinetic Sample Breakdown.
All EOT evaluations should occur within 30 (+10) days after the last dose of study drug, or before 
the start of subsequent antineoplastic therapy.
Refer to the Schedule of Events for the 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 the Screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy and include a 
description of prior therapies for it. In addition, concomitant medications will be recorded as 
specified in Section 10.4.8.
10.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.
10.4.5
Patient Height and Weight
Height will be measured only during Screening (within 28 days before the first dose of study drug 
[ie, MLN0128, MLN0128+MLN1117, or everolimus]). Body weight will be measured at the visits 
specified in the Schedule of Events.
10.4.6
Vital Signs
Vital sign measurements include diastolic and systolic blood pressure, heart rate, and temperature. 
Vital signs will be measured at the visits specified in the Schedule of Events.
10.4.7
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening. A 
urine pregnancy test must be performed predose on Day 1 of every cycle with negative results 
available before the first dose may be administered in that cycle. A serum pregnancy test may also 
be performed within 3 days before dosing in place of the Day 1 urine test.
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10.4.8
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from the first dose of study drug through 30 days after the last dose of study 
drug. See Section 9.4 and Section 9.5 for a list of medications and therapies that are prohibited 
and/or allowed during the study.
10.4.9
AEs
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.
10.4.10 Enrollment
A patient is considered to be enrolled in the study when they have been randomized into a 
treatment arm. Procedures for completion of the enrollment information are described in the Study 
Manual.
10.4.11 ECG
A single, 12-lead ECG will be administered at the time points specified in the Schedule of Events. 
Additional ECGs may be obtained as clinically indicated.
10.4.12 Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Clinical laboratory evaluations will be 
performed as outlined below:
Blood samples for analysis of the following clinical chemistry and hematological parameters and 
urine samples for urinalysis will be obtained as specified in the Schedule of Events. Specimens for 
analysis of the clinical chemistry, hematologic, 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 Schedule of Events.
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Table 10.a
Clinical Chemistry, Hematology, and Coagulation Tests
Hematology and Coagulation 
Serum Chemistry
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (ANC)
Platelet (count)
Activated partial thromboplastin time
Prothrombin time/international 
normalized ratio
Albumin
Alkaline phosphatase
ALT
Amylase
AST
Bilirubin (total and direct)
Blood urea nitrogen or urea 
Calcium (total)
Carbon dioxide or bicarbonate
Chloride
Creatinine
Gamma glutamyl transferase
Glucose
HbA1c (only at the timepoints specified in 
the Schedule of Events).
Lactate dehydrogenase
Magnesium
Phosphate
Potassium
Sodium
Protein (total)
Urate
Table 10.b
Clinical Urinalysis Tests
Urinalysis
Bilirubin
Glucose
Ketones
Leukocytes
Nitrite
Occult blood
pH
Protein
Specific gravity
Turbidity 
Color
Urobilinogen
Prospective monitoring for hyperlipidemia will be managed through fasting lipid testing. 
Sampling for the fasting lipid profile ( Appendix A (Schedule of Events).
Table 10.c) will be obtained at the times specified in Appendix A (Schedule of Events).
Table 10.c
Fasting Lipid Profile
Fasting Lipid Profile
Cholesterol (total)
Triglycerides
High-density lipoprotein cholesterol
Low-density lipoprotein cholesterol
10.4.13 Fasting Serum Glucose
Fasting serum glucose will be measured in the clinic at the time points specified in Appendix A
(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 everolimus in Arm A or MLN0128 and MLN1117 in 
Arm C, the sample should be taken approximately 2 hours after dose administration with patients 
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continuing to fast until after that sample is taken. For patients receiving MLN0128 QW in Arm B, 
the sample should be taken predose; after predose blood draws are complete, patients receiving 
MLN0128 QW in Arm B should consume a light meal before dosing (Section 9.1). In-home 
glucose monitoring is not required on days when fasting glucose is measured in the clinic.
10.4.14 In-Home Daily Fasting Glucose Monitoring
In addition to obtaining fasting glucose levels at the clinic visits as outlined in Appendix A
(Schedule of Events), all patients randomized to receive MLN0128 (ie, Arms B and C) will be 
given a glucometer to monitor their daily fasting blood glucose (FBG) levels at home. The level 
should be collected daily, predose on dosing days, and at approximately the same time each day. 
Before checking their blood glucose levels, patients should fast overnight (nothing except water 
and/or medications after midnight or for a minimum of 8 hours before the assessment). After 
fasted testing is complete, patients in Arm B should consume a light meal before 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 FBG level every morning (predose on 
dosing days), starting on Cycle 1 Day 2. Patients will be instructed to bring the glucometer with 
them to each study visit so that the data collected can be reviewed and recorded in the source 
documents. Investigators will be responsible for reviewing the home glucose monitoring logs for 
hyperglycemia.
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 9.7.1.
10.4.15 Disease Assessment
Patients will undergo contrast-enhanced imaging (CT or MRI) to monitor the overall disease 
burden unless contraindicated for a particular patient in accordance with RECIST version 1.1 [25]. 
As much as possible, the same imaging modalities and methods should be used for patients 
throughout the study. CT scans of the chest, in addition to CTs or MRIs of the abdomen and pelvis, 
will be obtained at Screening and all subsequent time points. Supplemental x-ray and/or bone 
scanning may be performed, but these methods are not suitable for lesion measurement. Objective 
assessments will be performed at each time point as described in the Schedule of Events. 
Anatomical measurements (summed across target lesions) and the presence of nontarget lesions 
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will be documented at Baseline/Screening, and the status of target, nontarget, and new lesions will 
be assessed at each subsequent imaging time point. When possible, the same qualified physician 
will interpret results to reduce variability.
Disease assessment images will be collected and reviewed by a sponsor-specified central imaging 
vendor. Radiographic images will also be maintained at the site, and test results and physician’s 
findings will be filed in patient source documents.
In the event of antitumor response, the sponsor may request electronic images for those patients 
who demonstrate tumor reduction.
10.4.16 PK Measurements
Sparse PK sampling to characterize the PK of MLN0128 (Arms B and C) and MLN1117 (Arm C), 
including patients who receive crossover treatment, will be performed at the times indicated in the 
Treatment Arm B Sparse Pharmacokinetic Sample Breakdown and Treatment Arm C Sparse 
Pharmacokinetic Sample Breakdown.
When the timing of a PK blood sample coincides with vital sign measurements, the vital sign 
measurement should be obtained before the PK blood sample. 
In addition to the PK sample collections specified, a blood sample to measure MLN0128 and 
MLN1117 concentrations should be obtained, if clinically feasible, at the time of a serious or 
unusual AE that is judged by the investigator to be treatment-related, irrespective of the cycle, day, 
or stage of occurrence of the AE. The date and exact time of the unscheduled sample collection 
should be recorded. Details on the collection, storage, processing, handling, and shipping of PK 
samples are in the Study Manual.
PK data for MLN0128 and MLN1117 collected in this study may 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. 
10.4.17 Pharmacodynamic Measurements
No pharmacodynamic measurements will be made. 
10.4.18 DNA Measurements
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Property of Takeda: For Non-Commercial Use O
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10.4.19 Banked Tumor Specimen Measurements; Tumor Biopsies
Banked formalin-fixed, paraffin-embedded tumor tissue (or fresh tumor biopsy as described below 
in this section) should be obtained at Screening for assessment of candidate biomarkers predictive 
of response, including, but not limited to somatic gene alterations and expression of markers such 
as PTEN, PIK3CA, mTOR, and phosphorylated (p-) AKT, p-S6, and p-4E-BP1. It is anticipated 
that developing these potential biomarkers of antitumor activity mediated by the combination of 
MLN0128 and MLN1117 will require analysis of the data from this study in combination with data 
from other clinical studies of this combination and each single agent.
If either a paraffin-embedded tumor block or a minimum of 15 unstained slides are not available, 
then the patient will be required to undergo a fresh tumor biopsy at Screening as indicated in the 
Schedule of Events. If fresh tumor biopsy collection is unsuccessful, enrollment is contingent upon 
discussion with the sponsor.
Detailed instructions for the collection, processing, and shipment of the fresh tumor biopsy 
samples are provided in the Study Manual.
10.4.20 QOL and Symptom Assessments
The QOL instruments, EORTC QLQ-C30 and FKSI-DRS, will be administered as specified in 
Appendix A (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 J). The time recall 
period for this instrument is 1 week (the past week). The EORTC QLQ-C30 is a reliable and valid 
measure of health-related QOL in patients with cancer [27]. The instrument consists of a brief 
(30-item) questionnaire that has been validated and used in many countries. 
The FKSI-DRS is a validated, 9-item questionnaire derived from the 15-item FSKI-15 
questionnaire designed to assess the effect of disease-related symptoms on patients with kidney 
cancer [28] (see Appendix K).
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Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable 
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10.5
Completion of Treatment
Patients will be considered to have completed treatment if they discontinue study drug for any of 
the reasons outlined in Section 10.7.
The maximum duration of treatment for patients will be 24 months unless, after discussion 
between the investigator and sponsor, it is determined that a patient would derive benefit from 
continued treatment beyond 24 months.
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 and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons:

AE.

Protocol violation.

Progressive disease. 

Symptomatic deterioration. 

Study terminated by sponsor.

Withdrawal by patient.

Lost to follow-up.

Other.
Patients must discontinue study drug if they experience disease progression or unacceptable 
toxicity, or if they become pregnant. 
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in Appendix A (Schedule of Events). The primary reason for study drug 
discontinuation will be recorded on the eCRF.
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.

Other.
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The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. Data on survival may be 
obtained from publicly 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 study drug for each treatment cycle and a diary in 
which to record their dosing. The study center staff will check the patient’s diary versus the 
patient’s supply of remaining study drug at each study visit to ensure proper compliance with 
dosing. Patients who are not compliant with the dosing schedule may be withdrawn from the study.
10.10 Post-Trial Access Program
If an open-label, rollover, PTA program becomes an option and the investigator and the sponsor 
agree that a patient would derive benefit from continued treatment or might be harmed without 
continued access to the medication, the patient may be given the opportunity to enroll. 
In the event of study closure by the sponsor, continued access to study treatment will be terminated 
for patients who are no longer benefiting from treatment (eg, their disease has progressed or 
treatment is no longer tolerable), the benefit-risk assessment is no longer favorable, or an 
appropriate alternative therapy becomes available. The PTA program may be terminated in a 
country or geographic region or terminated by the sponsor if study treatment can no longer be
supplied or study drug becomes available either commercially or via another access mechanism. 
Related SAEs during the PTA program must be reported to Takeda Global Pharmacovigilance 
department or designee. This includes deaths that the investigator considers related to study drug 
that occur after the EOT visit. 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 but 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 one of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
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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 [26]. Clarification should be made between 
an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms serious 
and severe are NOT synonymous. The general term severe is often used to describe the intensity 
(severity) of a specific event; the event itself, however, may be of relatively minor medical 
significance (such as a Grade 3 headache). This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with events that 
pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does not 
necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3 to 
less than 2000/mm3 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
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 Study Manual. 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.
SAE Reporting Contact Information
United States and Canada
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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Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. For serious 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 lab abnormality, will be determined using the NCI CTCAE 
version 4.03, effective date 14 June 2010 [29]. The criteria are provided in the Study Manual.
Relationship to study drug administration will be determined by the investigator responding yes 
or no to this question: Is there a reasonable possibility that the AE is associated with the study 
drug?
11.3
Monitoring of 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 in 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 in the eCRF.

Related and unrelated SAEs will be reported to the Takeda Global Pharmacovigilance
department or designee from the first dose of study drug through 30 days after administration 
of the last dose of study drug and recorded in the eCRF. After this period, only related SAEs 
must be reported to the Takeda Global Pharmacovigilance department or designee. SAEs 
should be monitored until they are resolved or are clearly determined to be due to a patient’s 
stable or chronic condition or intercurrent illness(es).
11.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study or 
during the PTA program, she must inform the investigator immediately and permanently 
discontinue study drug. The sponsor must also be contacted immediately by faxing a completed 
Pregnancy Form to the Takeda Global Pharmacovigilance department or designee (Section 11.2). 
The pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study or during the PTA program, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Takeda Global Pharmacovigilance department or designee (see 
Section 11.2). Every effort should be made to follow the pregnancy for the final pregnancy 
outcome.
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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 
and report the complaint. The contact 
information is as follows:
Medical Information Center:
Phone:
Fax:
Email:
Hours:
Mon-Fri, 9 AM-7 PM, ET
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 the IRB or IEC in accordance with national regulations.
CCI
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Property of Takeda: For Non-Commercial Use Only and Subject to the 
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12.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be 
used in this study.
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13.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization (WHO) Drug Dictionary.
13.1
eCRFs
Completed eCRFs are required for each 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, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change. 
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor.
13.2
Record Retention
The investigator agrees to keep the records stipulated in Section 13.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore, 
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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 will be prepared and finalized before database lock. This document will 
provide further details regarding the definition of analysis variables and analysis methodology to 
address all study objectives.
14.1.1
Analysis Sets

Full analysis set: all randomized patients.

Safety analysis set: patients who receive at least 1 dose of study drug.

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 (age, sex) and baseline characteristics (weight, height, and other parameters, as 
appropriate) will be summarized by treatment arm (ie, everolimus, MLN0128, or 
MLN0128+MLN1117).
14.1.3
Efficacy Analysis
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, 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% CIs, hazard ratio 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 
0.15 significance level (2-sided). The p-values from a stratified log-rank test and hazard ratios and 
will be presented for each pair-wise comparison.
Secondary Efficacy Endpoints
Secondary efficacy endpoints include OS, ORR, TTP, CBR with SD of any duration, and CBR 
with SD duration of at least 4 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 in the full analysis set.
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Objective response rate 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 4 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
Sparse PK data for MLN0128 and MLN1117 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 or MLN1117 is characterized for population PK analysis. The results of population 
PK analysis will be presented in a separate report. 
14.1.5
Pharmacodynamic Analysis 
Not applicable.
14.1.6
Other Analyses 
Patient-Reported Outcomes
Patient-reported outcome (PRO) assessments using the EORTC QLQ-C30 and FKSI-DRS 
questionnaires will be analyzed to determine if response to therapy and side effects of 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, and the 
global health status/QOL score from the EORTC QLQ-C30, and the FKSI-DRS score. Differences 
between treatment arms in the EORTC QLQ-C30 and FKSI-DRS 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, MLN1117, and everolimus) will be summarized
and reasons for discontinuation will be tabulated. Safety will be summarized by treatment arm 
(everolimus, MLN0128, MLN0128+MLN1117).
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TEAEs that occur after administration of the first dose of study drug and through 30 days after the 
last dose of study drug will be tabulated. 
AEs will be tabulated according to the MedDRA and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

The most commonly reported TEAEs. 

SAEs.
A listing of TEAEs resulting in study drug discontinuation will be provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
Baseline in clinical laboratory parameters) 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 Analysis
ECG intervals (QT and QTc with Fridericia correction, and PR), QRS duration, and ventricular 
rate will be summarized at each scheduled time point, along with mean change from 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 
Study data will be reviewed after the first 30 patients in each arm have received 2 cycles of study 
drug. If at the end of cycle 2, 50% or more patients in a treatment arm (ie, Arm B [single agent 
MLN0128] or Arm C (MLN0128+MLN1117) have either progressive disease or have died, or 
have discontinued study treatment due to treatment-related AEs, then that study arm may be 
closed. If both Arms B and C meet this criteria, then the study may be closed.
14.3
Determination of Sample Size
Approximately 189 patients will be enrolled in the 3 treatment arms. 
The primary efficacy endpoint is PFS. Assuming that the median PFS is 5 months for everolimus 
[20] and that MLN0128 (either as a single agent or in combination with MLN1117) can improve 
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the median PFS to 8 months (hazard ratio of 0.625), then a total of 95 PFS events are needed for 
each pair-wise comparison and approximately 63 patients are required for each treatment arm. The 
calculations are based on a power of 80%, 2-sided alpha of 15%, 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 total accrual will be approximately 14 months, where 
10% of the patients are enrolled within the first 3 months and 40% are enrolled at the end of 
7 months. The final analysis for the pair-wise comparisons of PFS between single-agent 
MLN0128 and everolimus and between the combination of MLN0128+MLN1117 and everolimus 
will occur approximately 9 months after the last 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 (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee 
(as long as blinding is not jeopardized), including but not limited to the Investigator’s Binder, 
study medication, subject medical records, informed consent documentation, documentation of 
subject authorization to use personal health information (if separate from the informed consent 
forms), and review of eCRFs and associated source documents. It is important that the investigator 
and other study personnel are available during the monitoring visits and that sufficient time is 
devoted to the process.
15.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation) from the inclusion or exclusion criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or IEC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol.
The investigator should document all protocol deviations.
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 
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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 IB, a copy of the informed consent 
form, and, if applicable, subject recruitment materials and/or advertisements and other documents 
required by all applicable laws and regulations, must be submitted to a central or local IRB or IEC 
for approval. The IRB’s or IEC’s written approval of the protocol and subject informed consent 
must be obtained and submitted to the sponsor or designee before commencement of the study 
(ie, before shipment of the sponsor-supplied drug or study specific screening activity). The IRB or 
IEC approval must refer to the study by exact protocol title, number, and version date; identify 
versions of other documents (eg, informed consent form) reviewed; and state the approval date. 
The sponsor will notify the site once the sponsor has confirmed the adequacy of site regulatory 
documentation and, when applicable, the sponsor has received permission from competent 
authority to begin the trial. Until the site receives notification no protocol activities, including 
screening, may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
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16.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted uses, 
transfers, and disclosures of the subject’s personal and personal health information for purposes of 
conducting the study. The informed consent form and the subject information sheet (if applicable) 
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the 
date informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) must 
be approved by both the IRB or IEC and the sponsor before 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 before the subject entering into the study. The subject or the subject’s legally 
acceptable representative should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. The investigator must also sign and date the informed consent 
form and subject authorization (if applicable) at the time of consent and before the subject entering 
into the study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization form 
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
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All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
16.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 16.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s [e]CRF).
16.4
Publication, Disclosure, and Clinical Trial Registration Policy
16.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
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16.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (as applicable), country, and recruiting 
status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
16.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws, and/or regulations.
16.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
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17.0
REFERENCES
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Trends in Renal Cell Carcinoma Incidence and Mortality. Eur Urol 2015;67(3):519-30.
2. Li P, Znaor A, Holcatova I, Fabianova E, Mates D, Wozniak MB, et al. Regional Geographic 
Variations in Kidney Cancer Incidence Rates in European Countries. European Urology 2014.
3. Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nature 
Reviews Urology 2010;7(5):245-57.
4. Lipworth L, Tarone RE, Lund L, McLaughlin JK. Epidemiologic characteristics and risk 
factors for renal cell cancer. Clin Epidemiol 2009;1:33-43.
5. Gudas LJ, Fu L, Minton DR, Mongan NP, Nanus DM. The role of HIF1alpha in renal cell 
carcinoma tumorigenesis. J Mol Med (Berl) 2014;92(8):825-36.
6. Brugarolas J. Molecular genetics of clear-cell renal cell carcinoma. Journal of Clinical 
Oncology 2014;32(18):1968-76.
7. Audenet F, Yates DR, Cancel-Tassin G, Cussenot O, Roupret M. Genetic pathways involved 
in carcinogenesis of clear cell renal cell carcinoma: genomics towards personalized medicine. 
BJU Int 2012;109(12):1864-70.
8. Pantuck AJ, Zeng G, Belldegrun AS, Figlin RA. Pathobiology, prognosis, and targeted therapy 
for renal cell carcinoma: exploiting the hypoxia-induced pathway. Clin Cancer Res 
2003;9(13):4641-52.
9. Laplante M, Sabatini, DM. mTOR Signaling in Growth Control and Disease. Cell 
2012;149(2):274-93.
10. Laplante M, Sabatini DM. mTOR Signaling. Cold Spring Harb Perspect Biol 2012;4(2).
11. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nature Reviews Cancer 
2006;6(9):729-34.
12. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation 
of mTOR inhibitors. Nature Reviews Drug Discovery 2011;10(11):868-80.
13. Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: the second 
generation of inhibitors. Molecular Cancer Therapeutics 2011;10(3):395-403.
14. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive 
mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. 
Journal of Biological Chemistry 2009;284(12):8023-32.
15. Thoreen CC, Sabatini DM. Rapamycin inhibits mTORC1, but not completely. Autophagy 
2009;5(5):725-6.
16. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. AZD8055 is a 
potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin 
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Page 81 of 104
Protocol Incorporating Amendment 10
03 December 2018
kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Research 
2010;70(1):288-98.
17. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel 
E, et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT 
signaling. Cancer Discov 2011;1(3):248-59.
18. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR Inhibition Induces 
Upstream Receptor Tyrosine Kinase Signaling and Activates Akt. Cancer Res 
2006;66(3):1500-8.
19. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, et al. Dose- and 
schedule-dependent inhibition of the mammalian target of rapamycin pathway with 
everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid tumors. J 
Clin Oncol 2008;26(10):1603-10.
20. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of 
everolimus for metastatic renal cell carcinoma : final results and analysis of prognostic factors. 
Cancer 2010;116(18):4256-65.
21. Cho DC, Cohen MB, Panka DJ, Collins M, Ghebremichael M, Atkins MB, et al. The efficacy 
of the novel dual PI3-kinase/mTOR inhibitor NVP-BEZ235 compared with rapamycin in renal 
cell carcinoma. Clinical Cancer Research 2010;16(14):3628-38.
22. Ko JJ, Xie W, Kroeger N, Lee JL, Rini BI, Knox JJ, et al. The International Metastatic Renal 
Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic 
renal cell carcinoma previously treated with first-line targeted therapy: a population-based 
study. Lancet Oncol 2015;16(3):293-300.
23. AFINITOR (everolimus) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals 
Corporation, 2015.
24. Afinitor [Summary of Product Characteristics]. Horsham, West Sussex, UK: Novartis 
Europharm Limited, 2014.
25. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47.
26. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. Department 
of Health and Human Services National Cancer Institute. 14 June 2010.
27. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for 
use in international clinical trials in oncology. Journal of the National Cancer Institute 
1993;85(5):365-76.
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28. Cella D, Yount S, Brucker PS, Du H, Bukowski R, Vogelzang N, et al. Development and 
validation of a scale to measure disease-related symptoms of kidney cancer. Value in Health 
2007;10(4):285-93.
29. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services Series v4.03. 
June 14, 2010. Publication No. 09-5410.
30. Karnofsky D, Burchenal J. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In: 
MacLeod C, editor. Evaluation of Chemotherapeutic Agents: Symposium Held at the New 
York Academy of Medicine. New York: Columbia University Press; 1949, p. 191-205.
31. Peus D, Newcomb N, Hofer S. Appraisal of the Karnofsky Performance Status and proposal of 
a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak 2013;13:72.
32. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
33. 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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CONFIDENTIAL
Schedule of Events
Screening (a)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6 and 
Beyond
EOT(b)
Days -28 to -1
Day 1
Day 15
Day 1
Day 15
Day 1
Day 
28
Day 1
Day 1
Day 1
Day 28
Informed consent
X
Inclusion/exclusion criteria
X
X
Demographics
X
Medical history
X
Physical examination (c)
X
X
X
X
X
X
X
XX
X
Height
X
Weight
X
X
X
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
X
Karnofsky performance status
X
X
X
X
X
X
X
X
Single, 12-lead ECG (e)
X
X
X
X
X
X
X
X
EORTC-QLQ-C30
X
X
X
X
X
X
X
FKSI-DRS
X
X
X
X
X
X
X
Radiographic tumor assessment by 
RECIST version 1.1 (f)
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 (g) will be reported from signing of the informed consent form through 30 days after the last dose of study drug.
Dosing (h)
Treatment Arm A 
Everolimus QD continuously 
Treatment Arm B
MLN0128 QW continuously 
Treatment Arm C
MLN0128+MLN1117 QD×3 each week continuously (on Days 1-3, 8-10, 15-17, and 22-24 of a 
28-day treatment cycle)
Patient diary review(i)
X
X
X
X
X
X
X
X
X
X
X
Samples/Laboratory Assessments
Pregnancy test(j)
X1
X1
X1
X1
X1
X1
Hematology/Chemistry(k)
X1
X1
X1
X1
X1
X1
X1
X1
X1
Coagulation (PT/INR, aPTT)
X1
X1
X1
X1
X1
X1
X1
Fasting serum glucose (l)
X1
X1
X1
X1
X1
X1
X1
In-home daily fasting glucose 
monitoring (m)
X
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Study No. C31005
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CONFIDENTIAL
Schedule of Events
Screening (a)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6 and 
Beyond
EOT(b)
Days -28 to -1
Day 1
Day 15
Day 1
Day 15
Day 1
Day 
28
Day 1
Day 1
Day 1
Day 28
HbA1c
X
X1
Q 3 cycles 
(n)
Fasting lipid profile (o)
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Tumor tissue (banked) or fresh 
biopsy sample (q)
X
Blood sample for PK (r)
Refer to Treatment Arm B Sparse Pharmacokinetic Sample Breakdown
and Treatment Arm C Sparse Pharmacokinetic Sample Breakdown
aPTT=activated partial thromboplastin time, C=cycle, INR=international normalized ratio, OSFU=overall survival follow-up, PC EOT=Precrossover End-of-Treatment, 
PFSFU=progression-free survival follow-up, PT=prothrombin time, Q=every.
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)
Unless otherwise noted, the Screening visit (and all screening assessments) must occur within 28 days before the day of the first dose of study drug (Cycle 1 Day 1). The 
informed consent form may be signed more than 28 days before Cycle 1 Day 1. Screening assessments performed no more than 3 days before D1 will qualify as baseline assessments 
and need not be repeated, unless otherwise specified. 
(b) Patients will attend an EOT/Early Termination visit 30 to 40 days after receiving their last dose of study drug or at the start of subsequent anticancer therapy. If subsequent 
anticancer therapy is required before 30 days after the last dose, the EOT/Early Termination visit should be conducted before the initiation of subsequent anticancer therapy. The study 
will be closed when the last patient discontinues treatment. 
(c)
Complete physical examination at Screening. Symptom-directed physical examinations at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 15, Day 1 on each cycle 
thereafter and during the EOT/Early Termination visit. The Cycle 1 Day 1 physical examination and medical history are not required if the physical examination at Screening was 
conducted and medical history obtained within 4 days before administration of the first dose of study drug (Cycle 1 Day 1).
(d) Perform vital signs measurement before study drug administration except on Cycle 1 Day 15, when patients should take their dose or doses of study drug early in the morning at 
home. Vital sign measurements include blood pressure (diastolic and systolic), heart rate, and temperature.
(e)
Single, 12-lead ECGs will be collected 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. All scheduled ECGs should be performed after the subject has rested quietly for at least 5 minutes in a supine position.
(f)
Radiological evaluations will be employed to assess the status of the patient’s underlying disease. Contrast-enhanced imaging of the same imaging modality (CT or MRI) should 
be used for a patient throughout the study unless contraindicated. Baseline CT of the chest and CT or MRI scan of the abdomen and pelvis must be obtained within 4 weeks before the 
first dose of study drug. Contrast-enhanced CT or MRI scans will be obtained on Day 28 (±3 days) of every 3 cycles (ie, Cycle 3 Day 28, Cycle 6 Day 28, etc). A contrast-enhanced 
CCI
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Property of Takeda: For Non-Commercial Use Only and
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MLN0128, MLN1117
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Page 86 of 104
Protocol Incorporating Amendment 10
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CONFIDENTIAL
CT or MRI scan is not required at the EOT visit for patients with documented radiographic disease progression. 
After the patient has completed 12 cycles of treatment, disease assessment may be performed every 6 cycles (after previous assessment) or otherwise per investigator’s discretion. 
(g)
Including serious PTEs; see Section 11.0.
(h) The first dose of study drug must be administered within 5 days after randomization on study. In Arm B, weekly MLN0128 will be administered with a light meal; in Arm C, 
MLN0128+MLN1117 will be administered on an empty stomach (see Section 9.1).
(i)
The study center staff will check the patient diary versus the patient’s supply of study drug (ie, MLN0128, MLN1117, or everolimus, as applicable) to assess compliance.
(j)
A serum pregnancy test will be performed for women of childbearing potential at Screening. A urine pregnancy test must be performed predose on Day 1 of every cycle with 
negative results available before the first dose may be administered in that cycle. A serum pregnancy test may also be performed within 3 days before dosing in place of the Day 1 
urine test.
(k) Refer to Section 10.4.12 for a list of the required clinical laboratory assessments. Laboratory assessments may be performed within 1 day 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. 
(l)
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 everolimus in Arm A or MLN0128 and MLN1117 in Arm C, the sample should be taken approximately 
2 hours after dose administration with the patient continuing to fast until after that sample is taken. For patients receiving MLN0128 QW in Arm B, the sample should be taken 
predose; after predose blood draws are complete, patients receiving MLN0128 QW in Arm B should consume a light meal before dosing (Section 9.1). In-home glucose monitoring 
is not required on days when fasting glucose is measured in the clinic.
See Sections 9.7.1 and 10.4.14 for further instructions. 
(m) Patients will be given a glucometer on Cycle 1 Day 1 to monitor daily fasting glucose levels at home and will be instructed to notify the study clinician when the fasting glucose 
is abnormal (ie, ≥150 mg/dL). See Sections 9.7.1 and 10.4.14 for further instructions.
(n) Every 3 cycles from Cycle 6 (ie, Cycle 6, Cycle 9, etc).
(o)
Total cholesterol, high density lipoprotein cholesterol, low density lipoprotein, and triglycerides.
(p)
(q) Archived tumor tissue, either paraffin blocks or a minimum of 15 unstained slides (paraffin blocks preferred) should be obtained from a previous resection or biopsy that was 
done as part of the patient’s standard care. These samples will be evaluated for candidate biomarkers predictive of response. Tumor tissue is to be collected only from enrolled patients 
and can be collected and sent to the sponsor after initiation of protocol treatment. If archival tumor tissue is not available, a tumor biopsy can be performed before the patient begins 
treatment with study drug(s). See Section 10.4.19 for requirements.
(r)
Blood specimens for PK analysis will be collected from patients randomized to Arms B (single-agent MLN0128) and C (MLN0128+MLN1117 combination) perr the Treatment 
Arm B Sparse Pharmacokinetic Sample Breakdown and Treatment Arm C Sparse Pharmacokinetic Sample Breakdown. Blood specimens for PK analysis will not be collected from 
patients randomized to Arm A (single-agent everolimus).
CCI
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
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MLN0128, MLN1117
Study No. C31005
Page 87 of 104
Protocol Incorporating Amendment 10 
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CONFIDENTIAL
Treatment Arm B Sparse Pharmacokinetic Sample Breakdown
Cycle 1
Day 1 (a)
Day 15 (b)
PK
PK
At time of clinic visit (anytime postdose)
X1
Approximately 1 hour after previous PK sample collection
X1
1-2 hours postdose (±15 min)
X1
3-6 hours postdose (±30 min)
X2 (c)
This PK sampling schedule applies to patients receiving crossover treatment as well as to patients initially randomized to Arm B.
X#=the number of samples required (eg, 2 samples=X2).
(a) 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 before 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 in the eCRF. Over the course of the study, a distribution of sampling times within this time range 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 
meal consumption, dosing, and PK sampling must be recorded in the eCRF. Over the course of the study, a distribution of clinic visit/sampling times (eg, morning 
through late afternoon) for this visit is encouraged.
(c) Two samples will be taken no less than 1 hr apart within the specified window.
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Study No. C31005
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Protocol Incorporating Amendment 10 
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CONFIDENTIAL
Treatment Arm C Sparse Pharmacokinetic Sample Breakdown
Cycle 1
Day 1
Day 15
PK
PK
At time of clinic visit (anytime postdose) (a)
X1
Approximately 1 hour after the last PK sample
X1
1-2 hours postdose (b)
X1
3-6 hours postdose (b)
X1
This PK sampling schedule applies to patients receiving crossover treatment as well as to patients initially randomized to Arm C.
X#=the number of samples required (eg, 2 samples=X2).
(a) On Cycle 1 Day 15, patients should take their dose or doses of study drug early in the morning at home, and note the date and time that the dose was taken. 
Patients should also note the date/time of the previous dose. Two postdose PK plasma specimens will be collected at the clinic. The first specimen may be collected 
after arrival at the clinic and the second specimen collected approximately 1 hour after the first. The date/time of dosing and PK sampling must be recorded in the 
eCRF. Over the course of the study, a distribution of clinic visit/sampling times (eg, morning through late afternoon) for this visit is encouraged. 
(b) On Cycle 1 Day 1, PK plasma specimens can be collected at any time during the sampling window. The date and time of MLN0128 dosing on Cycle 1 Day 1 and 
the date/time of PK sampling must be recorded in the eCRF. Over the course of the study, a distribution of sampling times within the windows is encouraged.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The 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:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. Ensure that study-related procedures, including study-specific (nonroutine/nonstandard panel) 
screening assessments are NOT performed on potential subjects, before the receipt of written 
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
5. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 Code of Federal Regulations (CFR) Part 56, ICH, and local regulatory requirements.
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
7. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH, and local 
regulations, are met.
8. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor. 
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
13. 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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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of the investigator, including his or her name, 
address, and other personally identifiable information. In addition, the 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.
The investigator’s personal information may be retained, processed, and transferred by Takeda 
and these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
The investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
The investigator acknowledges and consents to the use of his or her personal information by 
Takeda and other parties for the purposes described above.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


MLN0128, MLN1117
Study No. C31005
Page 92 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix D
Karnofsky Performance Status
Karnofsky Performance Status
Condition 
Percent
Description 
Able to carry on normal 
activity and to work. No 
special care is needed.
100
Normal, no complaints, no evidence of disease.
90
Able to carry on normal activity, minor signs or symptoms of disease.
80
Normal activity with effort, some signs or symptoms of disease.
Unable to work. Able to 
live at home, care for most 
personal needs. A varying 
degree of assistance is 
needed.
70
Cares for self. Unable to carry on normal activity or to do active work.
60
Requires occasional assistance, but is able to care for most of his needs.
50
Requires considerable assistance and frequent medical care.
Unable to care for self. 
Requires equivalent of 
institutional or hospital 
care. Disease may be 
progressing rapidly. 
40
Disabled, requires special care and assistance.
30
Severely disabled, hospitalization is indicated although death not imminent.
20
Hospitalization necessary, very sick, active supportive treatment necessary.
10
Moribund, fatal processes progressing rapidly.
0
Dead.
Sources:
Karnofsky, DA, Burchenal, JH. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In Evaluation of 
Chemotherapeutic Agents: Symposium Held at the New York Academy of Medicine, MacLeod CM (ed). (New York, 
Columbia University Press), 1949, 191-205. [30]
Péus D, Newcomb N, Hofer S. Appraisal of the Karnofsky Performance Status and proposal of a simple algorithmic 
system for its evaluation. BMC Med Inform Decis Mak. 2013 Jul 19;13:72. [31]
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MLN0128, MLN1117
Study No. C31005
Page 93 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix E
Methods of Contraception Considered to be Effective
Acceptable Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (a):
–
Oral.
–
Intravaginal.
–
Transdermal.

Progestogen-only hormonal contraception associated with inhibition of ovulation (a):
–
Oral.
–
Injectable.
–
Implantable (b).

Intrauterine device (b).

Intrauterine hormone-releasing system (b).

Bilateral tubal occlusion (b).

Vasectomized partner (b) (c).

Sexual abstinence (d).
Methods that are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.

Male or female condom with or without spermicide (e).

Cap, diaphragm, or sponge with spermicide (e).
__________________________________________________
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf
(a) Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.
(b) Contraception methods that in the context of this guidance are considered to have low user dependency.
(c) Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential participant of the study and that the vasectomized partner has received medical 
assessment of the surgical success.
(d) In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject.
(e) A combination of male condom with either cap, diaphragm or sponge with spermicide (double-barrier methods)
are also considered acceptable, but not highly effective, birth control methods.
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MLN0128, MLN1117
Study No. C31005
Page 94 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix F
Cockcroft-Gault Equation
For men:
Creatinine Clearance =
(140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
Creatinine Clearance =
(140-age [years])weight [kg]
0.81(serum creatinine [µmol/L])
For women:
Creatinine Clearance =
0.85 (140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
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 [32].
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MLN0128, MLN1117
Study No. C31005
Page 95 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix G
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 [33].
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


MLN0128, MLN1117
Study No. C31005
Page 96 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix H
List of Relevant Cytochrome P450 Inhibitors and Inducers
Moderate CYP1A2 Inhibitors
Cimetidine
Methoxsalen 
Strong CYP1A2 Inhibitors
Fluvoxamine
Ciprofloxacin
Clinically Significant Enzyme Inducers
Carbamazepine
Rifabutin
St. John’s wort
Phenobarbital
Rifampin
Phenytoin
Rifapentine 
Source: fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm.
Note that these lists are not exhaustive.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


MLN0128, MLN1117
Study No. C31005
Page 97 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix I
List of BCRP, OCT1, and OCT2 Substrates
BCRP, OCT1, and OCT2 Substrates
BCRP Substrates
OCT1 and OCT2 Substrates
Methotrexate
Metformin
Imatinib
Cimetidine
Topotecan
Amantadine
Lapatinib
Famotidine
Rosuvastatin
Pindolol
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


MLN0128, MLN1117
Study No. C31005
Page 98 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix J
EORTC QLQ-C30 Version 3
:
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MLN0128, MLN1117
Study No. C31005
Page 99 of 104
Protocol Incorporating Amendment 10 
03 December 2018
© 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, MLN1117
Study No. C31005
Page 100 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix K
Functional Assessment of Cancer Therapy Kidney Symptom 
Index-Disease-Related Symptoms
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MLN0128, MLN1117
Study No. C31005
Page 101 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Appendix L
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 10 are indicated. The 
corresponding text has been revised throughout the protocol.
Change #1: Removed long-term follow-up and the option for cross-over treatment, and added the 
option for patients to transfer to a Post-Trial Access program. 
The primary change occurs in Section 7.1 Overview of Study Design.
Initial wording:
Patients will receive MLN0128, MLN0128+MLN1117, or everolimus until 
they experience disease progression or unacceptable toxicity, withdraw 
consent, or die. Patients who experience progressive disease per RECIST 
version 1.1 during treatment with everolimus may be eligible to cross over to 
receive treatment with either MLN0128 or MLN0128+MLN1117. Patients 
who discontinue study treatment for reasons other than progressive disease will 
continue to have PFS follow-up visits every 2 months (±1 week) for the first 6 
months after the End-of-Treatment (EOT) visit, then every 3 months (±1 week) 
until disease progression or start of another anticancer therapy, whichever 
occurs first. After disease progression or start of another anticancer therapy, 
patients will be followed for OS every 3 months (±1 week).
Amended or new 
wording:
Patients will receive MLN0128, MLN0128+MLN1117, or everolimus until 
they experience disease progression or unacceptable toxicity, withdraw 
consent, die, or transfer to the Post-Trial Access program. or die. Patients 
who experience progressive disease per RECIST version 1.1 during treatment 
with everolimus may be eligible to cross over to receive treatment with either 
MLN0128 or MLN0128+MLN1117. Patients who discontinue study treatment 
for reasons other than progressive disease will continue to have PFS follow-up 
visits every 2 months (±1 week) for the first 6 months after the 
End-of-Treatment (EOT) visit, then every 3 months (±1 week) until disease 
progression or start of another anticancer therapy, whichever occurs first. After 
disease progression or start of another anticancer therapy, patients will be 
followed for OS every 3 months (±1 week). 
The study design figure (Figure 7.a) was also modified. 
This change also occurs in Section 2.0, Section 7.3, Section 10.4, Section 10.9, and the Schedule of 
Events. 
Rationale for Change: The study is to be closed.
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MLN0128, MLN1117
Study No. C31005
Page 102 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Change #2: Study closure was defined as then the last patient discontinues treatment. 
The primary change occurs in Section 7.3 Duration of Study.
Initial wording:
The study will be closed 2 years after the last patient is randomized or when the 
last patient discontinues study treatment.
Amended or new 
wording: 
The study will be closed 2 years after the last patient is randomized or when the 
last patient discontinues study treatment.
This change also occurs in Section 2.0 Study Summary and the Schedule of Events.
Rationale for Change: The study is be closed. 
Change #3: A new section was added (10.10) detailing the Post-Trial Access program.
New or amended 
wording:
If an open-label, rollover, PTA program becomes an option and the 
investigator and the sponsor agree that a patient would derive benefit 
from continued treatment or might be harmed without continued access 
to the medication, the patient may be given the opportunity to enroll. 
In the event of study closure by the sponsor, continued access to study 
treatment will be terminated for patients who are no longer benefiting 
from treatment (eg, their disease has progressed or treatment is no longer 
tolerable), the benefit-risk assessment is no longer favorable, or an 
appropriate alternative therapy becomes available. The PTA program 
may be terminated in a country or geographic region or terminated by the 
sponsor if study treatment can no longer be supplied or study drug 
becomes available either commercially or via another access mechanism.. 
Related SAEs during the PTA program must be reported to Takeda 
Global Pharmacovigilance department or designee. This includes deaths 
that the investigator considers related to study drug that occur after the 
EOT visit. Refer to Section 11.0 for details regarding definitions, 
documentation, and reporting of SAEs.
Rationale for Change: A PTA program was added to allow continued treatment after study 
closure for any patients receiving benefit.
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MLN0128, MLN1117
Study No. C31005
Page 103 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Change #4: Modified the exclusion criterion relating to PPIs.
The primary change occurs in Section 8.2 Exclusion Criteria #5,
Initial wording:
12. Patients requiring daily or chronic use of a proton pump inhibitor (PPI) 
and/or having taken a PPI within 7 days before receiving the first dose of 
study drug.
Amended or new 
wording:
12. Patients who have taken a PPI within 7 3 days before receiving the first 
dose of study drug.
Rationale for Change: This change was made to allow more flexibility in patient enrollment 
based on data on MLN0128 metabolism. 
This change also occurs in Section 2.0.
Change #5: Revised the restrictions on concomitant use of PPIs. 
The primary change occurs in Section 9.4.2 Excluded Concomitant Medications and Procedures 
for Arms B and C. 
Initial wording:

Concomitant administration of any PPI is not permitted during the study. 
Patients receiving PPI therapy before enrollment must stop using the PPI 7 
days before their first dose of study drugs. Examples of PPIs include 
omeprazole, esomeprazole, pantoprazole, lansoprazole, and rabeprazole.
Amended or New 
Wording:

Concomitant administration of any PPI is not permitted during the 
study prohibited only for patients randomized to MLN0128 + 
MLN1117. Patients receiving PPI therapy before enrollment must stop 
using the PPI 7 3 days before their first dose of study drugs. Examples 
of PPIs include omeprazole, esomeprazole, pantoprazole, lansoprazole, 
and rabeprazole. 
Rationale for Change: This change was made to update the recommendations on concomitant 
medication use during the study based on data on MLN0128 metabolism. 
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MLN0128, MLN1117
Study No. C31005
Page 104 of 104
Protocol Incorporating Amendment 10 
03 December 2018
Change #6: Physical examinations after Screening were changed to symptom-directed physical 
examinations.
The primary change occurs in the Schedule of Events.
Initial wording:
Complete physical examination at Screening, at Cycle 1 Day, Cycle 1 Day 15, 
Cycle 2 Day 1, Cyclle 2 Day 15, Day 1 of each cycle therafter and during the 
EOT/Early Termination Visit. 
Amended or new 
wording:
Complete physical examination at Screening. Symptom-directed physical 
examinations at Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Cycle 2 Day 
15, Day 1 on each cycle thereafter, and during the EOT/Early Termination 
visit.
Rationale for Change: Complete physical examinations were not felt necessary at subsequent 
visits. 
Change #7: The requirement for a confirmatory scan 4 weeks from the previous can for patients 
with a CR or PR was removed.
The primary change occurs in the Schedule of Events.
Deleted text: 
A confirmatory scan should be performed at approximately 4 weeks from the 
previous scan for all patients with a complete or partial response. 
Rationale for Change: The confirmatory scan was not felt necessary. 
Change #8: A recommendation was added for radiographic assessments every 6 months, or at the 
investigator’s discretion, after 12 cycles of treatment. 
The primary change occurs in the Schedule of Events. 
New wording:
After the patient has completed 12 cycles of treatment, disease 
assessment may be performed every 6 cycles (after previous 
assessment) or otherwise per investigator’s discretion.
Rationale for Change: To clarify timing of assessments after 12 cycles of treatment.
Change #9: The requirement for weight to be measured at Day 15 of Cycles 1 and 2 was removed.
The primary change occurs in the Schedule of Events. 
Rationale for Change: Weight measurement was not felt necessary at these timepoints. 
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: A Phase 2, Open-label Study to Evaluate the Efficacy and Safety of Single-Agent MLN0128 and 
the Combination of MLN0128+MLN1117 Compared With Everolimus in the Treatment of Adult 
Patients With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma That Has Progressed on 
Vascular Endothelial Growth Factor-Targeted Therapy
NCT Number: NCT02724020
SAP Approve Date: 03 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.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C31005
A Phase 2, Open-label Study to Evaluate the Efficacy and Safety of Single-Agent MLN0128 and 
the Combination of MLN0128+MLN1117 Compared With Everolimus in the Treatment of 
Adult Patients With Advanced or Metastatic Clear-Cell Renal Cell Carcinoma That Has 
Progressed on Vascular Endothelial Growth Factor-Targeted Therapy
PHASE 2
Version: Final
Date: 03 December 2018
Prepared by:
Based on:
Protocol Version: Protocol Amendment No. 06
Protocol Date: 02 October 2017
Prope
Takeda: For 
mmercial Use Only and Subject to the Applicable Terms of Use
Single
ingle-A
erolimus
rolimu
nal Cell
nal Ce
actor-
ctor-Ta
T
E 2
Versi
rsion
o :
ate
ate: 03
03 D
otocol
toco V
l
Protoc
Proto
CCI


C31005
Page 2 of 32
Statistical Analysis Plan
03 December 2018
1.1
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


C31005
Page 3 of 32
Statistical Analysis Plan
03 December 2018
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
APPROVAL SIGNATURES.....................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Quality of Life Objectives..........................................................................................7
4.4
Exploratory Objectives ..............................................................................................7
4.5
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Quality of Life Endpoints.........................................................................................10
5.4
Exploratory Endpoints .............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Methods for Handling Missing Data...................................................................12
7.1.2
Definitions of Baseline Values...........................................................................12
7.1.3
Definition of Study Days....................................................................................12
7.2
Analysis Sets ...........................................................................................................13
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................15
7.6
Medication History and Concomitant Medications...................................................15
7.6.1
Prior Therapies...................................................................................................15
7.6.2
Follow-up Anti-cancer Therapy .........................................................................15
7.7
Study Drug Exposure and Compliance.....................................................................16
7.7.1
Study Treatments ...............................................................................................16
7.7.2
Extent of Exposure.............................................................................................16
7.7.3
Action on Drug ..................................................................................................17
7.8
Efficacy Analysis.....................................................................................................17
7.8.1
Primary Efficacy Endpoint(s).............................................................................17
7.8.2
Secondary Efficacy Endpoint(s).........................................................................19
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7.8.3
Additional Efficacy Endpoint(s).........................................................................22
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................22
7.9.1
Pharmacokinetic Analysis ..................................................................................22
7.9.2
...............................................................................23
7.10
Patient Reported Outcomes......................................................................................23
7.11
Safety Analysis........................................................................................................24
7.11.1 Adverse Events ..................................................................................................24
7.11.2 Vital Signs .........................................................................................................27
7.11.3 12-Lead ECGs ...................................................................................................27
7.11.4 Karnofsky Performance Status ...........................................................................27
7.12
Interim Analysis ......................................................................................................27
7.13
Crossover Treatment................................................................................................28
7.14
Changes in the Statistical Analysis Plan...................................................................28
8.0
REFERENCES..............................................................................................................29
9.0
APPENDIX...................................................................................................................30
LIST OF APPENDICES
Appendix A
By-Subject Listings............................................................................................30
Appendix B
Date Imputation Rules........................................................................................31
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2
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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
CBR
clinical benefit rate
CR
complete response
CT
computed tomography
ECG
electrocardiogram
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
FKSI-DRS
Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms
HbA1c
glycosylated hemoglobin, hemoglobin A1c
HR
hazard ratio
IV
intravenous; intravenously
IRT
interactive response technology
mccRCC
metastatic clear-cell renal cell carcinoma
MedDRA
Medical Dictionary for Regulatory Activities
MLN0128
also known as TAK-228
MLN1117
also known as TAK-117
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
PFS
progression-free survival
PIK3CA
phosphoinositide-3-kinase, catalytic alpha polypeptide
PK
pharmacokinetic(s)
PR
partial response
PRO
patient-reported outcomes
PTEN
phosphatase and tensin homolog
QD
quaque die; each day; once daily
QD!3 QW
once daily for 3 days each week
QOL
quality of life
QW
every week
QTc
rate-corrected QT interval (msec) 
RCC
renal cell carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use
cer Qualit
er Qual
ymptom I
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imaging
maging
mammalia
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Statistical Analysis Plan
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SAE
serious adverse event
SD
stable disease
TAK-117
MLN01117
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
VEGF
vascular endothelial growth factor 
VHL
von Hippel-Lindau
WHO
World Health Organization
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4.0
OBJECTIVES
4.1
Primary Objectives
The primary objectives of the study are:
∀
To compare the efficacy of single-agent MLN0128 versus single-agent everolimus in patients 
with mccRCC.
∀
To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent 
everolimus in patients with mccRCC.
4.2
Secondary Objectives
The secondary objectives of the study are:
∀
To assess the safety and tolerability of MLN0128 and MLN0128+MLN1117.
∀
To compare the efficacy of the combination of MLN0128+MLN1117 versus single-agent
MLN0128 in patients with mccRCC.
∀
To evaluate the efficacy (endpoints other than PFS; ie, overall survival [OS], time-to-
progression [TTP], objective response rate [ORR], and clinical benefit rate [CBR]) among
the 3 treatment groups.
∀
To collect plasma concentration-time data with sparse PK sampling to contribute to future 
population PK analysis.
4.3
Quality of Life Objectives
The health-related quality of life (HRQL) objective is:
∀
To assess the HRQL and symptoms as measured by the EORTC-QLQ-C30 questionnaire and 
the FACT-Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS) questionnaire 
among the 3 treatment groups.
4.4
Exploratory Objectives
4.5
Study Design
This is a phase 2, open-label study of the safety and efficacy of MLN0128, as a single agent and 
in combination with MLN1117, in adult patients with advanced or mccRCC that has progressed 
on VEGF-targeted therapy. Eligibility will be determined during the Screening period, which 
Propert
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Statistical Analysis Plan
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may last for up to 28 days before the Cycle 1 Day 1 visit. Patients who meet all eligibility criteria 
and provide written informed consent will be enrolled in this study. Approximately 189 patients 
who meet the eligibility criteria will be stratified according to the number of prior lines of 
therapy (1, >1 prior line) and the International Metastatic Renal Cell Carcinoma Database 
Consortium risk category (Favorable, Intermediate, or Poor), and will be randomized at a ratio of 
1:1:1 to one of 3 treatment arms:

Arm A: single-agent everolimus.

Arm B: single-agent MLN0128.

Arm C: combination of MLN0128+MLN1117.
Patients will receive study drug(s) (ie, MLN0128, MLN1117, and everolimus) in 28-day cycles. 
Patients in Arm A will receive everolimus 10 mg QD according to current prescribing 
information in either the United States Prescribing Information (USPI) or Summary of Product 
Characteristics (SmPC) for everolimus. Patients in Arm B will receive MLN0128 30 mg orally 
once weekly (on Days 1, 8, 15, and 22 of a 28-day treatment cycle). Patients in Arm C will 
receive MLN0128 4 mg and MLN1117 200 mg orally both QDx3 days per week (on Days 1-3, 
8-10, 15-17, and 22-24 of a 28-day treatment cycle). Patients will receive MLN0128, 
MLN0128+MLN1117, or everolimus until they experience disease progression or unacceptable 
toxicity, withdraw consent, or die. Patients who experience progressive disease per RECIST 
Version 1.1 during treatment with everolimus may be eligible to cross over to receive treatment 
with either MLN0128 or MLN0128+MLN1117. Patients who discontinue study treatment for 
reasons other than progressive disease will continue to have PFS follow-up visits every 2 months 
(±1 week) for the first 6 months after the end-of-treatment (EOT) visit, then every 3 months (±1 
week) until disease progression or start of another anticancer therapy, whichever occurs first. 
After disease progression or start of another anticancer therapy, patients will be followed for OS 
every 3 months (±1 week).
Radiographic tumor evaluations (CT scan with intravenous [IV] contrast or MRI as clinically 
indicated) of the chest, abdomen, and pelvis will be used to evaluate disease response according 
to RECIST Version 1.1. 
Throughout the study, toxicity will be evaluated according to NCI CTCAE Version 4.03, 
effective date 14 June 2010. 
Adverse events will be assessed, and clinical laboratory values, vital signs, and 
electrocardiograms (ECGs) will be obtained to evaluate the safety and tolerability of single-agent 
MLN0128 and MLN0128+MLN1117 in combination.
Sparse PK samples will be collected in Cycle 1 from all patients enrolled in Arms B and C for 
plasma PK analysis of MLN0128 (Arms B and C) and MLN1117 (Arm C). Data generated in 
this study may be combined with data from other studies, in which the PK of MLN0128 or 
MLN1117 is characterized for a future population PK analysis.
Main analysis will be conducted when the required number of PFS events has been reached and 
then the final analysis when all patients have discontinued the study.
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There will be one interim analysis. Study data will be reviewed after the first 30 patients in each 
arm have received 2 cycles of study drug. If at the end of cycle 2, 50% or more patients in a 
treatment arm (ie, Arm B [single agent MLN0128] or Arm C (MLN0128+MLN1117) have either 
progressive disease or have died, or have discontinued study treatment due to treatment-related 
AEs, then that study arm may be closed. If both Arms B and C meet these criteria, then the study
may be closed.
Potential for crossover treatment
Patients in the single-agent everolimus arm (Arm A) who have radiographically confirmed 
disease progression may be allowed to receive crossover treatment with single-agent MLN0128 
or the combination of MLN0128+MLN1117. Once documented disease progression 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 limit of a total of 4 lines of prior systemic therapy would not apply if on-study everolimus 
was their fifth line of treatment), and eligibility for crossover will be confirmed by the sponsor’s 
project clinician (or designee). Eligible patients will then be randomized via the interactive voice 
and/or web response system (IXRS) in a 1:1 ratio to either single-agent MLN0128 or 
MLN0128+MLN1117.
Crossover treatment must begin after a 7-day washout period and within 28 days of documented 
disease progression. The first dose of single-agent MLN0128 or MLN0128+MLN1117 will be 
Cycle 1 Day 1 of the crossover treatment. Patients may receive crossover treatment until they 
experience disease progression 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 everolimus 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 and presented separately.
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Statistical Analysis Plan
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint is Progression Free Survival (PFS).
5.2
Secondary Endpoints
The secondary endpoints are:
∀
The number and percentage of patients with treatment-emergent adverse events.
∀
Overall survival (OS).
∀
Time-to-progression (TTP).
∀
Objective response rate (ORR; defined as complete response [CR]+partial response [PR] per
Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1).
∀
Clinical benefit rate (CBR; defined as CR+PR+stable disease) with SD of any duration
∀
CBR with SD duration of at least 4 months
5.3
Quality of Life Endpoints
The HRQL endpoints are:
∀
Changes from Baseline in functional and symptom scores, and global health status and
quality of life (QOL) score from the EORTC QLQ-C30 questionnaire and symptom scales 
from the FKSI-DRS questionnaire.
5.4
Exploratory Endpoints
Property of Take
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6.0
DETERMINATION OF SAMPLE SIZE
Approximately 189 patients will be enrolled in the 3 treatment arms.
The primary efficacy endpoint is PFS. Assuming that the median PFS is 5 months for everolimus
[1] and that MLN0128 (either as a single agent or in combination with MLN1117) can improve 
the median PFS to 8 months (hazard ratio of 0.625), then a total of 95 PFS events are needed for 
each pair-wise comparison and approximately 63 patients are required for each treatment arm. 
The calculations are based on a power of 80%, 2-sided alpha of 15%, 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 total accrual will be approximately 14 months, where 
10% of the patients are enrolled within the first 3 months and 40% are enrolled at the end of 7 
months. The final analysis for the pair-wise comparisons of PFS between single-agent MLN0128 
and everolimus and between the combination of MLN0128+MLN1117 and everolimus will 
occur approximately 9 months after the last patient is randomized.
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Statistical Analysis Plan
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4.
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. P-values should be presented to 3 decimal 
places, with values less than 0.001 presented as <0.001. 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 between everolimus vs. MLN0128 and 
between everolimus vs. MLN0128 + MLN1117. 
7.1.1
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 7.10. Data imputation 
rules for incomplete dates are described in Appendix B.
7.1.2
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.
7.1.3
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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Statistical Analysis Plan
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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 purposse 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.
7.2
Analysis Sets

Full analysis set: all randomized patients. Patients will be analyzed according to the 
randomization assignment. The full analysis set 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 analysis set will be 
used for all safety analyses. In addition, the safety analysis set will be used for a sensitivity 
analysis of secondary efficacy endpoints ORR, CBR, CBR-16 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 at Baseline, and have 1 post-Baseline disease assessment. Patients will be 
analyzed according to the randomization assignment. The response-evaluable analysis set 
will be used for the secondary efficacy endpoints of ORR, CBR, CBR-16 and the best overall 
response.
The number and percentage of patients in each analysis set will be summarized.
7.3
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 DB lock), discontinued from the study, and 
primary reason to discontinue from the study (including deaths). 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 everolimus arm who crossed over to 
receive MLN0128 or MLN0128 + MLN1117 will be summarized.
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Statistical Analysis Plan
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7.4
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 1
–
< 65 years
–
≥ 65 years

Age category 2
–
Adults (18-64 years)
–
From 65 to 84 years
–
85 years and over

Sex

Height (cm)

Weight (kg) – screening if available otherwise C1D1

Ethnicity

Race

Geographic Region, Country, Site
North America (Canada, United States)
Europe (Czech Republic, France, Hungary, Italy, Poland, Russia, Spain, United Kingdom)
Baseline characteristics consist of:

Time since initial diagnosis (months) [date of first dose – date of initial diagnosis/(30.4375))]

Disease subtype [Clear Cell Renal Cell Carcinoma; Multilocular Cystic Renal Cell 
Carcinoma; Other histology with clear-cell component]

Histopathology Variants [e.g. Renal Cell Carcinoma Associated with Neuroblastoma; 
Papillary Renal Cell Carcinoma, etc.]

Disease stage at study entry [II; III; IV; Other; Unknown]

Von Hippel-Lindau Syndrome status [Positive; Negative; Unknown]

Von Hippel-Lindau Syndrome Positive status [PTEN; VHL; Other, Specify]

Karnofsky Performance Status (KPS)
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Statistical Analysis Plan
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Stratification factors consist of:

Prior lines of therapy: 1, >1 prior line

International Metastatic Renal Cell Carcinoma Database Consortium risk category: 
Favorable, Intermediate, or Poor.
There will be separate summaries for stratification by original IRT and corrected IRT.
7.5
Medical History and Concurrent Medical Conditions
No summary for medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
No summary for medical history.
The number and percentage of patients taking concomitant medications will be tabulated by 
WHO standardized medication name based on safety analysis set. Concomitant medications are 
medications ongoing at the time of the first dose of study drug or medications that started after 
first dose and within 30 days of the last dose of study drug.
7.6.1
Prior Therapies
The number and percentage of patients with prior radiation, and prior anti-cancer therapies will 
be summarized based on safety analysis set. The following will be summarized for those patients 
with prior anti-cancer therapies:

Number of prior lines

Number of prior VEGF-targeted therapy

Type of prior VEGF-targeted therapy

Other types of prior treatments (non VEGF-targeted therapy) e.g. cytokines (eg, interleukin-
2, interferon-alpha), monoclonal antibodies, (eg, bevacizumab, anti-PD-1),

Best response to most recent prior therapy 
7.6.2
Follow-up Anti-cancer Therapy
Number and percentage of patients receiving any anti-cancer therapy, and type of anti-cancer 
therapy will be summarized based on safety analysis set.
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7.7
Study Drug Exposure and Compliance
7.7.1
Study Treatments
Cycles consist of 28 days for all treatment arms. In Treatment Arm A, everolimus will be 
administered 10 mg QD (every day of a 28-day treatment cycle). In Treatment Arm B, 30 mg of 
MLN0128 will be administered once weekly (on Days 1, 8, 15, and 22 of a 28-day treatment 
cycle) and should be taken on the same day of each week. In Treatment Arm C, MLN0128 4 mg
and MLN1117 200 mg will be administered together, 3 consecutive days per week (on Days 1-3, 
8-10, 15-17, and 22-24 of a 28-day treatment cycle), and should be taken on the same days of 
each week.
7.7.2
Extent of Exposure
Summaries and descriptive statistics of duration of treatment in weeks ((last dose date – start 
dose date + 1)/7), total number of cycles administered, average daily dose for everolimus, 
cumulative dose for each study drug, planned cumulative dose for each study drug and relative 
dose intensity will be summarized by treatment arm 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. This is defined as Actual Dose greater than zero for at least 
one of the dosing days in the cycle for any study drug.
Cumulative dose (mg) = Sum of all doses (mg) administered to a subject during the treatment 
period.
Relative dose intensity = (cumulative dose / planned cumulative dose.
Everolimus treatment (10 mg QD)
Average daily dose (mg/day) is defined as:
Cumulative dose) / duration of treatment in days
Planned cumulative dose: (Date of first dose in last cycle – Date of first dose + 28 days) * 4 
mg/day
MLN0128 treatment (30 mg QW)
Planned cumulative dose: 
[(Date of first dose in last cycle – Date of first dose + 28 days) / 7] * 30 mg/week
MLN0128+MLN1117 treatment (QDx3)
Planned cumulative dose for MLN0128 4 mg QDx3:
[(Date of first dose in last cycle – Date of first dose + 28 days) / 7] * 12 mg/week
Planned cumulative dose for MLN1117 200 mg QDx3:
[(Date of first dose in last cycle – Date of first dose + 28 days) / 7] * 600 mg/week
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Statistical Analysis Plan
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7.7.3
Action on Drug
Action on study drug will be summarized by each cycle (Cycles 1-8) and total, for each 
treatment arm in the safety analysis set.
7.8
Efficacy Analysis
The analysis of PFS, OS and TTP will be based on the full analysis set. The analysis of ORR, 
CBR and CBR-16 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.
7.8.1
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
In the event of progression, the date of progression is defined as the earliest date among target 
lesions, non-target and new lesions 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.   
The approach for handling of missing response assessments and censoring is presented below:
Situation
Date of Progression or 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 other than not evaluable, no 
assessment performed or missing (i.e. CR, PR, SD or PD).
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Statistical Analysis Plan
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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 6 and, 12 months will be presented. The primary hypothesis is to be tested at the 0.15 
significance level (2-sided). The p-values from 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 comparison of everolimus vs. MLN0128 and 
everolimus vs. MLN0128 + MLN1117. 
The stratification factors are the number of prior lines of therapy (1, >1 prior line) and the 
International Metastatic Renal Cell Carcinoma Database Consortium risk category (Favorable, 
Intermediate, or Poor). 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

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
Subgroup Analyses
The analysis of PFS will be repeated in each of the following subgroups. The focus of the 
subgroup analyses is to assess the consistency of treatment effects and to present number of 
patients with events/censored, 25th, median and 75th percentile with HR and 95% CI within each 
subgroup for the 2 comparisons: everolimus vs. MLN0128 and everolimus vs. 
MLN0128+MLN1117. In addition, number of events/number of patients in each arm, hazard 
ratio (HR) and 95% CI within each subgroup for the 2 treatment comparisons will be presented 
as part of the forest plots and individual Kaplan-Meier survival curves for each subgroup will be 
presented.
The analysis of PFS will be repeated in each of the following subgroups.

Stratification factors per IRT (original):

Number of prior lines of therapy (1, >1 prior line)

International Metastatic Renal Cell Carcinoma Database Consortium risk category 
(Favorable, Intermediate, or Poor)
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7.8.2
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 4 months (CBR-16). The analyses of OS and TTP will be done for 
the full analysis set. The analyses of ORR, CBR, and CBR-16 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 (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 
6 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 everolimus to MLN0128 and everolimus to 
MLN0128+MLN1117. The stratification factors are the number of prior lines of therapy (1, >1 
prior line) and the International Metastatic Renal Cell Carcinoma Database Consortium risk 
category (Favorable, Intermediate, or Poor). 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.
Best Overall Response (unconfirmed): 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.
Best Overall Response (confirmed): This will be the best response reported by the investigator; 
ordered from best to worst: Complete Response, Partial Response, Stable Disease, Progressive 
Disease. Complete or partial responses may be claimed as best response only if the criteria for 
each are met at a subsequent time point. For the best overall response (confirmed), the 
confirmation derivation rules will be as described in the following table.
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Statistical Analysis Plan
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Overall response 1st time 
point
Overall response subsequent 
time point
BEST overall response
CR
CR
CR
CR
PR
PR
CR
SD
SD
CR
PD
SD
CR
NE
SD
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD
PR
NE
SD
NE
NE
NE
Note: No adjustment for a minimum criteria for SD is needed as the first protocol scan is at the 
end of cycle 2, approximately 8 weeks from first dose.
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 
of response following RECIST 1.1. ORR will be summarized by both ORR based on 
unconfirmed best response and ORR based on confirmed best response. 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 (everolimus vs. MLN0128 and everolimus vs. 
MLN0128+MLN1117). 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. CBR will be presented for both CBR based on unconfirmed best response and CBR 
based on confirmed best response. A stratified Cochran-Mantel-Haenszel (CMH) test based on 
stratification factors will be used to compare CBR between treatment arms (everolimus vs. 
MLN0128 and everolimus vs. MLN0128+MLN1117). 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 4 months (CBR-16)
CBR with SD duration of at least 4 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 16 weeks (see 
below). CBR-16 will be summarized based on unconfirmed best response and confirmed best 
response. A stratified Cochran-Mantel-Haenszel (CMH) test based on stratification factors will 
be used to compare CBR-16 between treatment arms (paclitaxel vs. paclitaxel+MLN0128, 
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Statistical Analysis Plan
03 December 2018
paclitaxel vs. MLN0128 and paclitaxel vs. MLN0128+MLN1117). The Mantel-Haenszel 
estimate of the odds ratio and the associated 95% CIs will be presented for each comparison 
specified above.
SD for at least 16 weeks is a subset of SD, only calculated for those patients with a best response 
of SD. It is defined as SD at the end of Cycle 2 and at the end of Cycle 4. 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 16 weeks will 
include cases where two or more post baseline scans have SD (or PR/SD for confirmed response) 
and the duration of stable disease is greater than 112 days.
CBR at 16 weeks (unconfirmed) is defined as the number of patients who achieve CR or PR at 
any time or have SD for at least 16 weeks.
CBR at 16 weeks (confirmed) is defined as the number of patients who achieve confirmed CR or 
confirmed PR at any time or have SD for at least 16 weeks or meet the following criteria:
Overall response at end of 
Cycle 2
Overall response at end of 
Cycle 4
Meet criteria CBR at 16 
weeks?
CR/PR (unconfirmed)
SD
YES
SD
CR/PR (unconfirmed)
YES
In addition, the proportion of patients with the following best response will be summarized by 
treatment group: CR, PR, SD, SD at least 16 weeks, overall response (ORR), CBR and CBR-16 
weeks.
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 
6and 12 24 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 comparison of everolimus to MLN0128 and everolimus to 
MLN0128+MLN1117. The stratification factors are the number of prior lines of therapy (1, >1 
prior line) and the International Metastatic Renal Cell Carcinoma Database Consortium risk 
category (Favorable, Intermediate, or Poor).  The original IRT stratification factors will be used 
in models.
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7.8.3
Additional Efficacy Endpoint(s)
The duration of objective response (DOR) will be calculated for those patients with a best 
response of CR or PR (for unconfirmed), and is defined as the number of days from the start date 
of CR, or PR (whichever response is achieved first) until progressive disease or until the last 
adequate response assessment if there is no progressive disease. The Kaplan-Meier method will 
be used to analyze the distribution of DOR for each treatment arm. The 25th, 50th (median), and 
75th percentiles, along with median and 2-sided 95% confidence intervals (CIs) will be 
presented. The analysis of duration of response will be descriptive in nature and will be based on 
response-evaluable analysis set.
Waterfall plots of the best percentage change from baseline in the sum of the longest diameter 
(SLD) of the target lesions will be generated for each treatment group using the response-
evaluable analysis set. If one of the target lesion measurements is missing at a visit then the SLD 
at that visit will not be used for selecting the best percentage change from baseline in SLD for 
the waterfall plot. The SLD will be calculated based on the following rules:
1. If a target lesion at a visit is “too small to measure”, per the CRF completion guidelines the 
value of 5 mm should have been entered as the diameter.  This would be used to calculate the 
SLD.
2. If 2 target lesions conjoin into a single lesion (status=”coalesce”), per the CRF completion 
guidelines the LD of the resulting merged lesion is divided by 2 and reported in the CRF for 
each of the previous TL and then would be included in the SLD. 
3. If a target lesion splits into 2 lesions (status=”split”), the LDs of the fragmented portions are 
added up and reported in the CRF and would be included in the SLD.
4. Sum of the target lesions (SLD) [in mm] is defined as the sum of the longest diameters of all 
target lesions at each visit.
5. SLD change from baseline at visit x [in mm] is defined as the absolute change in the SLD 
from baseline to each visit = “SLD at visit x” – “SLD at baseline”.  Baseline SLD 
corresponds to the SLD from the screening visit.
6. Percentage change from baseline in SLD [in %] is defined as “SLD change from baseline at 
visit x” / “SLD at baseline” * 100.
7. Best percentage change in SLD is defined as the percentage change from baseline in SLD at 
the visit with the smallest SLD value among all the post screening visits.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Sparse PK data for MLN0128 and MLN1117 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 or MLN1117 is characterized for population PK analysis. The results of the 
population PK analysis will be presented in a separate report.
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Statistical Analysis Plan
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7.10
Patient Reported Outcomes
Patient-reported outcome (PRO) assessments will be collected through 2 different instruments: 
EORTC QLQ-C30 and FKSI-DRS. 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 FKSI-DRS 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. Patients with baseline scores, but with no follow-up scores, are not assessable for 
change from baseline. Published manuals/guidance for EORTC QLQ-C30 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.
7.10.1 EORTC QLQ-C30 and FKSI-DRS Score
Descriptive statistics (including 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 FKSI-DRS
questionnaires, the global health status/QOL score and summary score from the EORTC QLQ-
C30 questionnaire, and the FKSI-DRS summary score up to 6 cycles (extend beyond 6 cycles if 
at least 10 patients in each treatment arm have results).  In addition, the mean and mean change 
from baseline (including 95% CI) will also be presented over time by treatment group in figures 
up to 6 cycles (extend beyond 6 cycles if at least 10 patients in each treatment arm have results). 
The change from baseline of EORTC QLQ-C30 subscales, global health status/QOL, summary 
score,FKSI-DRS 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-
intercept only model with appropriate covariance structure will be used based on the following 
covariance structure in order from unstructured, spatial-power 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 6 cycles for each 
treatment arm (extend beyond 6 cycles if at least 10 patients in each treatment arm have results). 
The mean difference in each score and 95% CIs and p values for the pairwise comparison of 
everolimus to MLN0128 and everolimus to MLN0128+MLN1117 will be presented at each time 
point up to 6 cycles (extend beyond 6 cycles if at least 10 patients in each treatment arm have 
results).
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Statistical Analysis Plan
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7.11
Safety Analysis
All safety analyses will be performed using the Safety analysis set.
7.11.1 Adverse Events
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.
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)
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.
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Statistical Analysis Plan
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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
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
Mucosal inflammation
Mucosal membrane hyperplasia
Mucosal necrosis
Mucosal pain
Mucosal pigmentation
Mucosal roughness
Mucosal toxicity
Mucosal ulceration
Mucous membrane disorder
Oedema mucosal
Mucosal infection
Mucosal excoriation
Erythroplasia
Burning sensation mucosal
Paraesthesia mucosal
Leukoplakia
Drug eruption
Fixed eruption
Mucocutaneous haemorrhage
Rash
Mucocutaneous rash
Nodular rash
Rash
Rash erythematous
Rash generalised
Rash macular
Rash maculo-papular
Rash maculovesicular
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Statistical Analysis Plan
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Adverse event of interest
MedDRA Preferred Term
Rash morbilliform
Rash papular
Rash rubelliform
Rash scarlatiniform
Rash vesicular
7.11.1.1 Deaths
All deaths occurring on-study and during follow-up will be displayed (regardless of treatment-
emergent AE status). On-study death is defined as death that occurs between the first dose of 
study drug and 30 days after the last dose of study drug (adverse events with an outcome of 
death).
All cause mortality will be tabulated, which includes death of all causes, deaths related to disease 
under study, and deaths due to other reasons.  On-study deaths will be tabulated, which includes 
deaths related to disease under study, deaths due to other reasons, and deaths within 30 and 60 
days of first dose.
7.11.1.2 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 everolimus and MLN0128 + MLN1117 arms, and for the MLN0128 QW 
patients enrolled prior to protocol amendment no 4.  Similarly, the changes from pre-dose to 2 
hours post dose 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, 
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High-density lipoprotein cholesterol (HDL-C) and Low-density lipoprotein cholesterol (LDL-C) 
at each scheduled visit up to and including 6 cycles. Figures of mean actual values over time will 
also be generated for these clinical laboratory parameters (in SI units).
7.11.2 Vital Signs
The actual values 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. Change from baseline will also be presented. 
7.11.3 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. 
In addition, 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.
All QT values will be converted to QTcF using Fridericia’s correction:
(sec)
[Note: RR (sec) = 60 / ventricular rate in beats/minute].
7.11.4 Karnofsky Performance Status
Shifts from baseline to the worst post-baseline on study score will be tabulated by treatment arm.
7.12
Interim Analysis
As specified in the protocol
Study data will be reviewed after the first 30 patients in each arm have received 2 cycles of study 
drug. If at the end of cycle 2, 50% or more patients in a treatment arm (ie, Arm B [single agent 
MLN0128] or Arm C (MLN0128+MLN1117) have either progressive disease or have died, or 
have discontinued study treatment due to treatment-related AEs, then that study arm may be
closed. If both Arms B and C meet these criteria, then the study may be closed.
A second futility analysis not specified in the protocol was to be performed when 50% of PFS 
events occurred for each of the pairwise comparisons:  everolimus vs. MLN0128 QW and 
everolimus vs. MLN0128 + MLN1117.  The decision rule is based on a Bayesian framework: 
posterior probability (true HR > 0.74 | observed HR) is greater than 80%.  The futility criteria 
will be met if the observed PFS HR for either comparison is greater than or equal to 0.945.
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Statistical Analysis Plan
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7.13
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 
everolimus arm (presented by crossover treatment):

Duration of treatment (weeks) prior to/after crossover
In addition, TEAEs resulting in discontinuation of crossover treatment, serious AEs, and deaths 
while on cross-over treatment will be presented in by-patient listings.
7.14
Changes in the Statistical Analysis Plan 
1. Based on the results from the planned interim analysis (after the first 30 patients in each arm 
had received 2 cycles of study drug) enrollment to the study was permanently closed in all
treatment arms.  Therefore, the main analysis will no longer be conducted when the required 
number of PFS events has been reached.  The final analysis may be conducted when all 
patients have received at least 6 cycles of treatment or later.
2. 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.
3. 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 everolimus to MLN0128 and everolimus
to MLN0128+MLN1117. The protocol did not explicitly state the model for estimating the 
HRs.
4. For secondary endpoints e.g. ORR, CBR, and CBR-16 will be based on both confirmed and 
unconfirmed best overall response.
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8.0
REFERENCES
1. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of
everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic 
factors. Cancer 2010;116(18):4256-65.
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9.0
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 to include the following information:

Disposition of subjects (including crossover treatment, if applicable)

Demographic and other baseline characteristics (including stratification factors)

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

Important protocol deviations
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Statistical Analysis Plan
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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.
If year and month are present and day is missing:
Set day to last day of the month.
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Statistical Analysis Plan
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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
Property of Takeda: For Non-Commercial Use Only and Subject to the Applicable Terms of Use


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