Clinical trial NCT02049957
Conditions: Breast Cancer
Keywords: Sapanisertib MLN0128
Sponsor: Calithera Biosciences, Inc
Start date: 2014-02-13; Completion date: 2018-06-29
Enrollment: 118 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 1b/2 study of the safety and efficacy of sapanisertib (MLN0128) in combination with exemestane or fulvestrant therapy in women with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced or metastatic breast cancer who progressed on treatment with everolimus in combination with exemestane or fulvestrant.

Detailed description:
The drug being tested in this study is called sapanisertib (MLN0128). Sapanisertib is being tested in women with estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) advanced or metastatic breast cancer who progressed on treatment with everolimus. This study will look at the safety and efficacy of sapanisertib when given in combination with exemestane or fulvestrant.

The study enrolled 118 patients. This study has two phases: phase 1 and phase 2. Phase 1 has 2 parts. In part 1 of phase 1, unmilled active pharmaceutical ingredient (API) capsules were administered, while in part 2, capsules based on milled API were administered.

* Phase 1 (Part 1): sapanisertib 5 mg (unmilled) + exemestane
* Phase 1 (Part 1): sapanisertib 5 mg (unmilled) + fulvestrant
* Phase 1 (Part 2): sapanisertib 3 mg (milled) + exemestane
* Phase 1 (Part 2): sapanisertib 3 mg (milled) + fulvestrant
* Phase 1 (Part 2): sapanisertib 4 mg (milled) + exemestane

In phase 2, participants were enrolled into one of 2 parallel cohorts, depending on the quality and/or duration of their prior response to everolimus in combination with either exemestane (any country) or fulvestrant (US only).

Everolimus-Resistant Cohort: patients who had progressed on treatment with everolimus in combination with either exemestane (any country) or fulvestrant (US only) without achieving an objective response (CR or PR) or after achieving stable disease for \<6 months as their best response.

Everolimus-Sensitive Cohort: participants who had progressed on treatment after achieving a CR or PR of any duration, or stable disease for ≥6 months with prior everolimus treatment in combination with either exemestane (any country) or fulvestrant (US only). Participants were to receive MLN0128 in combination with the same dose of the previously administered treatment (exemestane \[any country\] or fulvestrant \[US only\]).

This multi-center trial will be conducted worldwide. The overall time to participate in this study was 52 months. Participants made multiple visits to the clinic and were contacted by telephone every 3 months for a follow-up assessment.

Arms: arm 1: Sapanisertib 5 mg, unmilled active pharmaceutical ingredient (API) capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 12 cycles). arm 2: Sapanisertib 5 mg, unmilled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection, intramuscularly (IM), once on Day 1 of each cycle (Up to 57 cycles). arm 3: Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 8 cycles). arm 4: Sapanisertib 3 mg, milled API capsule, once daily in a 28-day cycle up to 14 cycles plus fulvestrant 500 mg, injection, IM, once on Day 1 of each cycle (Up to 14 cycles). arm 5: Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 18 cycles). arm 6: Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus exemestane 25 mg, tablets, once daily in a 28-day cycle (Up to 14 cycles) in everolimus sensitive participants. arm 7: Sapanisertib 4 mg, milled API capsule once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 17 cycles) in everolimus sensitive participants. arm 8: Sapanisertib 4 mg, milled API capsule, once daily, in a 28-day cycle plus once daily in a 28-day cycle (Up to 12 cycles) in everolimus resistant participants. arm 9: Sapanisertib 4 mg, milled API capsule, once daily in a 28-day cycle plus fulvestrant 500 mg, injection IM, once on Day 1 of each cycle (Up to 9 cycles) in everolimus resistant participants.
Interventions: intervention 1: Sapanisertib intervention 2: Fulvestrant intervention 3: Exemestane
Intervention descriptions: intervention 1: Sapnisertib capsules intervention 2: Fulvestrant IM injection. intervention 3: Exemestane tablets.

Protocol documents:
Prot_000.pdf: 


•
Title: A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in 
Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With ER+/
HER2 Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With 
Everolimus in Combination With Exemestane or Fulvestrant
NCT Number: NCT02049957
Protocol Approve Date: 26 October 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


MLN0128
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CLINICAL STUDY PROTOCOL C31001 AMENDMENT 6
MLN0128
A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in 
Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With 
ER+/HER2! Advanced or Metastatic Breast Cancer That Has Progressed on Treatment 
With Everolimus in Combination With Exemestane or Fulvestrant
Protocol Number:
C31001
Indication:
Breast cancer
Phase:
1b/2
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2014-001921-34
Therapeutic Area:
Oncology
Protocol History
Original
06 September 2013
Amendment 4
22 October 2015
Amendment 1
16 June 2014
Amendment 5
12 May 2017
Amendment 2
15 September 2014
Amendment 6
26 October 2017
Amendment 3
12 March 2015
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
Approved by:
Note: If this document was approved electronically, the electronic approval signatures may
be found at the end of the document.
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior 
written authorization of Millennium Pharmaceuticals is expressly prohibited.
PPD


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Rationale for Amendment 6
This document describes the changes in reference to the protocol incorporating 
Amendment 6. The primary purpose of this amendment is to update sections affected by new 
nonclinical data for MLN0128 metabolism by specific cytochrome P450 (CYP) isoforms. 
The study’s exclusion criteria, list of prohibited concomitant medications, list of relevant 
CYP inhibitors, dietary restrictions related to CYP inhibitors and inducers, use of contrast 
with magnetic resonance imaging (MRI), and the description of potential drug-drug 
interactions have been updated accordingly.
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 changes are located, see Appendix 14.10.
Changes in Amendment 6
1. Remove the exclusion criterion relating to treatment with strong CYP inhibitors or 
inducers.
2. Update the list of concomitant medications prohibited during the study.
3. Update the list of relevant CYP inhibitors and inducers.
4. Remove dietary restrictions related to CYP inhibitors and inducers.
5. Clarify language surrounding the use of contrast with MRI.
6. Update the description of potential drug-drug interactions between MLN0128 and 
exemestane.
7. Update the signature page.


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PROTOCOL SUMMARY
Study Title: A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in 
Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With 
ER+/HER2! Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With 
Everolimus in Combination With Exemestane or Fulvestrant
Number of Patients: Approximately 128 patients will be enrolled in this study from approximately 
40 study centers in the United States (US), Belgium, and France. A patient will be considered 
enrolled after receiving the first dose of MLN0128.
Study Objectives:
Primary Objectives
The primary objectives include:
Phase 1b
∀To evaluate the safety and tolerability of MLN0128 in combination with either exemestane or 
fulvestrant.
Phase 2
∀To evaluate the antitumor activity by clinical benefit rate at 16 weeks (defined as the 
proportion of patients who achieve complete response [CR] or partial response of any 
duration, or have stable disease [SD] at 16 weeks) of treatment with MLN0128 in 
combination with either exemestane or fulvestrant.
Secondary Objectives
∀To further evaluate the antitumor activity of MLN0128 in combination with either 
exemestane or fulvestrant.
∀To evaluate the pharmacokinetics (PK) of MLN0128 and exemestane when administered in 
combination and to evaluate the PK of MLN0128 when administered in combination with 
fulvestrant.
∀To assess the safety and tolerability of MLN0128 in combination with either exemestane or 
fulvestrant.
Exploratory Objectives
CCI


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Overview of Study Design: This is a phase 1b/2 study of the safety and efficacy of MLN0128 (also 
known as TAK-228) in combination with exemestane or fulvestrant therapy in women with estrogen 
receptor-positive/human epidermal growth factor receptor 2-negative (ER+/HER2) advanced or 
metastatic breast cancer that has progressed on treatment with everolimus in combination with 
exemestane (any country) or fulvestrant (US only). Patients enrolled in this study will be given either 
exemestane (any country) or fulvestrant (US only) in combination with MLN0128.
In the phase 1b portion of the study, the safety and tolerability of MLN0128 using a capsule 
formulation based on unmilled (Part 1) and milled (Part 2) active pharmaceutical ingredient (API) in 
combination with either exemestane or fulvestrant will be evaluated. Patients enrolled in Part 1 will 
remain on MLN0128 capsules based on unmilled API and will continue to take their MLN0128 
doses with a light meal. Patients enrolled into Part 2 will receive MLN0128 capsules containing 
milled API and will take each MLN0128 dose on an empty stomach. Patients will be enrolled as 
follows:
Part 1 Patients (Capsules Based on Unmilled API):
MLN0128+Exemestane Safety Cohort: Six patients will receive MLN0128 capsule 
formulation based on unmilled API (5 mg once daily [QD]) in combination with exemestane 
(administered per prior therapy for the patient). Steady-state serial PK samples will be 
collected to quantify both MLN0128 and exemestane to characterize the PK of MLN0128 
and exemestane when administered in combination.
MLN0128+Fulvestrant Safety Cohort (US Only): Six patients will receive MLN0128 
capsule formulation based on unmilled API (5 mg QD) in combination with high-dose 
fulvestrant (500 mg intramuscularly every month).
Part 2 Patients (Capsules Based on Milled API):
MLN0128+Exemestane/Fulvestrant Safety Cohort 1: Six patients will receive MLN0128 
capsule formulation based on milled API (3 mg QD) in combination with either exemestane 
(any country) or fulvestrant (US only). Serial blood samples will be collected to evaluate the 
PK of MLN0128 when administered in combination with either exemestane or fulvestrant. 
After the last patient completes Cycle 1, a safety and tolerability assessment will be 
performed. If 2 dose-limiting toxicities (DLTs) occur in these 6 patients, the dose of 
MLN0128 will be reduced to 2 mg QD for patients subsequently enrolled in Cohort 2 of 
Part 2 of the phase 1b portion of this study. If 1 DLT occurs in Cohort 1, the dose of 
MLN0128 will be escalated to 4 mg QD for patients entering Cohort 2.
MLN0128+Exemestane/Fulvestrant Safety Cohort 2: Six patients will receive MLN0128 
capsule formulation based on milled API, either 4 or 2 mg QD based on the safety observed 
in Cohort 1, in combination with either exemestane (any country) or fulvestrant (US only). 
Serial PK samples will be collected as outlined for Cohort 1. After the last patient completes 
Cycle 1, a safety and tolerability assessment will be performed.
o
If ≥2 DLTs occur in the treatment group receiving 4 mg of MLN0128, the 
subsequent phase 2 portion of the study will be initiated at 3 mg of MLN0128 QD in 
combination with exemestane or fulvestrant.
o
If ≤1 DLT occurs in the treatment group (either at 4 mg or 2 mg QD), the 
subsequent phase 2 portion of the study will be initiated at the same dose (either 
2 mg or 4 mg MLN0128 QD) in combination with exemestane or fulvestrant.
o
If ≥2 DLTs occur in the treatment group receiving 2 mg of MLN0128 in 
combination with either exemestane and/or fulvestrant, the study will be stopped.


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In the phase 2 portion of the study, patients will be administered MLN0128 capsule formulation 
based on milled API at 4 mg QD in combination with either exemestane or fulvestrant, based on the 
outcome of the safety and tolerability analysis performed in the phase 1b portion of the study. 
Patients will be enrolled into one of 2 parallel cohorts, depending on the quality and/or duration of 
their prior response to everolimus in combination with either exemestane (any country) or fulvestrant 
(US only) as follows:
Everolimus-Resistant Cohort: This is a cohort of 56 response-evaluable patients who have 
progressed on prior treatment with everolimus in combination with either exemestane (any 
country) or fulvestrant (US only) without achieving an objective response (CR or partial 
response) or after achieving SD for 6 months as their best response. Patients will receive 
MLN0128 in combination with exemestane (any country) or fulvestrant (US only).
Everolimus-Sensitive Cohort: This is a cohort of 48 response-evaluable patients who have 
progressed on treatment after achieving a CR or partial response of any duration, or SD 
6 months with prior everolimus treatment in combination with either exemestane (any 
country) or fulvestrant (US only). Patients will receive MLN0128 in combination with 
exemestane (any country) or fulvestrant (US only).
Sparse PK samples will be collected from all patients enrolled in the study (regardless of whether 
they are administered MLN0128 in combination with exemestane or fulvestrant) for plasma PK 
analysis of MLN0128 only. Data generated in this study will be combined with data from other 
studies in which the PK of MLN0128 is characterized for population PK analysis.
Radiological tumor evaluations will be used to evaluate disease response according to Response 
Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1).
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for 
Adverse Events. Adverse events will be assessed and clinical laboratory values, vital signs, and 
electrocardiograms will be obtained to evaluate the safety and tolerability of MLN0128 in 
combination with either exemestane or fulvestrant.
Study Population: Female patients must be 18 years of age or older and postmenopausal for at least 
1 year before the Screening visit to be enrolled in the study. Patients must have advanced or 
metastatic breast cancer, and must have histological or cytological confirmation of ER+/HER2
status. Patients who have a history of treated brain metastasis are eligible for the study provided that 
there is no sign of disease progression or hemorrhage after treatment, they are off-treatment, and 
have no ongoing requirement for dexamethasone or antiepileptic drugs. Patients must have an 
Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate clinical laboratory 
values and left ventricular ejection fraction. Patients must provide paraffin blocks or a minimum of 
10 unstained slides of available archival tumor tissues (paraffin blocks are preferred) or a tumor 
biopsy before beginning treatment with MLN0128.
To be enrolled in the phase 1b portion of the study, patients may have SD or disease progression 
during their most recent treatment with exemestane (any country) or fulvestrant (US only). 
Exemestane or fulvestrant in combination with MLN0128 can also be initiated as a new line of 
therapy. To be enrolled in the phase 2 portion of the study, patients must have measureable disease 
defined as at least 1 extraosseous lesion that can be accurately measured in at least 1 dimension 
(RECIST, version 1.1) or bone lesions (lytic or mixed [lytic plus sclerotic]) and have had disease 
progression during treatment with everolimus in combination with either exemestane (any country) 
or fulvestrant (US only). Treatment with everolimus in combination with either exemestane (any 
country) or fulvestrant (US only) is not required to be the most recent treatment before enrollment.


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Duration of Study: Patients will receive MLN0128 in combination with either exemestane (any 
country) or fulvestrant (US only) until they experience disease progression. Patients will discontinue 
treatment if they have an unacceptable drug-related toxicity. The maximum duration of treatment 
will be 24 months. If after discussion between the investigator and sponsor it is determined that a 
patient would derive benefit, the patient may continue treatment beyond 24 months.
Patients will attend an End-of-Treatment (EOT)/Early Termination visit 30 days after receiving their 
last dose of MLN0128, or at the start of subsequent anticancer therapy. After EOT, patients will be 
followed for progression-free survival and overall survival. The study will be terminated 6 months 
after the last patient completes an EOT study visit.


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STUDY OVERVIEW DIAGRAM
Phase 1b (Safety Lead-In)


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Phase 2 (Safety and Efficacy)
Phase 1b patients are not eligible for participation in phase 2. In the phase 2 portion, patients will be enrolled 
into one of 2 parallel cohorts, depending on the quality and/or duration of their prior response to everolimus 
in combination with either exemestane (any country) or fulvestrant (United States only).
API=active pharmaceutical ingredient, OS=overall survival, PFS=progression-free survival, QD=once daily.


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SCHEDULE OF EVENTS
Screening 
(a)
TREATMENT CYCLES
EOT/ 
ET (b)
PFSFU
/OSFU
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5 and 
Beyond
Day -28 
to Day -1
Day 1
Day 15 
(±2 
Days)
Day 1
Day 15 
(±2 
Days)
Day 28 
(±2 
Days)
Day 1
Day 1
Day 28 
(±2 
Days)
Day 1
Day 28 
(±2 
Days)
Study Procedures
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history (c)
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital signs (d)
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
ECHO/MUGA
X
Single, 12-lead ECG
X
X (e)
X (e)
X (e)
X
Radiographic tumor evaluation 
(f)
X
X
X
X (f)
Q3mo 
(g)
Follow-up phone calls (OS and 
subsequent anticancer therapy)
Q3mo 
(g)
Monitoring of concomitant 
medications and procedures
Recorded from the first dose of MLN0128 through 30 days following the last dose 
Adverse event reporting
Recorded from the first dose of MLN0128 through 30 days after the last dose 
Serious adverse events (h) will be reported from signing of the ICF through 30 days after the last dose of MLN0128
MLN0128 administration
QD dosing (see Section 6.1) 


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Screening 
(a)
TREATMENT CYCLES
EOT/ 
ET (b)
PFSFU
/OSFU
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5 and 
Beyond
Day -28 
to Day -1
Day 1
Day 15 
(±2 
Days)
Day 1
Day 15 
(±2 
Days)
Day 28 
(±2 
Days)
Day 1
Day 1
Day 28 
(±2 
Days)
Day 1
Day 28 
(±2 
Days)
Antihormonal therapy 
administration
Exemestane orally QD or fulvestrant IM every month (i)
Samples/Laboratory Assessments
Hematology/chemistry
X1
X1 (j)
X1
X1
X1
X1
X1
X1
X1
Urinalysis
X1 (k)
X1 (j)
X1
X1
X1
X1
X1
X1
X1
Coagulation (PT/INR, aPTT) (l)
X1
X1 (j)
X1
X1
X1
X1
X1
X1
X1
Fasting serum glucose (m)
X1
X1
X1
X1
X1
X1
X1
In-home daily fasting glucose 
monitoring (n)
X
Fasting lipid profile
X1 (o)
X1
X1
X1
X1
X1
HbA1c
X1
X1
Q3C
Blood sample for PK analysis (p)
See the Phase 1b Pharmacokinetic and ECG Sample Breakdown and the Phase 2 Pharmacokinetic 
and ECG Sample Breakdown table
Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days) with permission from the medical monitor for holidays, vacations, 
and other administrative reasons. If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled procedure or assessment 
within this time, the patient may continue the study only with the written permission of the project clinician.
aPTT=activated partial thromboplastin time, C=cycle, CT=computed tomography, 
ECHO=echocardiogram, ECG=electrocardiogram, 
CCI
CCI
CCI
CCI
CCI


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Screening 
(a)
TREATMENT CYCLES
EOT/ 
ET (b)
PFSFU
/OSFU
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5 and 
Beyond
Day -28 
to Day -1
Day 1
Day 15 
(±2 
Days)
Day 1
Day 15 
(±2 
Days)
Day 28 
(±2 
Days)
Day 1
Day 1
Day 28 
(±2 
Days)
Day 1
Day 28 
(±2 
Days)
ECOG=Eastern Cooperative Oncology Group, eCRF=electronic case report form, EOT=End of Treatment (visit), ET=Early Termination, HbA1c=glycosylated 
hemoglobin, ICF=informed consent form, IM=intramuscular(ly), INR=international normalized ratio, mo=months, MRI=magnetic resonance imaging, 
MUGA=multiple gated acquisition (scan), OS=overall survival, OSFU=overall survival follow-up, PFS=progression-free survival, PFSFU=progression-free survival 
follow-up, PK=pharmacokinetic(s), PT=prothrombin time, Q=every, QD=once daily, RECIST=Response Evaluation Criteria in Solid Tumors, SmPC=Summary of 
Product Characteristics, USPI=United States Prescribing Information, X#=the number of samples required (eg, 2 samples=X2).
(a) Screening assessments are performed within 28 days before the Cycle 1 Day 1 MLN0128 dose. Screening assessments performed no more than 3 days before Day 1 
will qualify as baseline assessments and need not be repeated, unless otherwise specified.
(b) Patients will attend an EOT/ET visit 30 to 40 days after receiving their last dose of MLN0128 or at the start of subsequent anticancer therapy, at which time patients 
will enter posttreatment follow-up. If subsequent anticancer therapy is required before 30 days after the last dose, the EOT/ET visit should be conducted before the 
initiation of subsequent anticancer therapy.
(c) For patients enrolling into phase 2 who have measurable disease and are undergoing CT scans (rather than MRIs) for tumor assessment, the most recent CT scan 
performed before the baseline CT scan for this study will be collected, if available. See Section 7.4.3.
(d) Vital sign measurements include blood pressure (diastolic and systolic), heart rate, and temperature.
(e) Single, 12-lead ECGs will be collected according to the schedule presented in the Phase 1b Pharmacokinetic and ECG Sample Breakdown and the Phase 2 
Pharmacokinetic and ECG Sample Breakdown table. When the timing of an ECG coincides with blood samples for PK, the ECG should be completed first.
(f) Contrast-enhanced imaging CT or MRI of the chest, abdomen, and pelvis must be obtained at baseline within 4 weeks before the first dose of MLN0128. Unless 
contraindicated, such contrast-enhanced imaging CT or MRI scans will be obtained every 2 cycles from Cycle 2 through Cycle 6 (ie, Cycle 2 Day 28, Cycle 4 Day 28, 
and Cycle 6 Day 28) and then every 3 cycles thereafter (ie, Cycle 9 Day 28, Cycle 12 Day 28, Cycle 15 Day 28, etc). A confirmatory scan should be performed at 
approximately 4 weeks from the previous scan for all patients with a complete or partial response. For those patients who have documented radiographic disease 
progression, CT or MRI scans are not required at the EOT visit. The same imaging modality (CT or MRI) should be used throughout the study. 
(g) After EOT, patients will be followed for PFS and OS; see Section 7.10 for more details. For those patients who discontinue MLN0128 for any reason other than 
radiographic disease progression, contrast-enhanced imaging CT or MRI scans should be completed to further assess disease progression (per RECIST, version 1.1).
(h) Including serious pretreatment events; see Section 9.1.1.
(i) Exemestane or fulvestrant should be administered according to the USPI or SmPC and according to the dose administered during previous treatment.
(j) May be assessed up to 24 hours before the study visit.
(k) For screening, creatinine clearance must be ≥50 mL/min based either on Cockroft-Gault estimate or based on a 12- or 24-hour urine collection.
(l) Coagulation assessment is required for all patients at times specified in the Schedule of Events. When a tumor biopsy is required, coagulation assessment is required 
within 24 hours before obtaining the tumor biopsy. See Section 7.4.19 for additional information regarding tumor biopsy.
(m) 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 


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Screening 
(a)
TREATMENT CYCLES
EOT/ 
ET (b)
PFSFU
/OSFU
Cycle 1 
Cycle 2
Cycle 3 
Cycle 4
Cycles 5 and 
Beyond
Day -28 
to Day -1
Day 1
Day 15 
(±2 
Days)
Day 1
Day 15 
(±2 
Days)
Day 28 
(±2 
Days)
Day 1
Day 1
Day 28 
(±2 
Days)
Day 1
Day 28 
(±2 
Days)
minimum of 8 hours before the assessment) for each of these measurements. In-home glucose monitoring is not required on days when fasting glucose is measured in 
the clinic.
(n) 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 Section 7.4.16 for further instruction.
(o) To be completed within 14 days of Cycle 1 Day 1 dosing.
(p) Blood samples for PK analysis will be performed according to the schedule presented in the Phase 1b Pharmacokinetic and ECG Sample Breakdown and the Phase 2 
Pharmacokinetic and ECG Sample Breakdown table.
(q)
(r) 
(s)
CCI
CCI
CCI


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PHASE 1B PHARMACOKINETIC AND ECG SAMPLE BREAKDOWN
Phase 1B Patients (Parts 1 and 2) 
Cycle 1
Cycle 2
Day 1
Day 15
Day 1
Single, 
12-Lead 
ECG (a)
Single, 
12-Lead 
ECG (a)
PK 
(MLN0128+Exemestane 
Safety Cohort and All 
Part 2 patients)
Single, 
12-Lead 
ECG (a)
PK
Pre-MLN0128 dose (within 0.5 hours before dosing 
X
X
X1
X
X1
0.5 hours post-MLN0128 dose (10 min)
X1
X1
1 hour post-MLN0128 dose (10 min)
X1
X1
2 hours post-MLN0128 dose (30 min)
X
X
X1
X
X1
4 hours post-MLN0128 dose (30 min)
X
X1
X1
8 hours post-MLN0128 dose (45 min)
X1
ECG=electrocardiogram, PK=pharmacokinetic, X#=the number of samples required (eg, 2 samples=X2).
Refer to Section 7.4.18 for details regarding the number of patients required from each cohort where blood samples for PK analyses 
should be obtained.
(a) ECGs are assessed for all patients enrolled in the study. When the timing of an ECG coincides with blood samples for PK analysis, the 
ECG should be completed first.


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PHASE 2 PHARMACOKINETIC AND ECG SAMPLE BREAKDOWN
Phase 2
Cycle 1
Cycle 2
Day 1
Day 15
Day 1
Day 15
Single, 12-Lead 
ECG (a)
Single, 12-Lead 
ECG (a)
PK
Single, 12-Lead 
ECG (a)
PK (b)
At time of scheduled visit
X
Pre-MLN0128 dose (within 
0.5 hours before dosing)
X
X
X
2 hours post-MLN0128 dose 
(±30 min)
X
X
X
X
1 hour after previous PK 
sample
X
ECG=electrocardiogram, PK=pharmacokinetic.
Refer to Section 7.4.18 for details regarding the number of patients required from each cohort where blood samples for PK analyses should 
be obtained.
(a) ECGs are assessed for all patients enrolled in the study. When the timing of an ECG coincides with blood samples for PK analysis, the ECG 
should be completed first.
(b) On Cycle 2 Day 15, all patients should take their MLN0128 dose at home before arriving at the clinic for the scheduled visit. All dates and times 
of the doses taken at home must be recorded on the patient diary card. The first Cycle 2 Day 15 PK sample may be collected at any time during 
the clinic visit, and a second PK sample will be collected 1 hour after the first PK sample.


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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................18
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................19
1. BACKGROUND AND STUDY RATIONALE..............................................................22
1.1 Scientific Background ..............................................................................................22
1.1.1 Disease Under Treatment...................................................................................22
1.1.2 Study Drug ........................................................................................................24
1.2 Nonclinical Experience.............................................................................................26
1.3 Clinical Experience ..................................................................................................27
1.3.1 Clinical Experience With MLN0128..................................................................27
1.4 Study Rationale ........................................................................................................28
1.4.1 Mutual DDI Assessment ....................................................................................31
1.4.2 Rationale for Genotyping, Assessment of Biomarkers in Archived Tumor 
Tissues, and Assessment of Prognostic Factors ...........................................32
1.5 Potential Risks and Benefits .....................................................................................33
2. STUDY OBJECTIVES ..................................................................................................33
2.1 Primary Objectives ...................................................................................................33
2.2 Secondary Objectives ...............................................................................................34
2.3 Exploratory Objectives.............................................................................................34
3. STUDY ENDPOINTS....................................................................................................35
3.1 Primary Endpoints....................................................................................................35
3.2 Secondary Endpoints................................................................................................35
3.3 Exploratory Endpoints..............................................................................................36
4. STUDY DESIGN...........................................................................................................36
4.1 Overview of Study Design........................................................................................36
4.1.1 Phase 1b ............................................................................................................36
4.1.2 Phase 2 ..............................................................................................................39
4.2 Number of Patients...................................................................................................40
4.3 Duration of Study.....................................................................................................40
5. STUDY POPULATION.................................................................................................41
5.1 Inclusion Criteria......................................................................................................41
5.1.1 Phase 1b and Phase 2 .........................................................................................41
5.1.2 Phase 1b Only....................................................................................................43
5.1.3 Phase 2 Only......................................................................................................43
5.2 Exclusion Criteria.....................................................................................................44
5.2.1 Phase 1b and Phase 2 .........................................................................................44
5.2.2 Phase 1b Only....................................................................................................46
5.2.3 Phase 2 Only......................................................................................................46
6. STUDY DRUG..............................................................................................................46
6.1 Study Drug Administration.......................................................................................46
6.2 Definitions of DLT for the Phase 1b Portion of the Study.........................................47
6.3 Dose-Modification Guidelines for the Phase 2 Portion of the Study..........................49
6.3.1 Dose Modification or Treatment Delay for MLN0128-Related Toxicity.............49
6.4 Excluded Concomitant Medications and Procedures.................................................50
6.5 Permitted Concomitant Medications and Procedures.................................................51
6.6 Precautions and Restrictions .....................................................................................51


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6.7 Management of Clinical Events................................................................................51
6.7.1 Management of Hyperglycemia .........................................................................51
6.7.2 Management of Hyperlipidemia.........................................................................53
6.7.3 Management of Oral Mucositis..........................................................................54
6.7.4 Management of Rash .........................................................................................56
6.7.5 Management of Nausea and/or Vomiting ...........................................................56
6.7.6 Management of Noninfectious Pneumonitis.......................................................57
6.8 Blinding and Unblinding ..........................................................................................57
6.9 Description of Investigational Agents.......................................................................57
6.10 Preparation, Reconstitution, and Dispensation ........................................................58
6.11 Packaging and Labeling..........................................................................................58
6.12 Storage, Handling, and Accountability....................................................................59
7. STUDY CONDUCT ......................................................................................................60
7.1 Study Personnel and Organizations...........................................................................60
7.2 Arrangements for Recruitment of Patients ................................................................60
7.3 Treatment Group Assignments .................................................................................60
7.4 Study Procedures......................................................................................................61
7.4.1 Informed Consent ..............................................................................................61
7.4.2 Patient Demographics ........................................................................................61
7.4.3 Medical History.................................................................................................61
7.4.4 Physical Examination.........................................................................................61
7.4.5 Patient Height and Weight .................................................................................61
7.4.6 Vital Signs .........................................................................................................61
7.4.7 ECOG Performance Status.................................................................................62
7.4.8 MUGA Scan or ECHO ......................................................................................62
7.4.9 Pregnancy Test ..................................................................................................62
7.4.10 Concomitant Medications and Procedures........................................................62
7.4.11 AEs..................................................................................................................62
7.4.12 Enrollment .......................................................................................................62
7.4.13 ECG.................................................................................................................62
7.4.14 Clinical Laboratory Evaluations.......................................................................63
7.4.15 Fasting Serum Glucose ....................................................................................64
7.4.16 In-Home Daily Fasting Glucose Monitoring.....................................................64
7.4.17 Disease Assessment .........................................................................................65
7.4.18
......................................65
7.4.19
.....................................66
7.4.20
........................................................................................66
7.4.21
...............................................................................................................67
7.5 Completion of Treatment..........................................................................................67
7.6 Completion of Study.................................................................................................67
7.7 Discontinuation of Treatment With Study Drug and Patient Replacement.................67
7.8 Withdrawal of Patients From Study..........................................................................68
7.9 Study Compliance ....................................................................................................68
7.10 Posttreatment Follow-up Assessments (PFS and OS)..............................................68
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................69
8.1 Statistical Methods ...................................................................................................69
CCI
CCI
CCI


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8.1.1 Determination of Sample Size............................................................................69
8.1.2 Randomization and Stratification .......................................................................70
8.1.3 Populations for Analysis ....................................................................................70
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................70
8.1.5 Demographic and Baseline Characteristics.........................................................70
8.1.6 Efficacy Analysis...............................................................................................70
8.1.7 PK/Pharmacodynamics/Biomarkers ...................................................................71
8.1.8 Safety Analyses .................................................................................................73
8.1.9 Interim Analysis.................................................................................................74
9. ADVERSE EVENTS .....................................................................................................75
9.1 Definitions................................................................................................................75
9.1.1 Pretreatment Event Definition............................................................................75
9.1.2 AE Definition ....................................................................................................76
9.1.3 SAE Definition ..................................................................................................76
9.2 Procedures for Recording and Reporting AEs and SAEs...........................................77
9.3 Monitoring of AEs and Period of Observation ..........................................................78
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........79
9.5 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities ...........79
10. ADMINISTRATIVE REQUIREMENTS .....................................................................80
10.1 GCP .......................................................................................................................80
10.2 Data Quality Assurance ..........................................................................................80
10.3 eCRF Completion...................................................................................................80
10.4 Study Monitoring ...................................................................................................81
10.5 Ethical Considerations............................................................................................81
10.6 Patient Information and Informed Consent..............................................................81
10.7 Patient Confidentiality............................................................................................81
10.8 Investigator Compliance.........................................................................................82
10.9 On-site Audits ........................................................................................................82
10.10 Investigator and Site Responsibility for Drug Accountability................................82
10.11 Product Complaints ..............................................................................................82
10.12 Closure of the Study .............................................................................................83
10.13 Record Retention..................................................................................................84
11. USE OF INFORMATION............................................................................................84
12. INVESTIGATOR AGREEMENT................................................................................85
13. REFERENCES.............................................................................................................86
14. APPENDICES .............................................................................................................90
14.1 ECOG Scale for Performance Status.......................................................................90
14.2 New York Heart Association Classification of Cardiac Disease ..............................90
14.3 Cockcroft-Gault Equation.......................................................................................91
14.4 List of Relevant CYP Inhibitors and Inducers.........................................................92
14.5 Amendment 1 Rationale and Purposes....................................................................93
14.6 Amendment 2 Rationale and Purposes....................................................................95
14.7 Amendment 3 Rationale and Purposes....................................................................96
14.8 Amendment 4 Rationale and Purposes....................................................................97
14.9 Amendment 5 Rationale and Purposes....................................................................99
14.10 Amendment 6 Detailed Summary of Changes.....................................................100


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LIST OF TABLES
Table 6-1
Management of Hyperglycemia...................................................................52
Table 6-2
Management of Hyperlipidemia ..................................................................54
Table 6-3
Management of Oral Mucositis ...................................................................55
Table 6-4
Management of Rash...................................................................................56
Table 6-5
Management of Nausea and/or Vomiting ....................................................56
Table 6-6
Management of Noninfectious Pneumonitis ................................................57
Table 8-1
Interim Analyses in the Everolimus-Resistant Cohort..................................75
Table 8-2
Interim Analyses in the Everolimus-Sensitive Cohort..................................75


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
4E-BP1
eukaryotic initiation factor 4-binding protein
AE
adverse event
AI
aromatase inhibitors
AKT
serine/threonine-specific protein kinase (also known as protein kinase B)
ALT
alanine aminotransferase
ANC
absolute neutrophil count
API
active pharmaceutical ingredient
ASCO
American Society of Clinical Oncology
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration versus time curve
AUC24 hr
area under the plasma concentration versus time curve from zero to 24 hours
AUCt
area under the plasma concentration versus time curve from zero to the last 
measurable concentration
BOLERO-2
Breast Cancer Trials of Oral Everolimus-2
CBR
clinical benefit rate
CBR-16
clinical benefit rate at 16 weeks
CBR-24
clinical benefit rate at 24 weeks
Cmax
single-dose maximum (peak) concentration
CAP
College of American Pathologists
CR
complete response
CT
computed tomography
CTC
circulating tumor cell
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOT
End of Treatment (visit)


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Abbreviation
Term
ER
estrogen receptor
ER/HER2
estrogen receptor positive/human epidermal growth factor receptor-2 negative
FBG
fasting blood glucose
GCP
Good Clinical Practice
GI
gastrointestinal
HbA1c
glycosylated hemoglobin
HDPE
high-density polyethylene
HER2
human epidermal growth factor receptor-2
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF1R
insulin-like growth factor 1 receptor
IM
intramuscular; intramuscularly
IRB
institutional review board
IV
intravenous; intravenously
LVEF
left ventricular ejection fraction
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MLN0128
also known as TAK-228
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTOR
mammalian (or mechanistic) target of rapamycin
MUGA
multiple gated acquisition (scan)
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PFS
progression-free survival
PI3K
phosphoinositide 3-kinase
PIK3CA
phosphoinositide 3-kinase, catalytic alpha polypeptide
PK
pharmacokinetic(s)
PPI
proton pump inhibitor
PR
progesterone receptor
PTEN
phosphatase and tensin homolog
PT/INR
prothrombin time/international normalized ratio


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Abbreviation
Term
QD
quaque die; each day; once daily
QTc
rate-corrected QT interval (msec) of electrocardiograph
RECIST
Response Evaluation Criteria in Solid Tumors
S473
serine 473
S6K
ribosomal protein S6 kinase
SAE
serious adverse event
SD
stable disease
SERD
selective estrogen receptor down regulator
SLD
sum of the longest diameter
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal disposition half-life
TAK-228
MLN0128
TAMRAD
tamoxifen plus everolimus
TEAE
treatment-emergent adverse event
Tmax
single-dose first time of occurrence of maximum (peak) concentration
TORC1
mammalian (or mechanistic) target of rapamycin complex 1
TORC2
mammalian (or mechanistic) target of rapamycin complex 2
ULN
upper limit of the normal range
US
United States
USPI
United States Prescribing Information
WBC
white blood cell
WHO
World Health Organization


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1. BACKGROUND AND STUDY RATIONALE
1.1
Scientific Background
1.1.1
Disease Under Treatment
Epidemiology
Breast cancer is the most frequent cancer diagnosis in women and is the leading cause of 
cancer-related deaths in women in Europe and the second leading cause of cancer-related 
deaths in women in the United States (US).[1,2] The American Cancer Society estimates 
that approximately 232,340 women will receive a new diagnosis of breast cancer in this 
year. Approximately 39,620 women in the US and 88,886 women in Europe are predicted to 
die from their disease in 2013.[1,2]
Breast cancer is a heterogeneous disease with different histologies, prognoses, natural 
history, responses to treatment, and molecular characteristics.[3-5] Breast cancer can be 
classified into 3 major categories or subtypes: hormone receptor-positive tumors that express 
estrogen or progesterone receptors (PRs) or both; tumors that over-express the receptor for 
human epidermal growth factor receptor-2 (HER2); and basal epithelial-like or 
“triple-negative tumors” that do not express hormone receptors or HER2.[3,6] The hormone 
receptor-positive tumors, which represent 66% to 75% of breast cancer tumors, consist of 
2 main subtypes: luminal A and luminal B.[3,5,7-9]
Antiestrogen Treatment
Antiestrogen therapy remains the first line of therapy for estrogen receptor (ER)-positive 
tumors both in the adjuvant and metastatic disease settings.[10] Standard antiestrogen 
therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer 
involves the sequential use of selective ER modulators (eg, tamoxifen), nonsteroidal or 
steroidal aromatase inhibitors (AIs), and selective ER down regulators (SERDs; eg, 
fulvestrant).[9] In the first-line metastatic disease setting, antiestrogen therapy in 
postmenopausal women may be either monotherapy with a third-generation, nonsteroidal AI 
(anastrozole or letrozole) or the steroidal AI exemestane or sequential therapy with 
tamoxifen followed by a third-generation AI.[11,12]
Resistance to antiestrogen treatment occurs commonly in patients and is an important 
therapeutic limitation. Approximately 30% of patients with metastatic disease have primary 
resistance to initial endocrine therapy and develop progressive disease within 6 months after 
initiation of antiestrogen therapy.[9,13] Many other patients may initially respond to 


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hormonal therapy but then develop secondary resistance defined as progressive disease 
occurring more than 6 months after initiation of antiestrogen therapy.[9,13] The resistant 
tumors have not completely lost estrogen dependence and may respond to an additional or 
alternative antiestrogen therapy, such as the SERD fulvestrant, which binds irreversibly to 
the ER, leading to receptor blockade and degradation.[14,15] However, the duration of 
response or remission after subsequent, alternative therapy is often shorter than that 
achieved with earlier therapy.[15] This suggests that during estrogen deprivation, adaptive 
changes occur in tumor cells that allow them to proliferate and survive in a low-estrogen 
environment.
Estrogen Action and Resistance
Several mechanisms may lead to endocrine resistance, but evidence from studies of estrogen 
action and cell signaling in breast cancer cells indicates that crosstalk between the 
phosphoinositide 3-kinase (PI3K)/serine/threonine-specific protein kinase 
(AKT)/mammalian (or mechanistic) target of rapamycin (mTOR) pathway and the ER is an 
important potential mechanism of resistance to hormone therapy in ER-positive breast 
cancer. In the classical ligand-dependent genomic action of the ER, estrogen binding to the 
ERs leads to receptor dimerization that forms a complex with coactivators or corepressors 
that then binds to estrogen response elements in the promoter region of estrogen responsive 
genes with subsequent enhancement or repression of transcription.[15,16] However, ERs 
can be activated via ligand-independent genomic mechanisms that can contribute to 
endocrine resistance by inducing estrogen-independent growth. Ligand-independent, 
genomic activation of the ER is mediated through growth factor receptor signaling, such as 
epidermal growth factor and insulin-like growth factor 1 receptors (IGF1Rs), and 
subsequent up-regulation of the PI3K/AKT/mTOR signaling pathway. Activated 
PI3K/AKT/mTOR signaling ultimately leads to phosphorylation of the ER. The 
phosphorylated ER binds, even in the absence of its physiological ligand, to 
estrogen-responsive DNA elements to modulate estrogen-responsive target genes inducing 
proliferation and survival of tumor cells independent of estrogen.[15,17] These data suggest 
that activation of the PI3K/AKT/mTOR pathway is critical to induce estrogen-independent 
tumor growth and resistance to antihormonal treatment in breast cancer.
Growth factor and PI3K/AKT/mTOR signaling is often dysregulated in ER+ breast tumors. 
Approximately 28% to 47% of luminal tumors harbor activating mutations of 
phosphoinositide 3-kinase, catalytic alpha polypeptide (PIK3CA), and 41% to 48% have 
activation mutations consisting of the amplification of the IGF1R.[18] Cells in which the 


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PI3K/AKT/mTOR signaling pathway is activated can proliferate and survive in a 
low-estrogen environment and are likely to become resistant to estrogen deprivation therapy. 
Thus, several lines of evidence indicate that PI3K/AKT/mTOR signaling has a central role 
in paths leading to endocrine resistance. This strongly suggests that inhibitors of the 
PI3K/AKT/mTOR pathway would have the potential to restore endocrine sensitivity in 
ER/PRbreast cancers.
1.1.2
Study Drug
1.1.2.1
MLN0128
mTOR Inhibitors
The mTOR serine/threonine kinase has a central role in regulating cellular growth and 
metabolism in response to external environmental factors.[19,20] 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 initiation factor 4-binding protein (4E-BP1).[21] The TORC2 
complex is activated by growth factors and promotes cell survival, proliferation, and actin 
cytoskeleton organization by phosphorylating and activating kinases, such as AKT kinase 
(also known as protein kinase B), which is a regulator of apoptosis.[22,23]
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.[20] Thus, rapamycin and the 
rapalogs are only partial inhibitors of TORC1.[20]
The ATP-competitive inhibitors (also known as mTOR kinase inhibitors or TORKinibs), 
such as MLN0128 (also known as TAK-228), bind to the catalytic domain of mTOR and 
thus inhibit both TORC1 and TORC2 complexes, including the rapamycin-insensitive or 
resistant actions of TORC1, such as phosphorylation of 4E-BP1.[24-26]
The rapalogs temsirolimus and everolimus have been approved by the US Food and Drug 
Administration as monotherapy for patients with advanced renal cell carcinoma 
(temsirolimus and everolimus), advanced pancreatic neuroendocrine tumors (everolimus), 


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and subependymal giant cell astrocytoma associated with tuberous sclerosis (everolimus). 
However, resistance to single-agent rapalog therapy occurs and may be related to either 
incomplete inhibition of the targeted pathway (such as phosphorylation of 4E-BP1 as 
discussed above) or 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 PI3K pathway.[23,27] 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.[20,23,27]
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.[28] Half the paired tumor samples had a posttreatment increase in the 
phosphorylation of AKT at S473.[28] These results provide direct evidence that loss of S6K 
feedback and subsequent PI3K/TORC2-induced activation of AKT occurs commonly in 
patients with solid tumors receiving single-agent everolimus.
Clinical Evidence Supporting the Use of mTOR Inhibitors in Breast Cancer
The utility of targeting the PI3K/AKT/mTOR signaling pathway to overcome or ameliorate 
endocrine therapy resistance has been evaluated in 2 randomized clinical trials in 
postmenopausal women with metastatic breast cancer. In the phase 3 study Breast Cancer 
Trials of Oral Everolimus-2 (BOLERO-2), 724 postmenopausal women with hormone 
receptor-positive, HER2-negative, metastatic breast cancer who developed progressive 
disease while on nonsteroidal AI therapy were randomized in a 2:1 ratio to receive either the 
steroidal AI exemestane in combination with everolimus or exemestane plus placebo.[29] At 
the interim analysis, the median progression-free survival (PFS) was longer in patients who 
received the combination of exemestane and everolimus compared with those who received 
exemestane and placebo, according to both local assessments by the investigators (6.9 
versus 2.8 months) and a central assessment (10.6 versus 4.1 months).[29] In a smaller, 
open-label, phase 2 study (TAMRAD study), postmenopausal women with hormone 
receptor-positive, HER2-negative, and AI-resistant metastatic breast cancer were stratified 
according to primary or secondary hormone resistance and randomized to receive either 
tamoxifen and everolimus (n=54) or tamoxifen alone (n=57).[30] The 6-month clinical 


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benefit rate (CBR), defined as the percentage of patients who achieved complete response 
(CR) or partial response or stable disease (SD) at 6 months, was higher for patients who 
received the combination of tamoxifen and everolimus compared with those who received 
tamoxifen alone (61% [95% CI of 47 to 74] versus 42% [95% CI of 29 to 56]).[30] Both of 
these studies demonstrated that targeting the PI3K/AKT/mTOR signaling pathway with 
everolimus can overcome acquired resistance to antiestrogen agents in postmenopausal 
women with hormone receptor-positive, AI-resistant breast cancer.
The results of the clinical trials of everolimus in postmenopausal women with hormone 
receptor-positive, AI-resistant breast cancer demonstrate the clinical utility of targeting the 
PI3K/AKT/mTOR signaling pathway with a rapalog to overcome resistance to antiestrogen 
therapy in this population. However, it is likely that patients receiving everolimus may 
develop resistance to everolimus due to the loss of feedback inhibition and subsequent 
TORC2-induced activation of AKT, which is suggested by the pharmacodynamic results 
from a phase 1 study with everolimus.[28] The goal of this study (C31001) is to test the 
hypothesis that acquired resistance to combination antihormonal treatment with everolimus 
in patients with hormone receptor-positive breast cancer is due to feedback reactivation of 
PI3K/AKT signaling and that antihormonal sensitivity can be restored by targeting this 
pathway with the dual TORC1/2 inhibitor MLN0128.
1.2
Nonclinical Experience
MLN0128, also known as INK-0128, is an orally available, potent, and highly selective ATP 
competitive inhibitor of mTOR kinase that exhibits dual specificity against both the TORC1 
and TORC2 complexes. MLN0128 is a second-generation mTOR inhibitor that targets the 
kinase domain of the mTOR enzyme to suppress TORC1 and TORC2 functions, a feature 
believed to increase the antitumor effect relative to currently available mTOR inhibitors, 
which as a class, are derivatives of rapamycin and referred to as rapalogs. These agents are 
TORC1-only inhibitors and operate through a distinct mechanism to MLN0128.
In vitro studies have demonstrated that MLN0128 selectively and potently inhibits the 
mTOR kinases (1 nM), but relative to mTOR inhibition, MLN0128 has >100-fold less 
potency on class I (PI3K isoforms α, β, ɣ, δ), class II (PI3KC2α and PI3K2Cβ), and class III 
(VPS34) PI3K family members. MLN0128 inhibits (> 80%) the biochemical activity of 
5 kinases (mTOR, DNA-PK, PDGFRα, Flt3, and CK1 epsilon kinases) out of a panel of 
222 protein kinases. Out of a panel of 402 distinct kinases, MLN0128 inhibits the ligand 
binding of only 10 receptor and intracellular protein kinases (ACVR1, BMPR1B, CSF1R, 


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CSNK1D, CSNK1E, DDR1, MEK1, MEK2, PDGFRα, and RIPK2). MLN0128 also 
displays potent cellular inhibition of both the TORC1 and TORC2 pathway with cellular 
pharmacodynamic concentration producing 50% inhibition values of less than 10 nM.
MLN0128, administered orally in multiple human tumor xenograft mouse models, can 
inhibit angiogenesis and tumor growth by inhibiting mTOR signaling at plasma 
concentrations associated with in vitro inhibition of mTOR in a dose- and time-dependent 
manner. These effects display a clear pharmacokinetic (PK)-to-pharmacodynamic 
relationship.[31] MLN0128 inhibits both the phosphorylation of S6 and 4E-BP1, the 
downstream substrates of TORC1, and selectively inhibits AKT phosphorylation at S473, as 
evidenced by decreased pAKT, the downstream substrate of TORC2.[31-33] Dual TORC1/2 
inhibition mitigates the feedback activation of AKT, which is known to cause resistance to 
TORC1-only inhibitors such as rapamycin.[34] MLN0128 inhibits mTOR signaling and has 
demonstrated anticancer activity against a number of human solid tumor cell-line xenograft 
mouse models, including phosphatase and tensin homolog (PTEN) mutant endometrial, 
breast, and renal cell carcinomas.
Additional details related to nonclinical experience with MLN0128 may be found in the 
Investigator’s Brochure (IB).
1.3
Clinical Experience
1.3.1
Clinical Experience With MLN0128
Single-agent MLN0128 is in clinical development with 2 phase 1 studies in patients with 
advanced solid malignancies (INK128-001) and in patients with relapsed or refractory 
multiple myeloma or Waldenström macroglobulinemia (INK128-002). A third phase 1 study 
of MLN0128 is in combination with paclitaxel with or without trastuzumab in patients with 
advanced solid tumors (INK128-003). These studies have been designed to investigate the 
safety, PK, pharmacodynamics, and preliminary efficacy of MLN0128 for the treatment of 
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advanced solid tumors and hematologic malignancies either as a single agent or in 
combination with chemotherapy and/or HER2-targeting agents. Additionally, the 
combination of MLN0128 with MLN1117 (an oral PI3Kα inhibitor) is being evaluated in a 
phase 1b study in adult patients with advanced nonhematologic malignancies (Study 
C32001).
Refer to the current edition of the IB for updated summaries of the clinical experience with 
MLN0128.
1.3.1.1
Clinical PK of MLN0128
The PK parameters measured for MLN0128 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 single-dose first time of occurrence of maximum 
(peak) concentration (Tmax) occurring between 1 and 4 hours after dosing. The mean 
terminal disposition half-life (t1/2) of MLN0128 is approximately 8 hours, and no 
accumulation has been observed in plasma after repeat daily dosing.
The PK properties of MLN0128 are detailed in the IB.
1.4
Study Rationale
The primary objective of this phase 1b/2 study is to evaluate the safety and efficacy of 
MLN0128, in combination with either exemestane or fulvestrant, in postmenopausal women 
with estrogen receptor-positive/human epidermal growth factor receptor-2-negative 
(ER+/HER2) advanced or metastatic breast cancer with disease progression after previous 
treatment with everolimus (in combination with either exemestane (any country) or 
fulvestrant [US only]).
The PI3K/AKT/mTOR pathway is often activated in ER/PR+ breast cancer with 
approximately 20% to 25% of tumors harboring activating PIK3CA mutations and 15% to 
35% having loss of the PTEN tumor suppressor protein.[7,35,36] Beyond this, several lines 
of evidence suggest that reactivation of the pathway is a cellular response to long-term 
estrogen deprivation and plays a key role in acquired antiestrogen resistance.[18,37,38]
Combined targeting of both ER and PI3K/AKT/mTOR pathways, as demonstrated by the 
BOLERO-2[29] and TAMRAD[30] studies, is a promising and proven therapeutic approach 
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MLN0128 is a potent, highly selective, ATP-competitive inhibitor of mTOR. MLN0128 is 
mechanistically distinct from the allosteric inhibitors of mTOR (rapamycin and its 
derivatives, referred to as rapalogs). The rapalogs only partially inhibit TORC1, whereas 
MLN0128 inhibits both TORC1 (more completely S6K and 4E-BP1) and TORC2. Dual 
TORC1/2 inhibition mitigates feedback activation of PI3K and AKT, known to cause 
resistance to TORC1-only inhibitors, such as everolimus.[34]
MLN0128 administered in combination with antihormonal therapy may restore sensitivity to 
antihormonal treatments in patients who have progressed on such therapies in combination 
with everolimus.
Rationale for Starting Dose of MLN0128
The starting doses of 5 mg MLN0128 and 4 mg MLN0128, in combination with exemestane 
or fulvestrant, are both predicted to provide an area under the plasma concentration versus 
time curve (AUC) that will be above those considered bioactive in nonclinical 
pharmacology studies conducted in tumor xenograft models and associated with stasis. The 
4 mg once daily (QD) dose of MLN0128 already provides daily plasma exposures that are 
comparable to those observed with a 10 mg QD dose of the TORC1 inhibitor everolimus, 
after accounting for differences in plasma protein binding and in-vitro cell proliferation 
assay inhibitory potency for each agent.
The single-agent maximum tolerated dose (MTD) of MLN0128 for continuous QD dosing 
established in the escalation phase of Study INK128-001 is 6 mg QD; however, a substantial 
number of patients required dose modification after prolonged exposure at this dose. The 
expansion phase of Study INK0128-001 has established that 5 mg QD is the recommended 
phase 2 dose of MLN0128. Because no PK-based drug-drug interactions (DDIs) between 
MLN0128 and either exemestane or fulvestrant are expected, it is projected that the plasma 
exposures of MLN0128 in combination with either exemestane or fulvestrant will be less 
than those at the respective single-agent exposures at the MLN0128 MTD of 6 mg QD.
Part 1 of the phase 1 portion of the study will initiate with enrollment of 6 patients at the 
starting dose of 5 mg QD of MLN0128 capsules based on unmilled active pharmaceutical 
ingredient (API) in combination with either exemestane (at the established dose) or 
high-dose fulvestrant (500 mg intramuscular [IM] once a month). After completing 2 cycles 
of treatment with MLN0128 (Cycle 2 Day 28) in combination with either exemestane or 
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Part 2 of the phase 1 portion of the study will initiate with enrollment of 6 patients at a 
starting dose of 3 mg QD of MLN0128 capsules based on milled API. The starting dose of 
3 mg was chosen to account for the possibility of increased absorption with MLN0128 
capsules based on milled API and on emerging safety data from Part 1 of the phase 1b 
portion of this study with MLN0128 dosing at 5 mg QD in combination with either 
exemestane (any country) or fulvestrant (US only). During Part 2 of the phase 1 portion of 
this study:

If ≥2 dose-limiting toxicities (DLTs) occur in the treatment group receiving 4 mg of 
MLN0128, the subsequent phase 2 portion of the study will be initiated at 3 mg of 
MLN0128 QD in combination with exemestane or fulvestrant.

If ≤1 DLT occurs in the treatment group (either at 4 mg or 2 mg QD), the subsequent 
phase 2 portion of the study will be initiated at the same dose (either 2 mg or 4 mg of 
MLN0128 QD) in combination with exemestane or fulvestrant.

If ≥2 DLTs occur in the treatment group receiving 2 mg of MLN0128 in 
combination with either exemestane and/or fulvestrant, the study will be stopped.
Based on the outcome of a safety and tolerability analysis performed in the phase 1b portion 
of the study, MLN0128 4 mg QD in combination with either exemestane or fulvestrant was 
determined as the Phase 2 starting dose. Another safety and tolerability assessment will be 
performed during the phase 2 portion of the study where the first 6 patients treated with 
MLN0128 (4 mg QD) in combination with exemestane (any country) or fulvestrant (US 
only) who have completed 2 cycles of treatment with MLN0128 will be evaluated for 
treatment-emergent adverse events (TEAEs). Enrollment of patients into the study will 
continue during this safety and tolerability assessment.
In addition, during the phase 2 portion of the study, both tolerability and need for dose 
reductions and/or modifications will continue to be monitored for all patients in all cycles. 
If, based on this assessment, the 4 mg QD starting dose identified in Part 2 of the phase 1 
portion is deemed unfavorable, in conjunction with agreement of the study investigators and 
the medical monitor, the starting dose may be adjusted to 2 or 3 mg QD, respectively, for all 
newly enrolled patients to improve long-term tolerability. Patients who were enrolled at 3 or 
4 mg QD in Part 2 of the phase 1 portion and the phase 2 portion will be maintained at this 
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reduction, if required, will be documented to all study sites by formal written 
communication.
1.4.1
Mutual DDI Assessment
Mutual DDI Assessment Between MLN0128 and Exemestane
Recently completed in vitro metabolism experiments in human hepatocytes using 
14C-labeled MLN0128 suggest that MLN0128 is metabolized primarily via cytochrome 
P450 (CYP) 1A2 (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 non–uridine diphosphate 
glucuronosyltransferase pathway (approximately 18%). The new data differ from the 
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.
MLN0128 neither inhibited nor induced any of the major CYP enzymes. MLN0128 did not 
inhibit P-glycoprotein but did inhibit breast cancer resistance protein at a relatively high 
concentration not expected at the dose of 5 mg QD proposed for administration to patients in 
this study. 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 (see Section 14.4) should be administered only with caution and at the 
discretion of the investigator during the study.
Exemestane is metabolized by various CYP enzymes, including CYP3A4, CYP1A1>2A6, 
and 4A11. Exemestane did not inhibit any of the major CYP enzymes (CYP1A2, 2C9, 2D6, 
2E1, or 3A4). Exemestane did not affect the PK of tamoxifen, a CYP3A4 substrate, in 
clinical DDI studies, suggesting a low risk for DDI with other CYP3A4 substrates. 
Ketoconazole, a potent CYP3A4 inhibitor, did not significantly affect the PK of exemestane, 
but rifampin, a potent CYP3A4 inducer, decreased exemestane exposure by approximately 
41%.[39] Inducers of CYP3A4 (such as rifampin, phenytoin, carbamazepine, phenobarbital, 
and St. John’s wort) should be avoided during this study (refer to Section 6.4).
It is not known if exemestane is a substrate for any of the major drug transporters. Based on 
the available information for both of these agents, the risk of a clinically meaningful DDI 
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To assess this risk, steady-state, serial PK samples will be collected to quantify both 
MLN0128 and exemestane. The PK data collected for this assessment will be compared 
against historic PK data for the respective agents to evaluate the risk for mutual DDI 
between these agents.
Mutual DDI Assessment Between MLN0128 and Fulvestrant
A mutual DDI assessment between MLN0128 and fulvestrant is not planned in this study. 
Fulvestrant is metabolized by numerous biotransformation pathways (including oxidation by 
CYP3A4) and is not known to inhibit any of the major CYP enzymes. No meaningful 
change in fulvestrant PK was observed when co-administered with ketoconazole (a potent 
CYP3A4 inhibitor), rifampin (a potent CYP3A4 inducer), or midazolam (a CYP3A4 
substrate).[40] Collectively, this information suggests a low risk for DDI between MLN0128 
and fulvestrant.
In addition, fulvestrant is administered IM, and its peak plasma concentrations, when 
administered by this route, are observed approximately 168 hours (or 7 days) after dosing. 
Fulvestrant also has a plasma half-life of approximately 40 days, making it difficult to fully 
characterize the PK of fulvestrant.[40] Based on this information, and given the relatively 
low risk for DDI between MLN0128 and fulvestrant, no serial PK samples will be collected 
for mutual DDI assessment between these agents; however, sparse PK samples will be 
collected to characterize the PK of MLN0128 (as a population PK assessment). Population 
PK analysis can then be used to assess clinically meaningful changes in the PK of 
MLN0128, when co-administered with fulvestrant.
1.4.2
CCI
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1.5
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, and blood creatinine increased.
During the phase 1 portion of the study, risk mitigation strategies for potential adverse 
events (AEs) include criteria for determining DLTs. Additionally, in both the phase 1 and 
phase 2 portions of the 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 AEs and serious adverse events (SAEs) by 
the sponsor.
The potential benefits of MLN0128 are discussed in Section 1.1.2.1.
Further details are presented in the IB.
Refer to the most recent US Prescribing Information (USPI) or the Summary of Product 
Characteristics (SmPC) for exemestane and fulvestrant for information regarding potential 
risks and benefits for these medications.[39,40]
2. STUDY OBJECTIVES
2.1
Primary Objectives
The primary objectives include:
Phase 1b
∀
To evaluate the safety and tolerability of MLN0128 in combination with either 
exemestane or fulvestrant.
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Phase 2
∀
To evaluate the antitumor activity by CBR at 16 weeks (CBR-16; defined as the 
proportion of patients who achieve CR or partial response of any duration or have 
SD at 16 weeks) of treatment with MLN0128 in combination with either exemestane 
or fulvestrant.
2.2
Secondary Objectives
The secondary objectives include:
∀
To further evaluate the antitumor activity of MLN0128 in combination with either 
exemestane or fulvestrant.
∀
To evaluate the PK of MLN0128 and exemestane when administered in combination 
and to evaluate the PK of MLN0128 when administered in combination with 
fulvestrant.
∀
To assess the safety and tolerability of MLN0128 in combination with either 
exemestane or fulvestrant.
2.3
Exploratory Objectives
The exploratory objectives include:
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3. STUDY ENDPOINTS
3.1
Primary Endpoints
The primary endpoints include:
Phase 1b

AEs, SAEs, assessments of clinical laboratory values, vital sign measurements, 
physical examination findings, and electrocardiograms (ECGs).
Phase 2

CBR-16.
3.2
Secondary Endpoints
The secondary endpoints include:

CBR at 24 weeks (CBR-24; defined as the proportion of patients who achieve CR or 
partial response of any duration or have SD at 24 weeks).

Overall response rate (ORR; defined as best response of CR or partial response).

PFS.

Overall survival (OS).

Change in tumor size from Baseline.

Steady-state PK parameters of MLN0128 and exemestane including, but not limited 
to, single-dose maximum (peak) concentration (Cmax), Tmax, AUC from zero to 
24 hours (AUC24h), AUC from zero to the last measurable concentration (AUCt), and 
t1/2.

AE, SAEs, assessments of clinical laboratory values, vital sign measurements, 
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3.3
Exploratory Endpoints
The exploratory endpoints include:
4. STUDY DESIGN
4.1
Overview of Study Design
This is a phase 1b/2 study of the safety and efficacy of MLN0128 in combination with 
exemestane or fulvestrant therapy in women with ER+/HER2! advanced or metastatic 
breast cancer that has progressed on treatment with everolimus in combination with 
exemestane (any country) or fulvestrant (US only). Patients enrolled in this study will be 
given the same prior therapy (either exemestane or fulvestrant) at their established dose.
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. MLN0128 will be administered in 28-day 
treatment cycles.
4.1.1
Phase 1b
In the phase 1b portion of the study, the safety and tolerability of MLN0128 using a capsule 
formulation based on unmilled (Part 1) and milled (Part 2) API in combination with either 
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exemestane (any country) or fulvestrant (US only) will be evaluated. Patients enrolled in 
Part 1 will remain on MLN0128 capsules based on unmilled API. Patients will be enrolled 
as follows:
Part 1 (Capsules Based on Unmilled API):
MLN0128+Exemestane Safety Cohort: Six patients will receive MLN0128 capsule 
formulation based on unmilled API (5 mg QD) in combination with exemestane 
(administered per prior therapy for the patient). Steady-state serial PK samples will 
be collected to quantify both MLN0128 and exemestane to characterize the PK of 
MLN0128 and exemestane when administered in combination.
MLN0128+Fulvestrant Safety Cohort (US Only): Six patients will receive 
MLN0128 capsule formulation based on unmilled API (5 mg QD) in combination 
with high-dose fulvestrant (500 mg IM every month). After completing 2 cycles of 
treatment with MLN0128 (Cycle 2 Day 28) in combination with fulvestrant, a safety 
and tolerability assessment will be performed. If 2 DLTs occur in either treatment 
group (exemestane or fulvestrant) after completing 2 cycles of treatment with 
MLN0128 (5 mg QD), the dose of MLN0128 will be reduced in that treatment group 
(MLN0128 in combination with exemestane or MLN0128 in combination with 
fulvestrant) to 4 mg QD for patients subsequently enrolled in the phase 2 portion 
study (refer to Section 6.2 for additional details).
Part 2 (Capsules Based on Milled API):
MLN0128+Exemestane (Any Country)/Fulvestrant (US Only) Safety Cohort 1: 
Six patients will receive MLN0128 capsule formulation based on milled API (3 mg 
QD) in combination with either exemestane or fulvestrant. Serial blood samples will 
be collected to evaluate the PK of MLN0128 when administered in combination with 
either exemestane or fulvestrant. After the last patient completes Cycle 1, a safety 
and tolerability assessment will be performed. If 2 DLTs occur in these 6 patients, 
the dose of MLN0128 will be reduced to 2 mg QD for patients subsequently enrolled 
in Cohort 2 of Part 2 of the phase 1b portion of this study. If 1 DLT occurs in 
Cohort 1, the dose of MLN0128 will be escalated to 4 mg QD for patients entering 
Cohort 2.
MLN0128+Exemestane (Any Country)/Fulvestrant (US Only) Safety Cohort 2: 
Six patients will receive MLN0128 capsule formulation based on milled API, either 


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4 or 2 mg QD based on the safety observed in Cohort 1, in combination with either 
exemestane or fulvestrant. Serial PK samples will be collected as outlined for 
Cohort 1. After the last patient completes Cycle 1, a safety and tolerability 
assessment will be performed.

If ≥2 DLTs occur in the treatment group receiving 4 mg of MLN0128, the 
subsequent phase 2 portion of the study will be initiated at 3 mg of MLN0128 QD in 
combination with exemestane or fulvestrant.

If ≤1 DLT occurs in the treatment group (either at 4 or 2 mg QD), the subsequent 
phase 2 portion of the study will be initiated at the same dose (either 2 or 4 mg of 
MLN0128 QD) in combination with exemestane or fulvestrant.

If ≥2 DLTs occur in the treatment group receiving 2 mg of MLN0128 in 
combination with either exemestane and/or fulvestrant, the study will be stopped.
Enrollment in the phase 2 portion of the study will commence for patients on MLN0128 in 
combination with exemestane or fulvestrant therapy once the safety assessment has been 
completed for the phase 1b portion of the study. Patients enrolled in phase 1b will not be 
eligible for participation in phase 2.
Based on the outcome of a safety and tolerability analysis performed in the phase 1b portion 
of the study, MLN0128 4 mg QD in combination with either exemestane or fulvestrant was 
determined as the phase 2 starting dose. Another safety and tolerability assessment will be 
performed during the phase 2 portion of the study where the first 6 patients treated with 
MLN0128 4 mg QD in combination with exemestane or fulvestrant who have completed 
2 cycles of treatment with MLN0128 will be evaluated for TEAEs. Enrollment of patients 
into the study will continue during this safety and tolerability assessment.
In addition, during the phase 2 portion of the study, both tolerability and need for dose 
reductions and/or modifications will continue to be monitored for all patients in all cycles. 
If, based on this assessment, the 4 mg QD starting dose identified in Part 2 of the phase 1 
portion is deemed unfavorable, in conjunction with agreement of the study investigators and 
the medical monitor, the starting dose may be adjusted to 2 mg or 3 mg QD, respectively, 
for all newly enrolled patients to improve long-term tolerability. Patients who were enrolled 
at 3 mg or 4 mg QD in Part 2 of the phase 1 portion and the phase 2 portion will be 
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A starting dose reduction, if required, will be documented to all study sites by formal written 
communication.
4.1.2
Phase 2
In the phase 2 portion of the study, the safety and efficacy of MLN0128 in combination with 
either exemestane (any country) or fulvestrant (US only) will be evaluated. Patients will be 
administered MLN0128 at 4 mg QD in combination with either exemestane (any country) or 
fulvestrant (US only), based on the outcome of the safety and tolerability analysis performed 
in the phase 1b portion of the study.
Patients will be enrolled into one of 2 parallel cohorts, depending on the quality and/or 
duration of their prior response to everolimus in combination with either exemestane (any 
country) or fulvestrant (US only) as follows:
Everolimus-Resistant Cohort: This is a cohort of 56 response-evaluable patients 
who have progressed on treatment with everolimus in combination with either 
exemestane (any country) or fulvestrant (US only) without achieving an objective 
response (CR or partial response) or after achieving SD for 6 months as their best 
response. Patients will receive MLN0128 in combination with the same dose of the 
previously administered treatment (exemestane [any country] or fulvestrant [US 
only]).
Everolimus-Sensitive Cohort: This is a cohort of 48 response-evaluable patients 
who have progressed on treatment after achieving a CR or partial response of any 
duration, or SD 6 months with prior everolimus treatment in combination with 
either exemestane (any country) or fulvestrant (US only). Patients will receive 
MLN0128 in combination with the same dose of the previously administered 
treatment (exemestane [any country] or fulvestrant [US only]).
Sparse PK samples will be collected from all patients enrolled in the study (regardless of 
whether they are administered MLN0128 in combination with exemestane or fulvestrant) for 
plasma PK analysis of MLN0128 only. Blood samples for all PK analyses will be collected 
at the time points specified in the Phase 1b Pharmacokinetic and ECG Sample Breakdown
and the Phase 2 Pharmacokinetic and ECG Sample Breakdown table. Data generated in this 
study will be combined with data from other studies in which the PK of MLN0128 is 
characterized for population PK analysis.


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Radiographic tumor evaluations will be performed on contrast-enhanced imaging (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.[42] 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 by the investigator at the 
time points specified in the Schedule of Events.
Throughout the study, 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.[43] Definitions of DLTs for the phase 1 portion of the study are in 
Section 6.2 and dose modification guidelines for the phase 2 portion of the study are in 
Section 6.3.
AEs will be assessed, and clinical laboratory values, vital signs, and ECGs will be obtained 
to evaluate the safety and tolerability of MLN0128 in combination with either exemestane or 
fulvestrant.
4.2
Number of Patients
Approximately 128 patients will be enrolled in this study from approximately 40 study 
centers in the US, Belgium, and France. A patient will be considered enrolled after receiving 
the first dose of MLN0128.
4.3
Duration of Study
Patients will receive MLN0128 in combination with either exemestane (any country) or 
fulvestrant (US only) until they experience disease progression. Patients will discontinue 
treatment with MLN0128 if they have an unacceptable drug-related toxicity. The maximum 
duration of treatment will be 24 months. If after discussion between the investigator and 
sponsor it is determined that a patient would derive benefit, the patient may continue 
treatment beyond 24 months. The study will be terminated 6 months after the last patient 
completes an End-of-Treatment (EOT) study visit.
Patients will attend an EOT/Early Termination visit 30 to 40 days after receiving their last 
dose of MLN0128 or at the start of subsequent anticancer therapy. After EOT, patients will 
be followed for PFS and OS. For those patients who discontinue MLN0128 for any reason 
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should be completed to further assess disease progression (per RECIST, version 1.1).[42]
See Section 7.10 for additional posttreatment follow-up details.
5. STUDY POPULATION
5.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
5.1.1
Phase 1b and Phase 2
1. Advanced or metastatic breast cancer.
2. Histological or cytological confirmation of ER+ status (defined as >1% positive 
tumor cells), and histological or cytological confirmation of HER2-negative (HER2-) 
status by local laboratory testing using criteria in the American Society of Oncology 
(ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline 
update.[44]
3. Female patients 18 years of age or older who:

Are postmenopausal for at least 1 year before the Screening visit, where 
menopause is defined by:
o
Age ≥55 years and 1 year or more of amenorrhea.
o
Age <55 years and 1 year or more of amenorrhea, with an estradiol assay 
<20 pg/mL.
o
Surgical menopause with bilateral oophorectomy.
Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone 
agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of 
ovarian suppression.
4. Patients who have a history of brain metastasis are eligible for the study provided 
that all the following criteria are met:

Brain metastases which have been treated.


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
No evidence of disease progression for 3 months or hemorrhage after treatment.

Off-treatment with dexamethasone for 4 weeks before administration of the first 
dose of MLN0128.

No ongoing requirement for dexamethasone or antiepileptic drugs.
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 (refer to 
Section 14.1).
6. Clinical laboratory values as specified below within 4 weeks before the first dose of 
MLN0128:

Bone marrow reserve consistent with absolute neutrophil count (ANC) 
≥1.5109/L; platelet count ≥100109/L; hemoglobin ≥9 g/dL.

Total bilirubin ≤1.5 times the upper limit of the normal range (ULN), aspartate 
aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5ULN 
(≤5ULN if liver metastases are present).

Creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate (refer 
to Section 14.3) or based on a 12- or 24-hour urine collection.

Fasting serum glucose ≤130 mg/dL and fasting triglycerides ≤300 mg/dL.
7. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of 
institutional standard of normal as measured by echocardiogram (ECHO) or multiple 
gated acquisition (MUGA) scan within 4 weeks before the first dose of MLN0128
(ie, if the institutional standard of normal is 50%, LVEF may be as low as 45% to be 
eligible for the study).
8. Able to provide paraffin blocks or a minimum of 10 unstained slides of available 
archival tumor tissues (paraffin blocks are preferred). If archival tumor tissue is not 
available, a tumor biopsy may be performed before the patient begins treatment with 
MLN0128. If fewer than 10 slides are available or the tumor content/area 
requirements are not met, study eligibility will be determined upon discussion with 
the sponsor.


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9. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, 
and suitable venous access for the study-required blood sampling.
10. Voluntary written consent must be given before the 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.
5.1.2
Phase 1b Only
In addition to the previously mentioned inclusion criteria, each patient must meet the 
following inclusion criterion to be enrolled in the phase 1b portion of the study:
11. Patients may have SD or disease progression during their most recent treatment with 
exemestane or fulvestrant, or everolimus in combination with either exemestane (any 
country) or fulvestrant (US only). Exemestane or fulvestrant in combination with
MLN0128 can also be initiated as a new line of therapy.
5.1.3
Phase 2 Only
In addition to the previously mentioned inclusion criteria, each patient must meet all of the 
following inclusion criteria to be enrolled in the phase 2 portion of the study:
12. Measureable disease defined as follows:

At least 1 extraosseous lesion that can be accurately measured in at least 1 
dimension. The lesion must measure ≥20 mm with conventional imaging 
techniques or ≥10 mm with spiral CT or MRI, or

Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable 
disease as defined above.
13. Patients must have had disease progression during treatment with everolimus in 
combination with either exemestane (any country) or fulvestrant (US only) (duration 
of treatment 4 weeks) and must have tolerated everolimus treatment in combination 
with exemestane (any country) or fulvestrant (US only) adequately according to the 
treating physician’s judgment. Everolimus in combination with exemestane or 
fulvestrant is not required to be the most recent treatment before enrollment, but 
progression on the most recent anticancer therapy is required for enrollment.


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5.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
5.2.1
Phase 1b and Phase 2
1. Prior anticancer therapy or other investigational therapy within 2 weeks before 
administration of the first dose of MLN0128 (except for exemestane or fulvestrant, 
which should be continued). Treatment with everolimus must be discontinued 
2 weeks before administration of the first dose of MLN0128.
2. Chronic concomitant therapy with bisphosphonates or denosumab for the prevention 
of bone metastases. Concomitant treatment with bisphosphonates or denosumab is 
permitted for treatment of osteoporosis or management of existing bone metastases if 
initiated at least 4 weeks before administration of the first dose of MLN0128.
3. Exclusion criterion 3 was removed as of Protocol Amendment 6.
4. Initiation of treatment with hematopoietic growth factors, transfusions of blood and 
blood products, or systemic corticosteroids (either IV or oral steroids, excluding 
inhalers) within 1 week before administration of the first dose of MLN0128 (patients 
already receiving erythropoietin on a chronic basis for ≥4 weeks are eligible).
5. Previous treatment with dual PI3K/mTOR inhibitors or TORC1/2 inhibitors.
6. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI 
disease, or for an unknown reason that may alter the absorption of MLN0128.
7. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin 
(HbA1c) >7%; patients with a history of transient glucose intolerance due to 
corticosteroid administration may be enrolled in this study if all other 
inclusion/exclusion criteria are met.
8. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active central nervous system disease, active infection, or any other condition that 
could compromise participation of the patient in the study.
9. Known human immunodeficiency virus infection.


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10. History of any of the following within the last 6 months before administration of the 
first dose of MLN0128:

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 Section 14.2).

Pulmonary embolism.
11. Significant active cardiovascular or pulmonary disease before administration of the 
first dose of MLN0128, including:

Uncontrolled hypertension (ie, systolic blood pressure >180 mm Hg; diastolic 
blood pressure >95 mm Hg).

Pulmonary hypertension.

Uncontrolled asthma or oxygen saturation <90% by arterial blood gas analysis or 
pulse oximetry on room air.

Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention; or history of valve 
replacement.

Medically significant (symptomatic) bradycardia.

History of arrhythmia requiring an implantable cardiac defibrillator.


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
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).
12. Diagnosed or treated for another malignancy within 2 years before administration of 
the first dose of MLN0128 or previously diagnosed with another malignancy and 
have any evidence of residual disease. Patients with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone complete 
resection.
5.2.2
Phase 1b Only
In addition to the previously mentioned exclusion criteria, patients meeting the following 
exclusion criterion are not to be enrolled in the phase 1b portion of the study:
13. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease.
5.2.3
Phase 2 Only
In addition to the previously mentioned exclusion criteria, patients meeting the following 
exclusion criterion are not to be enrolled in the phase 2 portion of the study:
14. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease.
6. STUDY DRUG
6.1
Study Drug Administration
All protocol-specific criteria for administration of MLN0128 must be met and documented 
before drug administration. Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
For all patients, MLN0128 will be administered QD at approximately the same time each 
day. It is recommended that each dose of MLN0128 be given orally with 8 ounces (240 mL) 
of water.

For patients receiving MLN0128 capsules with unmilled API: MLN0128 will be 
administered with a light meal.


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
For patients receiving MLN0128 capsules with milled API: MLN0128 will be 
administered on an empty stomach. The 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.
If severe emesis or mucositis prevents the patient from taking an MLN0128 dose, that dose 
will be skipped. If emesis occurs after study medication ingestion and whole capsule(s) are 
visible in the vomitus, replacement capsule(s) should be taken; otherwise the dose will not 
be readministered, and patients should simply adhere to the dosing schedule and resume 
dosing at the next scheduled time with the prescribed dosage. Patients should record the time 
of the emesis in their dosing diary (see the Study Manual). Under no circumstance should a 
patient repeat a dose or double-up doses.
Exemestane and fulvestrant will be administered per their current USPIs or SmPCs, and 
according to the dose regimen administered before study entry.
For patients assigned to receive MLN0128 in combination with exemestane:

MLN0128 should be administered first on an empty stomach (ie, nothing to eat or 
drink for 2 hours before and 1 hour after MLN0128 dosing).

Patients should have a meal before taking their exemestane dose, which may be 
taken between 1 and 6 hours after MLN0128 dosing.
6.2
Definitions of DLT for the Phase 1b Portion of the Study
DLTs are defined according to the AE profile observed during the first 28 days of study 
drug administration in phase 1b of the study and as described below. All AEs should be 
considered possibly related to the study drug unless such relationship can be definitively 
excluded. In Part 2 of the phase 1b portion of the study:

If ≥2 DLTs occur in the treatment group receiving 4 mg of MLN0128, the 
subsequent phase 2 portion of the study will be initiated at 3 mg of MLN0128 QD in 
combination with exemestane or fulvestrant.

If ≤1 DLT occurs in the treatment group (either at 4 mg or 2 mg QD), the subsequent 
phase 2 portion of the study will be initiated at the same dose (either 2 mg or 4 mg of 
MLN0128 QD) in combination with exemestane or fulvestrant.


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
If ≥2 DLTs occur in the treatment group receiving 2 mg of MLN0128 in 
combination with either exemestane and/or fulvestrant, the study will be stopped.
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective 14 June 
2010.[43] These criteria are provided in the Study Manual. A DLT will be defined as any of 
the following events that are considered by the investigator to be at least possibly related to 
treatment with MLN0128 in combination with either exemestane or fulvestrant:

Grade 3 or higher nonhematologic toxicity, despite adequate treatment, except for 
the following:
o
Grade 3 hyperglycemia lasting ≤14 days (all patients should receive optimal 
antiglycemic treatment, including insulin).
o
Grade 3 rash lasting ≤3 days (all patients should receive topical steroid treatment, 
oral antihistamines, and oral steroids, if necessary).

Grade 4 neutropenia lasting >7 days in the absence of growth factor support.

Grade 4 neutropenia of any duration accompanied by fever ≥38.5°C and/or systemic 
infection.

Any other ≥Grade 4 hematologic toxicity.

Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 
due to study drug-related toxicity.

Any clinically significant occurrence that the investigator and sponsor agree would 
place patients at an undue safety risk.
Patients who experience an AE that meets the definition of a DLT during or after completing 
Cycle 1 should have their study drug treatment interrupted. If the event resolves to Grade 1 
or baseline values within 2 weeks of interrupting planned therapy, and in the opinion of the 
investigator and the sponsor’s project clinician the benefits of continuing treatment outweigh 
the risks posed by the toxicity, patients may continue study treatment with MLN0128 at a 
25% to 50% dose reduction (ie, dose reduced from 4 mg to 3 mg [25%]; from 3 mg to 2 mg 
[33%]; or from 2 mg to 1 mg [50%] QD) with approval of the sponsor’s project clinician. 
Alternatively, if dose modification is required for patients receiving 2 mg QD, then the 
dosing frequency may also be decreased to 5 days per week (28% reduction) instead of 


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decreasing the daily dose administered. If study drug dosing is delayed for more than 
14 consecutive days for MLN0128-related toxicity, despite supportive treatment per 
standard clinical practice, or more than 2 dose reductions of MLN0128 are required, the 
patient will be discontinued from the study.
6.3
Dose-Modification Guidelines for the Phase 2 Portion of the Study
6.3.1
Dose Modification or Treatment Delay for MLN0128-Related Toxicity
Based on the outcome of a safety and tolerability analysis performed in the phase 1b portion 
of the study, MLN0128 4 mg QD in combination with either exemestane or fulvestrant was 
determined as the phase 2 starting dose. Another safety and tolerability assessment will be 
performed during the phase 2 portion of the study where the first 6 patients treated with 
MLN0128 4 mg QD in combination with exemestane or fulvestrant who have completed 
2 cycles of treatment with MLN0128 will be evaluated for TEAEs. Enrollment of patients 
into the study will continue during this safety and tolerability assessment.
In addition, during the phase 2 portion of the study, both tolerability and need for dose 
reductions and/or modifications will continue to be monitored for all patients in all cycles. 
If, based on this assessment, the 4 mg QD starting dose identified in Part 2 of the phase 1 
portion is deemed unfavorable, in conjunction with agreement of the study investigators and 
the medical monitor, the starting dose may be adjusted to 2 or 3 mg QD for all newly 
enrolled patients to improve long-term tolerability. Patients who were enrolled at 3 or 4 mg 
QD in Part 2 of the phase 1 portion and the phase 2 portion will be maintained at this dose 
unless dose modifications are required due to individual tolerability. A starting dose 
reduction, if required, will be documented to all study sites by formal written 
communication.
MLN0128 administration should be withheld for MLN0128-related toxicities that are 
≥Grade 3 despite supportive treatment per standard clinical practice. If the event resolves to 
Grade 1 or baseline values within 2 weeks of interrupting treatment, the patient may resume 
study treatment at a 25% to 50% dose reduction (ie, 2 mg QD). Alternatively, if dose 
modification is required for patients receiving 2 mg QD, then the dosing frequency should 
be decreased to 5 days per week instead of decreasing the daily dose administered. If 
MLN0128 dosing is delayed for more than 14 consecutive days for MLN0128-related 
toxicity despite supportive treatment per standard clinical practice, or more than 2 dose 
reductions of MLN0128 are required in a patient, stop MLN0128 therapy, discontinue the 
patient from the study, and complete the EOT visit within 30 to 40 days after the last dose of 


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MLN0128. The sponsor’s project clinician should be contacted before any dose 
modification in MLN0128 for any patient in the study.
6.4
Excluded Concomitant Medications and Procedures
All prescription and over-the-counter medications, including influenza vaccines, taken by a 
patient as of the first MLN0128 administration through 30 days following the last dose will 
be recorded on the designated case report form.
The following medications/therapies 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 an MLN0128-related AE (eg, rash).

Strong CYP1A2 inhibitors and CYP inducers should be administered with caution 
and at the discretion of the investigator (see Section 14.4 for a list of these agents).

Antiepileptic drugs for patients with a history of treated brain metastasis.

Concomitant administration of any proton pump inhibitor (PPI) is not permitted 
during the study. Patients receiving PPI therapy before enrollment must stop using 
the PPI for 7 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 study drug administration. Patients receiving histamine H2 receptor 
antagonists before enrollment must stop using these medications for at least 24 hours 
before their first dose of study drug. Examples of histamine H2 receptor antagonists 
include ranitidine, famotidine, and nizatidine. Cimetidine, a moderate CYP1A2 
inhibitor, is not recommended as a first choice H2 receptor antagonist (see 
Section 14.4).


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
Administration of neutralizing antacids and calcium preparations is permitted except 
from 4 hours before until 2 hours after MLN0128 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.
6.5
Permitted Concomitant Medications and Procedures
Prophylactic use of antiemetic (including ondansetron and granisetron), antinausea, and 
antidiarrheal medications is encouraged, and these may be administered before the first dose 
of MLN0128, as needed throughout the study before each dosing, and as clinically indicated 
per standard practice.
Concomitant treatment with bisphosphonates is permitted for treatment of osteoporosis or 
management of existing bone metastases if initiated at least 4 weeks before administration of 
the first dose of MLN0128. Bisphosphonates should be given after Cycle 1 to minimize 
confounding factors that may contribute to potential drug-related toxicities.
Other medications considered necessary for the safety and wellbeing of the patient may be 
administered at the discretion of the investigator. Any concomitant medications added or 
discontinued during the study should be recorded on the electronic case report form (eCRF).
6.6
Precautions and Restrictions
No dietary restrictions will be imposed on study patients other than daily fasting for glucose 
monitoring (refer to Section 7.4.16).
Patients who show evidence of hyperglycemia during the study should be encouraged to 
follow a low-carbohydrate diet.
6.7
Management of Clinical Events
6.7.1
Management of Hyperglycemia
In addition to obtaining fasting serum glucose levels at the clinic visits as outlined in the 
Schedule of Events, all patients will be provided with a glucometer and trained in its use to 
monitor their daily predose fasting blood glucose (FBG) levels at home. Patients will be 
instructed to notify the study staff immediately of any abnormal readings (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. Investigators will be 
responsible for reviewing the home glucose monitoring logs for hyperglycemia. If no 


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irregularities in the FBG level are observed during a minimum of 6 consecutive months, 
then the frequency of in-home fasting glucose testing may be reduced to twice weekly if the 
investigator approves. Patients will continue to notify the investigator of FBG levels 
≥150 mg/dL, and if blood glucose levels are not well controlled, or if they require 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. Guidelines for management of 
hyperglycemia are presented in Table 6-1.
Table 6-1
Management of Hyperglycemia
Grade
Description
Treatment
MLN0128 Dose Modification
1
FBG>ULN–
160 mg/dL
Continue close monitoring of 
blood glucose. Initiate oral 
hypoglycemic agent.
None
2
FBG>160–250 
mg/dL
Initiate oral hypoglycemic 
agent and/or insulin if not 
well controlled on oral agent.
None
≥ 3
FBG>250 mg/dL
Initiate oral hypoglycemic 
agent and/or insulin.
Hold drug until ≤Grade 2.
Resume MLN0128 based on timing of 
recovery:

≤1 week: resume at same dose and 
schedule.

>1 but ≤2 weeks: reduce dose. (a)

2 weeks: stop MLN0128 and 
discontinue patient from the study.
Prevention/Prophylaxis

Follow fasting serum glucose levels during clinic visits.

Monitor home glucometer test results.

Check HbA1c levels every 3 months during therapy.

Recommend lifestyle modifications, as appropriate (balanced diet, limited alcohol consumption, 
increased physical activity).

Most episodes of Grade 1 and 2 hyperglycemia respond quickly to oral metformin. Early initiation of 
therapy is recommended to prevent higher-grade hyperglycemia.

FBG levels ≥150 mg/dL by glucometer should be followed by closer monitoring of serum glucose and 
possible intervention.
QD5D=once daily for 5 days each week.
(a) Phase 1b Part 1 cohorts: for patients receiving a starting dose of 5 mg, reduce by 20% (to 4 mg). If dose 
modification is required for patients receiving 4 mg QD, then the frequency of dosing should be 
decreased to QD5D, rather than decreasing the daily dose administered. For all other patients: the initial 
dose reduction should be from 4 mg to 3 mg, with further reduction to 2 mg if necessary.
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 


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of the blood draw (ie, nothing by mouth for at least 8 hours before). To aggressively manage 
the hyperglycemia per standard clinical practice, the following guidelines are provided to aid 
the investigator in initiating antiglycemic therapies.
Based on the clinical experience in MLN0128 trials, most episodes of hyperglycemia 
observed have been Grade 1 or Grade 2 and have responded quickly to oral metformin. 
Hyperglycemia has not been dose-limiting since instituting a standard regimen for early 
treatment of hyperglycemia. All patients developing hyperglycemia on the study should 
have their glucose closely monitored by study staff. The investigator may choose either to 
continue close monitoring of patients who develop Grade 1 hyperglycemia (fasting serum 
glucose>ULN≤160 mg/dL) or consider initiating treatment with an oral hypoglycemic agent, 
such as metformin. All patients with ≥Grade 2 hyperglycemia (fasting serum glucose 
>160 mg/dL) must be treated aggressively with oral hypoglycemic agents and/or insulin as 
clinically indicated while continuing on MLN0128 treatment. The investigator should 
consult an endocrinologist if needed to aid in optimizing the hyperglycemia treatment plan 
of the patient.
It is recommended that patients be treated initially 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.
6.7.2
Management of Hyperlipidemia
Guidance on MLN0128 dose modification for patients with hyperlipidemia is provided in 
Table 6-2.


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Table 6-2
Management of Hyperlipidemia
Grade
Description
Treatment
MLN0128 Dose Modification
1
Cholesterol:
>ULN - 300 mg/dL
Triglycerides:
> 150-300 mg/dL
None
None
2
Cholesterol:
>300-400 mg/dL
Triglycerides:
>300-500 mg/dL
Treat hyperlipidemia according 
to standard guidelines. 
Triglycerides ≥500 mg/dL 
should be treated urgently due 
to risk of pancreatitis.
Maintain dose if tolerable. If 
toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤Grade 1. Reinitiate 
at same dose.
3
Cholesterol:
>400-500 mg/dL
Triglycerides:
> 500-1000 mg/dL
Same as for Grade 2
Hold dose until recovery to 
≤Grade 1, then restart with a 
dose reduction (a).
4
Cholesterol:
>500 mg/dL
Triglycerides:
>1000 mg/dL
Same as for Grade 2
Discontinue treatment.
Prevention/Prophylaxis

Recommend lifestyle modifications, as appropriate (balanced diet, limited consumption of alcoholic 
beverages, increased physical activity).
QD5D=once daily for 5 days each week.
(a) Phase 1b Part 1 cohorts: for patients receiving a starting dose of 5 mg, reduce by 20% (to 4 mg). If dose 
modification is required for patients receiving 4 mg QD, then the frequency of dosing should be decreased 
to QD5D, rather than decreasing the daily dose administered. For all other patients: the initial dose 
reduction should be from 4 mg to 3 mg, with further reduction to 2 mg if necessary. 
6.7.3
Management of Oral Mucositis
Guidance for the management of oral mucositis is provided in Table 6-3.


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Table 6-3
Management of Oral Mucositis
Grade
Description
Treatment
MLN0128 Dose Modification
1
Asymptomatic or mild 
symptoms 
Nonalcoholic mouth wash or 
0.9% salt water rinse; consider 
topical corticosteroids at earliest 
signs of mucositis.
None
2
Moderate pain not 
interfering with oral intake; 
modified diet indicated 
Topical analgesic mouth 
treatments; topical 
corticosteroids; initiate antiviral 
or antifungal therapy, if 
indicated.
Maintain dose if tolerable. If 
toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤Grade 1. Reinitiate 
at same dose.
3
Severe pain interfering with 
oral intake
Same as for Grade 2; consider 
intralesional corticosteroids.
Hold dose until recovery to 
≤Grade 1, then restart with a 
dose reduction. (a)
4
Life-threatening 
consequences 
Same as for Grade 2; consider 
intralesional corticosteroids.
Discontinue treatment.
Prevention/Prophylaxis

Consider initiation of a nonalcoholic mouth wash or 0.9% salt water rinses 4-6 times daily with start of 
therapy before signs of mucositis develop.

Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis as they may worsen mouth ulcers.
QD5D=once daily for 5 days each week.
(a) Phase 1b Part 1 cohorts: for patients receiving a starting dose of 5 mg, reduce by 20% (to 4 mg). If dose 
modification is required for patients receiving ≤4 mg QD, then the frequency of dosing should be decreased 
to QD5D, rather than decreasing the daily dose administered. For all other patients: the initial dose 
reduction should be from 4 mg to 3 mg, with further reduction to 2 mg if necessary. 


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6.7.4
Management of Rash
Guidance for management of rash is provided in Table 6-4.
Table 6-4
Management of Rash
Grade
Description
Treatment
MLN0128 Dose Modification
2
Macules/papules covering 
≤30% body surface area 
with or without symptoms 
Consider treatment with topical 
steroid cream/ointment and/or 
oral antihistamines.
None
3
Macules/papules covering 
30% body surface area 
with or without symptoms 
Consider treatment with topical 
steroid cream/ointment, oral 
antihistamines, and/or pulsed 
steroids.
Hold until Grade 2; resume 
MLN0128 based on timing of 
recovery:
≤2 weeks: reduce dose. (a)
>2 weeks: stop MLN0128 and 
discontinue patient from the study.
QD5D=once daily for 5 days each week.
(a) Phase 1b Part 1 cohorts: for patients receiving a starting dose of 5 mg, reduce by 20% (to 4 mg). If dose 
modification is required for patients receiving 4 mg QD, then the frequency of dosing should be decreased 
to QD5D, rather than decreasing the daily dose administered. For all other patients: the initial dose 
reduction should be from 4 mg to 3 mg, with further reduction to 2 mg if necessary. 
6.7.5
Management of Nausea and/or Vomiting
Guidance for the management of nausea and/or vomiting is provided in Table 6-5.
Table 6-5
Management of Nausea and/or Vomiting
Grade
Description
Treatment
MLN0128 Dose Modification
2
Loss of appetite with or 
without decreased oral 
intake; 1-5 episodes of 
vomiting within 24 hours
Maximize antiemetic 
therapy; consider IV fluid 
hydration.
None
3
Inadequate oral intake; 
≥6 episodes of vomiting 
within 24 hours
Maximize antiemetic 
therapy; initiate tube 
feeding, IVF, or TPN.
Hold until Grade 1; resume 
MLN0128 without dose 
modification.
Prevention/Prophylaxis
Prophylactic use of antiemetic, antinausea, and antidiarrheal medications is encouraged, and these may be 
administered before each dose of MLN0128 as needed throughout the study.
IVF=intravenous fluids, TPN=total parenteral nutrition.


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6.7.6
Management of Noninfectious Pneumonitis
Guidance for the management of pneumonitis is provided in Table 6-6.
Table 6-6
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 MLN0128 treatment:

When symptoms ≤Grade 1, 
reinitiate MLN0128 treatment with 
a dose reduction. (a)

If no recovery within 4 weeks, then 
discontinue MLN0128 treatment.
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 MLN0128 treatment until 
symptoms resolve to ≤Grade 1.

Consider reinitiating MLN0128 
treatment with a dose reduction. (a)

If toxicity recurs at Grade 3, 
discontinue MLN0128 treatment.
4
Life-threatening:
Ventilatory support 
indicated
Rule out infection and consider 
treatment with corticosteroids.
Discontinue MLN0128 treatment.
QD5D=once daily for 5 days each week.
(a) Phase 1b Part 1 cohorts: for patients receiving a starting dose of 5 mg, reduce by 20% (to 4 mg). If dose 
modification is required for patients receiving 4 mg QD, then the frequency of dosing should be decreased 
to QD5D, rather than decreasing the daily dose administered. For all other patients: the initial dose 
reduction should be from 4 mg to 3 mg, with further reduction to 2 mg if necessary. 
6.8
Blinding and Unblinding
This is an open-label study.
6.9
Description of Investigational Agents
MLN0128 will be supplied as capsules for oral administration. MLN0128 is available in 
3 dose strengths, 1 mg, 3 mg, and 5 mg, each containing 1 mg, 3 mg, 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 color.


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
3 mg MLN0128 capsules: Swedish orange opaque color.

5 mg MLN0128 capsules: gray opaque color.
The original MLN0128 capsules based on unmilled API will continue to be supplied to 
support treatment for ongoing patients in Part 1 of the phase 1b portion of the study. The 
new MLN0128 capsules based on milled API will be administered to patients in Part 2 of 
the phase 1b and the phase 2 portions of the study.
Exemestane is a commercially available oral drug supplied as tablets.[39] Fulvestrant is a 
commercially available drug administered as an IM injection.[40]
6.10 Preparation, Reconstitution, and Dispensation
MLN0128 will be provided in 60-cc high-density polyethylene (HDPE) bottles with 
polypropylene, child-resistant caps and induction seal. MLN0128 will be dispensed with 
dosing instructions for home use, including the requirement that capsules are stored in their 
original containers and that capsules be swallowed whole and not opened, chewed, or 
manipulated in any way. Materials provided by the sponsor should be dispensed to patients 
with clear administration instructions from the investigator.
MLN0128 is an anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling MLN0128 capsules.
6.11 Packaging and Labeling
MLN0128 will be provided by Millennium and will be handled at the investigative site as 
open-label material. MLN0128 capsules are packaged in 60-cc HDPE bottles with 
polypropylene, child-resistant caps and induction seal. For all 3 dose strengths, each bottle 
contains 30 capsules and will have a label containing pertinent study information, country-
specific requirements, and a caution statement.
Supplies of the new MLN0128 capsules based on milled API will be accompanied with a 
new label to differentiate them from the existing supplies of the MLN0128 capsules that are 
based on unmilled API.
While the patient is enrolled in the study, exemestane and fulvestrant may be supplied either 
by the site from commercial sources (US sites) or provided by Millennium (ex-US sites). 
When provided by Millennium, exemestane and fulvestrant will be appropriately labeled in 
compliance with local and regional regulations.


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6.12 Storage, Handling, and Accountability
Upon receipt at the investigative site, MLN0128 should be stored in the original bottles until 
use and stored at room temperature from 15C to 30C (59F to 86F). All temperature 
excursions will be reported to the sponsor for assessment and authorization for continued 
use. All investigational supplies must be stored in a secure area with controlled access and 
will be stored in original packaging. All MLN0128 should be used before the retest expiry 
date.
A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the patients, will be provided and kept at the study site. Storage area 
temperature conditions must be monitored and recorded daily. A daily temperature log will 
also be kept at the study site.
Because MLN0128 is an investigational agent, it should be handled with due care. In case of 
contact with broken capsules, raising dust should be avoided during the clean-up operation. 
The product may be harmful if inhaled, ingested, or absorbed through the skin. Gloves and 
protective clothing should be worn during the clean-up operation. The area should be 
ventilated and the spill site washed after material pick-up is complete. The spilled material 
should be disposed of as hazardous medical waste in compliance with federal, state, and 
local regulations. In case of contact with the powder (eg, from a broken capsule), 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. Patients 
will also receive diary cards to record dosing compliance of MLN0128, the appropriate 
combination therapy (exemestane or fulvestrant), and instructions for their completion.
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.
Exemestane and fulvestrant should be stored according to instructions provided in the 
manufacturer’s most recent package insert or SmPC.


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7. 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.
7.1
Study Personnel and Organizations
The contact information for the Millennium Study Monitor for this study, the central 
laboratory and any additional clinical laboratories, and other third-party vendors may be 
found in the Study Manual. A full list of investigators is available in the sponsor’s 
investigator database.
7.2
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). It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3
Treatment Group Assignments
For Part 1 of the phase 1b portion of the study, all enrolled patients will be assigned to 
receive MLN0128 capsules based on unmilled API at 5 mg QD in combination with either 
fulvestrant or exemestane, at the same dose previously administered.
For Part 2 of the phase 1b portion of the study, the first 6 patients (Cohort 1) will be 
assigned to receive MLN0128 capsules based on milled API at 3 mg QD with either 
exemestane or fulvestrant, at the same dose previously administered. Based on safety and 
tolerability assessments of Cohort 1, an additional 6 patients (Cohort 2) will then be 
assigned to receive MLN0128, at either 4 or 2 mg QD, in combination with either 
exemestane or fulvestrant.
Enrollment in the phase 2 portion of the study will commence for patients on MLN0128 in 
combination with exemestane or fulvestrant therapy once the safety assessment has been 
completed for the phase 1b portion of the study.
Additional details regarding treatment cohorts are provided in Section 4.1.


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7.4
Study Procedures
Refer to the Schedule of Events for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
7.4.1
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.
7.4.2
Patient Demographics
The date of birth, race, and ethnicity of the patient are to be recorded during Screening.
7.4.3
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 the disease. In addition, concomitant medications 
will be recorded as specified in Section 7.4.10.
For patients enrolling into phase 2 (only) who have measurable disease and are undergoing 
CT scans (rather than MRIs) for tumor assessment, the most recent CT scan performed 
before their baseline CT scan in this study will be collected, if available, and forwarded to a 
third-party vendor for tumor volume/size analysis (see Section 8.1.7.3). The date of the scan 
should be indicated, if known. Availability of the scan is not a prerequisite for study 
eligibility.
7.4.4
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.
7.4.5
Patient Height and Weight
Height will be measured only during Screening. Weight will be measured at the times 
specified in the Schedule of Events.
7.4.6
Vital Signs
Vital signs will be assessed at the times specified in the Schedule of Events.


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7.4.7
ECOG Performance Status
The ECOG performance status (refer to Section 14.1) will be assessed at the times specified 
in the Schedule of Events.
7.4.8
MUGA Scan or ECHO
A MUGA scan or ECHO will be administered at the time points specified in the Schedule of 
Events.
7.4.9
Pregnancy Test
Pregnancy testing will not be performed in this study as enrollment is restricted to 
postmenopausal women only.
7.4.10
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF from first dose of MLN0128 through 30 days after the last dose. See 
Section 6.4 and Section 6.5 for a list of medications and therapies that are prohibited and/or 
permitted during the study.
7.4.11
AEs
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events. Refer to Section 9 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.
7.4.12
Enrollment
A patient is considered to be enrolled in the study when the first dose of MLN0128 is 
administered. Procedures for completing the enrollment information are described in the 
Study Manual.
7.4.13
ECG
A single, 12-lead ECG will be administered at the time points specified in the Schedule of 
Events and in the Phase 1b Pharmacokinetic and ECG Sample Breakdown and the Phase 2 
Pharmacokinetic and ECG Sample Breakdown table. Additional ECGs may be obtained as 
clinically indicated.


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7.4.14
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Handling and shipment of clinical 
laboratory samples will be outlined in the Study Manual and/or laboratory manual. Clinical 
laboratory evaluations will be performed as outlined below.
Clinical Chemistry, Hematology/Coagulation, and Urinalysis
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. 
Results of hematology and clinical chemistry safety labs must be available and reviewed by 
the investigator before enrollment and initial administration of MLN0128.
Hematology/Coagulation
A blood sample for complete blood count with platelet count and white blood cell (WBC) 
count with differential will be obtained at the times specified in the Schedule of Events.
The hematology and coagulation panels include the following:

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (ANC)

Activated partial thromboplastin time (aPTT)

Prothrombin time/international normalized ratio 
(PT/INR)
Clinical Chemistry
A blood sample for the clinical chemistry panel will be obtained at the times specified in the 
Schedule of Events.
The clinical chemistry panel includes the following:

Blood urea nitrogen

Creatinine

Bilirubin (total)

Urate

Lactate 
dehydrogenase

Gamma glutamyl 
transferase

Phosphate

Albumin

Alkaline phosphatase

AST

ALT

Glucose

Sodium

Potassium

Calcium

Chloride

Carbon dioxide

Magnesium

Amylase

HbA1c (only at the 
time points specified in 
the Schedule of Events)


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Urinalysis
Urine samples for urinalysis will be obtained at the times points specified in the Schedule of 
Events. Urinalysis will include macroscopic assessment of the amount of protein, glucose, 
WBCs, and blood if they are present (levels should be recorded if available) and 
microscopic analysis if abnormality is noted.
The urinalysis panel includes the following:

Turbidity and color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult blood

Nitrite

Urobilinogen

Glucose

Leukocytes
Fasting Lipid Profile
Prospective monitoring for hyperlipidemia will be managed through fasting lipid testing at 
the time points specified in the Schedule of Events.
The fasting lipid profile includes the following:

Total cholesterol

Triglycerides

High-density lipoprotein 
cholesterol

Low-density lipoprotein 
cholesterol
7.4.15
Fasting Serum Glucose
Fasting serum glucose will be measured at the time points specified in the Schedule of 
Events before administration of MLN0128. Patients are required to fast overnight (nothing 
except water and/or medications after midnight or for a minimum of 8 hours) for each of 
these measurements.
7.4.16
In-Home Daily Fasting Glucose Monitoring
Patients will be instructed to complete daily glucose monitoring at home after fasting 
overnight (nothing except water and/or medications after midnight or for a minimum of 
8 hours) for each of these measurements. Patients will be instructed to bring the glucometer 
with them to each study visit so that the data collected can be reviewed and recorded into 
source documents. Based on investigator judgment, and upon the 6 consecutive months of 
well-controlled blood glucose levels, the frequency of in-home fasting glucose testing may 
be reduced to twice weekly. During this period of reduced monitoring, patients will continue 
to notify the investigator of FBG levels that exceed 150 mg/dL. If blood glucose levels are 
not well controlled at any time during the study, or if the patient requires either oral 


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hypoglycemic agents or insulin to control blood glucose levels, in-home testing of FBG 
levels will be resumed daily with the provided glucometer. On study visit days where fasting 
glucose is assessed in the clinic, the in-home daily fasting glucose monitoring does not need 
to be completed.
7.4.17
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 1.1 [25], 
where measureable disease is defined as at least 1 extraosseous lesion that can be accurately 
measured in at least 1 dimension.[42] Anatomical measurements (summed across target 
lesions) will be collected at Baseline and at each subsequent evaluation using an imaging 
modality consistent with that used at Screening. 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 specified in the Schedule of Events. When possible, the same
qualified physician will interpret results to reduce variability.
In the absence of measurable disease at Baseline, the following will be considered disease 
progression among patients with bone-only disease:

The appearance of 1 or more new lytic lesions in bone.

The appearance any extraosseous lesions.

Unequivocal progression of existing bone lesions.
Radiographic images will be maintained at the site, and test results and physicians’ findings 
will be filed in patient source documents. The sponsor may request electronic images for 
those patients who demonstrate a response. Digital Imaging and Communications in 
Medicine-formatted images of radiologic scans will be electronically transferred to a third-
party vendor for a centralized assessment of tumor volumes/sizes.
7.4.18 PK Measurements
PK samples collected in this study will be used to quantify MLN0128 or exemestane only. 
The plasma concentration of fulvestrant will not be measured in this study. The dates and 


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exact times when MLN0128 and exemestane were administered and the dates and exact 
times at which PK samples were obtained will be noted in the eCRF. Blood samples will be 
collected at the time points specified in the Phase 1b Pharmacokinetic and ECG Sample 
Breakdown and the Phase 2 Pharmacokinetic and ECG Sample Breakdown tables.
7.4.19
Archival (Banked) Tumor Tissue and Tumor Biopsies
7.4.20
DNA Measurements
Blood samples will be collected at the time points specified in the Schedule of Events, and 
 
 
 
 
Such analysis will be exploratory in nature and may or may not be completed as part of this 
study assessment; hence, the deliverable of the results from such analyses will not adhere to 
this study’s timelines. 
 
 
 The results of such analyses will thus not 
be presented in the clinical study report for this study and will be presented in a separate 
population PK analysis report at a later time.
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7.4.21
7.5
Completion of Treatment
Patients will be considered to have completed treatment if they discontinue MLN0128 for 
any of the reasons outlined in Section 7.7.
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.
7.6
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 7.8.
7.7
Discontinuation of Treatment With Study Drug and Patient Replacement
Treatment with MLN0128 may be discontinued for any of the following reasons:
∀
AE.
∀
Protocol violation.
∀
Progressive disease.
∀
Study terminated by sponsor.
∀
Withdrawal by subject.
∀
Lost to follow-up.
∀
Other.
Once MLN0128 has been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the Schedule of Events. The primary reason for MLN0128 
discontinuation will be recorded on the eCRF.
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Patients in the Everolimus-Resistant Cohort and in the Everolimus-Sensitive Cohort who are 
not response evaluable (refer to Section 8.1.3) will need to be replaced.
Note that some patients may discontinue MLN0128 for reasons other than progressive 
disease. These patients will remain in the study for posttreatment assessments as outlined in 
the Schedule of Events and in Section 7.10.
7.8
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.
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.
7.9
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s). The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
Patients will receive a sufficient quantity of MLN0128 for each treatment cycle and a diary 
in which to record their dosing. Patients should continue taking the same dose of either 
exemestane or fulvestrant as previously administered. The study center staff will check the 
patient’s diary versus the patient’s supply of remaining MLN0128 and either exemestane or 
fulvestrant 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.
7.10 Posttreatment Follow-up Assessments (PFS and OS)
After EOT, patients will be followed for PFS and OS. Survivor information may be 
collected by methods that include, but are not limited to, telephone, email, mail, or retrieved 
from online or other databases (eg, Social Security indexes). In addition, the start of another 
anticancer therapy will be collected. For those patients who discontinue MLN0128 for any 


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reason other than radiographic disease progression, CT (with contrast) or MRI scans (with 
contrast, unless contra-indicated) should be completed to further assess disease progression 
(per RECIST, version 1.1).[42] Refer to the Schedule of Events for appropriate assessments 
during posttreatment follow-up.
The study (including the posttreatment follow-up period) will be terminated 6 months after 
the last patient completes an EOT study visit.
NOTE: Related SAEs must be reported to the Millennium Department of Pharmacovigilance 
or designee. This includes deaths that the investigator considers related to MLN0128 that 
occur during the posttreatment follow-up. Refer to Section 9 for details regarding 
definitions, documentation, and reporting of SAEs.
8. STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
8.1.1
Determination of Sample Size
Phase 1b
The safety and tolerability of MLN0128 in combination with either exemestane or 
fulvestrant will be evaluated. Patients will be enrolled as follows:

In Part 1 of the phase 1b portion of the study, up to 6 patients will be enrolled into the 
MLN0128+Exemestane Safety Cohort and up to 6 patients will be enrolled into the 
MLN0128+Fulvestrant Safety Cohort. The number of patients is based on clinical 
considerations.

In Part 2 of the phase 1b portion of the study, 6 patients will be enrolled into 
MLN0128+Exemestane/Fulvestrant Safety Cohort 1, and 6 patients will be enrolled 
into MLN0128+Exemestane/Fulvestrant Safety Cohort 2. The number of patients is 
based on clinical considerations.
Phase 2
The sample size for each cohort in the phase 2 portion of the study is based on a standard 
Simon two-stage design. A Bayesian predictive probability design was used to allow 
multiple interim analyses to stop early for futility.[45] See Section 8.1.9 for sample size 


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assumptions. Up to 56 response-evaluable patients will be enrolled in the
Everolimus-Resistant Cohort. In the Everolimus-Sensitive Cohort, up to 
48 response-evaluable patients will be enrolled.
8.1.2
Randomization and Stratification
This study will not require randomization or stratification.
8.1.3
Populations for Analysis
The populations used for analysis will include the following:

Safety population: patients who receive at least 1 dose of MLN0128.

PK population: patients with sufficient dosing and PK data to reliably estimate PK 
parameters.

Response-Evaluable population: patients who receive at least 1 dose of MLN0128 
and have measurable disease at Baseline.
8.1.4
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations. No 
imputation of values for missing data will be performed.
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
8.1.5
Demographic and Baseline Characteristics
Demographic and baseline characteristics (age, race, weight, height, and other parameters as 
appropriate) will be summarized by drug combination (MLN0128 in combination with 
exemestane and MLN0128 in combination with fulvestrant) in the phase 1b portion of the 
study and by cohort (Everolimus-Sensitive Cohort and Everolimus-Resistant Cohort) in the 
phase 2 portion of the study.
8.1.6
Efficacy Analysis
Analysis of efficacy measures will be descriptive. Investigators will assess disease response 
according to RECIST guidelines (version 1.1)[42] at each time point. The best overall 


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response for each patient will be derived programmatically from among the reported 
responses at the end of Cycle 4 and for the entire treatment period.
Data listings will present the tumor measurements on contrast-enhanced CT or MRI
(including changes from Baseline) scans, disease response category (eg, CR, partial 
response, and SD), and other endpoints as appropriate.
Primary Efficacy Endpoint
The primary efficacy endpoint in the phase 2 portion of the study is CBR-16.
The number and percentage of patients achieving clinical benefit at 16 weeks will be 
tabulated, and the estimate of the CBR-16 will be presented with a 2-sided 95% exact 
binomial CI for each cohort.
Secondary Efficacy Endpoints
The number and percentage of patients in each response category (CR, partial response, SD, 
disease progression, ORR, CBR-24, and CBR) will be tabulated for each cohort.
PFS is defined as the time from the date of first MLN0128 administration to the date of first 
documentation of disease progression or death. OS is defined as the time from the date of 
first MLN0128 administration to the date of death. PFS and OS will be analyzed using 
Kaplan-Meier methodology for each cohort.
Waterfall plots of the best percentage of change from Baseline in the sum of the longest 
diameter (SLD) of the target lesion will be generated for each cohort.
8.1.7
PK/Pharmacodynamics/Biomarkers
8.1.7.1
PK Analysis and Modeling
Individual patient plasma concentrationtime data and individual patient concentrationtime 
plots for MLN0128 and exemestane will be provided as listings. Additionally, mean 
concentrationtime data for MLN0128 and exemestane will be provided.
Data permitting, PK parameters including, but not limited to, Cmax, Tmax, AUC24h, AUCt, and 
t1/2 will be reported for MLN0128 and exemestane.
A formal DDI assessment between MLN0128 and exemestane is not planned in this study; 
however, for the purpose of assessment of DDI between MLN0128 and exemestane, plasma 


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concentration!time data and relevant PK parameters (such as Cmax, AUC24h, and t1/2) of
MLN0128 and exemestane will be compared against historical, single-agent PK data for 
these agents. The PK of MLN0128 and exemestane on Cycle 1 Day 15 will be assessed 
based on evaluable patients from the MLN0128+Exemestane Safety Cohort. Blood samples 
for PK analysis may be required from patients from other cohorts where MLN0128 is 
administered in combination with exemestane to obtain an appropriate sample size for the 
DDI assessment.
Data generated in this study will be combined with data from other studies in which the PK 
of MLN0128 is characterized for population PK analysis. The results of population PK 
analysis will be presented in a separate report.
8.1.7.2
8.1.7.3
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8.1.8
Safety Analyses
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from Baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
safety population. Exposure to MLN0128 and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of MLN0128 and through 30 days 
after the last dose of MLN0128 will be tabulated.
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities 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 MLN0128 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.
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Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. The number and percentage of patients taking concomitant medications will be 
tabulated by WHO drug generic term by cohort in the safety population.
Additional safety analyses may be performed to more clearly enumerate rates of toxicities 
and to further define the safety profile.
ECG Analysis
ECG intervals (QT and QTc with Fridericia correction, PR, and QRS) and ventricular rate 
will be summarized at each scheduled time point, along with mean change from Baseline to 
each posttreatment time point. The number and percentage of patients with ECG 
abnormalities will be summarized at each time point.
8.1.9
Interim Analysis
There will be 3 interim analyses for futility in the Everolimus-Resistant Cohort and 
2 interim analyses for futility in the Everolimus-Sensitive Cohort. The investigator-assessed 
CBR-16 rate will be used as the endpoint for the interim analysis. The interim analysis will 
be based on response-evaluable patients who have had the opportunity to complete a 
minimum of 4 cycles of treatment with MLN0128 or have discontinued treatment with 
MLN0128 before the end of Cycle 4.
In the Everolimus-Resistant Cohort, there will be 3 interim analyses based on the following 
assumptions:

Ineffective CBR-16 rate (Ho): 10%.

Effective CBR-16 rate (Ha): 20%.

Alpha=10%; power=80%.

Prior Beta Distribution Parameters: ao=0.10, b0=0.90.

Probability of early termination under Ho: 68%.


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Table 8-1
Interim Analyses in the Everolimus-Resistant Cohort 
Stage
No. of Patients 
Evaluated
Number of Patients With CBR-16 to Proceed or Declare Active
1
29
≥ 3
2
39
≥ 4
3
49
≥ 6
Final
56
≥ 9
In the Everolimus-Sensitive Cohort, there will be 2 interim analyses based on the following 
assumptions:

Ineffective CBR-16 rate (Ho): 15%.

Effective CBR-16 rate (Ha): 30%.

Alpha=5%; power=80%.

Prior Beta Distribution Parameters: ao=0.15, b0=0.85.

Probability of early termination under Ho: 71%.
Table 8-2
Interim Analyses in the Everolimus-Sensitive Cohort
Stage
No. of Patients
Evaluated
Number of Patients With CBR-16 to Proceed or Declare Active
1
23
≥4
2
38
≥7
Final
48
≥12
9. ADVERSE EVENTS
9.1
Definitions
9.1.1
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 


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medication; it does not necessarily have to have a causal relationship with study 
participation.
9.1.2
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 MLN0128.
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.
9.1.3
SAE Definition
Serious AE 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 below 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. 


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Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, version 4.03, effective date 14 June 2010.[43] Clarification should be 
made between a serious AE and an AE that is considered severe in intensity (Grade 3 or 4), 
because the terms serious and severe are NOT synonymous. The general term severe is often 
used to describe the intensity (severity) of a specific event; the event itself, however, may be 
of relatively minor medical significance (such as a Grade 3 headache). This is NOT the 
same as serious, which is based on patient/event outcome or action criteria described above, 
and is usually associated with events that pose a threat to a patient’s life or ability to 
function. A severe AE (Grade 3 or 4) does not necessarily need to be considered serious. For 
example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious. Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
9.2
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 9.3 for the 
period of observation). Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE. When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 9.1) 
must be reported (see Section 9.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance 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 Millennium, will be provided to each 
clinical study site. A sample of the SAE Form may be found in the Study Manual. 
Follow-up information on the SAE or serious pretreatment event may be requested by 
Millennium. SAE report information must be consistent with the data provided on the eCRF.


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SAE Reporting Contact Information
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before MLN0128 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 pretreatment 
events, the investigator must determine both the intensity of the event and the relationship of 
the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, version 4.03, effective date 14 June 2010.[43] 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?
9.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:
∀
AEs will be reported from the first dose of MLN0128 through 30 days after 
administration of the last dose of MLN0128 and recorded in the eCRFs.
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
Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the informed consent 
form (ICF) up to first dose of MLN0128 but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of MLN0128 through 30 days 
after administration of the last dose of MLN0128 and recorded in the eCRF. After 
this period, only related SAEs must be reported to the Millennium Department of 
Pharmacovigilance 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).
9.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
Reporting drug exposure during pregnancy and birth events is not applicable for this study 
as enrollment is restricted to postmenopausal women only.
9.5
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, including the 
European Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in 
accordance with national regulations in the countries where the study is conducted. Relative 
to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as an expedited report 
within 7 calendar days for fatal and life-threatening events and 15 calendar days for other 
serious events, unless otherwise required by national regulations. The sponsor will also 
prepare an expedited report for other safety issues where these might materially alter the 
current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in 
the overall conduct of the trial. The investigational site also will forward a copy of all 
expedited reports to his or her IRB or IEC in accordance with national regulations.


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10. ADMINISTRATIVE REQUIREMENTS
10.1 GCP
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s). The investigator will be thoroughly familiar with the appropriate use of the 
MLN0128 as described in the protocol and the IB.
10.2 Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient. Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application. Millennium will have access to all 
data upon entry in the EDC application.
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution. Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
10.3 eCRF Completion
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient. It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible. The audit trail entry will show the user’s 
identification information and the date and time of the correction.


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Millennium, or a designee, will retain the eCRF data and corresponding audit trails. A copy 
of the final archival eCRF in the form of a compact disk or other electronic media will be 
placed in the investigator’s study file.
10.4 Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation. During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.
10.5 Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards. The IRB/IEC will review all appropriate study documentation 
to safeguard the rights, safety, and well-being of the patients. The study will be conducted 
only at sites where IRB/IEC approval has been obtained. The protocol, IB, ICF, 
advertisements (if applicable), written information given to the patients (including diary 
cards), safety updates, annual progress reports, and any revisions to these documents will be 
provided to the IRB/IEC by the investigator or the sponsor, as allowed by local regulations.
10.6 Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation. The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
10.7 Patient Confidentiality
To maintain patient privacy, all eCRFs, MLN0128 accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number. The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.


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10.8 Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies). Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium. Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients. Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 
circumstances permit, to discuss the planned course of action. Any departures from the 
protocol must be documented.
10.9 On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
10.10
Investigator and Site Responsibility for Drug Accountability
Accountability for the MLN0128 at the trial site is the responsibility of the investigator. 
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site. Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing MLN0128 will be treated and disposed of in accordance with 
governing regulations.
10.11
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 


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Medical Information Call Center/
and report the 
complaint. The contact information is as follows:
Medical Information Call 
Center:
Phone:
Fax:
Email:
Hours:
Whenever possible, the associated product should be maintained in accordance with the 
label instructions pending further guidance from a Millennium Quality representative.
Product complaints in and of themselves are not AEs. If a product complaint results in an 
SAE, an SAE form should be completed and sent to 
 (refer to Section 9.2).
10.12
Closure of the Study
The study (including the posttreatment follow-up period) will be terminated 6 months after 
the last patient completes an EOT study visit.
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause. Written 
notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:
∀
Determination of unexpected, significant, or unacceptable risk to patients.
∀
Failure to enter patients at an acceptable rate.
∀
Insufficient adherence to protocol requirements.
∀
Insufficient, incomplete, and/or unevaluable data.
∀
Determination of efficacy based on interim analysis.
∀
Plans to modify, suspend or discontinue the development of the study drug.
CCI
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C
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Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded. In the event 
that any access devices for the EDC application have been provided, these will be returned 
to Millennium once the site’s participation in the study has concluded.
10.13
Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s). If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.
11. USE OF INFORMATION
All information regarding MLN0128 supplied by Millennium to the investigator is 
privileged and confidential information. The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from 
Millennium. It is understood that there is an obligation to provide Millennium with complete 
data obtained during the study. The information obtained from the clinical study will be used 
toward the development of MLN0128 and may be disclosed to regulatory authority(ies), 
other investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.


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12. INVESTIGATOR AGREEMENT
I have read Protocol C31001 Amendment 6: A Phase 1b/2 Study of Safety and Efficacy of 
MLN0128 (Dual TORC1/2 Inhibitor) in Combination With Exemestane or Fulvestrant 
Therapy in Postmenopausal Women With ER+/HER2Advanced or Metastatic Breast 
Cancer That Has Progressed on Treatment With Everolimus in Combination With 
Exemestane or Fulvestrant.
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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2012.
41.
Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. 
Circulating tumor cells, disease progression, and survival in metastatic breast cancer. 
N Engl J Med 2004;351(8):781-91.
42.
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.
43.
U.S. Department of Health and Human Services. National Cancer Institute. Common 
Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 2010 June 14.
44.
Wolff AC, Hammond ME, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. 
Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in 
Breast Cancer: American Society of Clinical Oncology/College of American 
Pathologists Clinical Practice Guideline Update]. Arch Pathol Lab Med 2013.
45.
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. 
Clin Trials 2008;5(2):93-106.
46.
Stein A, Wang W, Carter AA, Chiparus O, Hollaender N, Kim H, et al. Dynamic 
tumor modeling of the dose-response relationship for everolimus in metastatic renal 
cell carcinoma using data from the phase 3 RECORD-1 trial. BMC Cancer 
2012;12:311.
47.
Suzuki C, Jacobsson H, Hatschek T, Torkzad MR, Boden K, Eriksson-Alm Y, et al. 
Radiologic measurements of tumor response to treatment: practical approaches and 
limitations. Radiographics 2008;28(2):329-44.
48.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J 
Clin Oncol 1982;5(6):649-55.
49.
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.
50.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.


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14. APPENDICES
14.1 ECOG Scale for Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair
5
Dead
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.[48]
14.2 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. 9th Ed. Boston, MA: Little, Brown & Co; 1994:253-256.[49]


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14.3 Cockcroft-Gault Equation
Creatinine Clearance =
0.85 (140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
0.85 (140-age [years])weight [kg]
0.81(serum creatinine [µmol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine.
Nephron 1976;16(1):31-41.[50]


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14.4 List of Relevant CYP 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.


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14.5 Amendment 1 Rationale and Purposes
Rationale for Amendment 1
The primary purpose of this amendment is to expand the number of investigative sites to 
include sites in the United States (US), Belgium, and France. In conjunction with this 
expansion, it has been noted that Millennium will provide exemestane and fulvestrant to 
sites outside of the US and references to the Summary of Product Characteristics (SmPCs) 
for each agent have been added. This amendment also incorporates procedural clarifications 
that were contained in prior administrative letters and clarifies posttreatment follow-up 
procedures, including a specification for an overall study ending time point. 
To optimize analysis of the phase 2 exploratory endpoint of
 
Several eligibility criteria have been clarified. The inclusion criterion for human epidermal 
growth factor receptor 2 (HER2)-negative status was simplified to reference the updated 
HER2 testing criteria of the American Society of Clinical Oncology (ASCO) and the
College of American Pathologists (CAP). The exclusion criterion for treatment with 
cytochrome P450 (CYP) inhibitors has been aligned with the prohibited concomitant 
medications.
The revisions and clarifications in this protocol amendment are listed below.
Purposes for Amendment 1
The purposes of this amendment are to:
Study Administration 
∀
Increase the number of investigative sites to approximately 40, including sites in the 
US, Belgium, and France
∀
Add the EudraCT (European Clinical Trials Database) number 
∀
Update the contact information for the reporting of serious adverse events in both the 
US and the rest of the world (incorporates Administrative Letter #1, 06 December 
2013) 
∀
Specify that the study will end no later than 6 months after the last patient completes 
the end-of-treatment visit 
Eligibility
∀
Refine the HER2-status inclusion criterion by clarifying the language and revising the 
reference histologic criteria to conform with the recently updated ASCO/CAP 
recommendations for HER2 testing in breast cancer
∀
Align the eligibility criteria with the list of prohibited concomitant medications 
regarding moderate inhibitors of CYP2C9
∀
Clarify that patients enrolled in the phase 1b portion are not eligible to participate in 
the phase 2 portion of the study 
CCI


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Study Drug and Investigational Agents 
∀
Replace “study drug” with “MLN0128” where applicable, for clarity
∀
Specify that MLN0128 should be taken once daily at approximately the same time 
each day 
∀
Specify that exemestane and fulvestrant will be provided by Millennium 
Pharmaceuticals, Inc., to the investigative sites located outside of the US 
∀
Clarify that patients in the phase 1b portion who receive exemestane as their prior 
therapy will continue their therapy at their previously established dose 
∀
Reference the current version of the SmPC for exemestane and fulvestrant in addition 
to the US Prescribing Information
Procedures and Assessments
∀
Clarify that information on concomitant medications is collected from the time of the 
first dose of MLN0128 through 30 days after last dose of MLN0128 (incorporates 
Administrative Letter #2, 06 February 2014) 
∀
Clarify the language regarding food and beverage restrictions
∀
Simplify the wording of the definition of dose-limiting toxicity in phase 1b 
∀
Revise the procedure subsection heading to emphasize that either (but not both) a 
multiple gated acquisition scan or echocardiogram should be performed (incorporates 
Administrative Letter #2, 06 February 2014) 
∀
Specify that coagulation assessments are required for all patients at the time points 
listed in the Schedule of Events
∀
Specify that the coagulation assessments are included in the list of hematology 
assessments in the clinical laboratory evaluations section 
∀
Clarify that glycosylated hemoglobin testing is required only at the time points 
specified in the Schedule of Events (incorporates Administrative Letter #2, 
06 February 2014) 
∀
Clarify that tumor responses are based on RECIST (Response Evaluation Criteria in 
Solid Tumors) guidelines (Version 1.1), without any modification
∀
Add a request for the most recent historical prebaseline CT scans (if available) for 
patients enrolling into phase 2 who have measurable disease
∀
 
∀
∀
Clarify the procedures for posttreatment follow-up 
∀
Add 2 assumptions to the interim analyses for futility 
Administrative 
∀
Delete a description of the overall safety profile of MLN0128 because the IB is 
intended to be the primary source of safety information pertaining to the drug 
candidate 
CCI
CCI


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
Update the List of Abbreviations and Glossary of Terms to include ASCO, CAP, and 
SmPC

Insert a cross-reference in Section 8.1.1 to Section 8.1.9 to direct the reader to the 
sample size assumptions for this study

Correct typographical errors, punctuation, grammar, and formatting
14.6 Amendment 2 Rationale and Purposes
Rationale for Amendment 2
Clinical Study Protocol C31001 is being amended to evaluate the safety, tolerability, and 
pharmacokinetics (PK) of a new MLN0128 capsule based on milled active pharmaceutical 
ingredient (API) before initiation of the phase 2 portion of the study. The new capsules 
based on milled API are to be taken on an empty stomach. 
Purposes for Amendment 2
The purposes of this amendment are to:
The purposes of this amendment are to:

Evaluate the safety, tolerability, and PK of a new MLN0128 capsule based on milled 
API (Part 2 of the phase 1b portion of the study)

Add 12 patients to be enrolled into the study

Add blood sampling for PK analysis in Part 2 of the phase 1b portion of the study

Provide rationale for the starting dose of the new MLN0128 capsules based on milled 
API

Update dose-limiting toxicity (DLT) definitions for patients in Part 2 of the phase 1b 
portion of the study

Update information on dose reductions in patients in the phase 1b portion of the study

Update information on dose reductions in patients in the phase 2 portion of the study

Provide clarification on drug supply information for the MLN0128 capsules based on 
unmilled and milled API 

Provide information on packaging and labeling of the new MLN0128 capsules based 
on milled API

Provide information on treatment group assignment for patients in Part 2 of the phase 
1b portion of the study

Provide instruction that MLN0128 capsules with milled API will be taken on an 
empty stomach, but capsules with unmilled API will continue to be taken with a light 
meal 

Remove PK sampling in the phase 2 part of the study on Cycle 2, Day 15 and
Cycle 3, Day 8 for all patients and replace with PK samples on Cycle 1, Day 15 and 
Cycle 2, Day 1

Clarify the PK and ECG sampling time points for the 2 phases of the study


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
Provide clarification in the description of statistical analyses used to determine 
sample size in the phase 2 portion of the study

Correct the assumptions for the interim analysis of the Everolimus-Sensitive Cohort 
in the phase 2 portion of the study

Provide clarification in the inclusion criteria that exemestane or fulvestrant in 
combination with MLN0128 can also be initiated as a new line of therapy in patients 
enrolled into the phase 1b portion of the study 

Provide clarification that concomitant treatment with denosumab is permitted for 
treatment of osteoporosis or management of existing bone metastases 

Correct typographical errors, punctuation, grammar, and formatting
14.7 Amendment 3 Rationale and Purposes
Rationale for Amendment 3
Clinical Study Protocol C31001 is being amended to clarify that enrolled patients in France 
or Belgium will not have had prior combination therapy with fulvestrant and everolimus, 
and will not receive this combination in the study. Additionally, this amendment clarifies the 
timing of MLN0128 and exemestane administration to allow for exemestane to be 
administered after a meal in accordance with the product label. Lastly, a guide for managing 
patients with noninfectious pneumonitis has been added, and the vendor and contact 
information to report product complaints has been updated. 
Purposes for Amendment 3
The purposes of this amendment are to:

Clarify in the inclusion criteria that patients with advanced or metastatic breast cancer 
in the United States (US) would have received prior everolimus in combination with 
either exemestane or fulvestrant, whereas patients outside of the US participating in 
this trial would have received prior everolimus in combination with exemestane, but 
not fulvestrant.

Clarify that, because of the change in the inclusion criteria, patients enrolled in any 
country may receive MLN0128 plus exemestane, but only patients enrolled in the US 
may receive MLN0128 plus fulvestrant.

Clarify that patients in the MLN0128 + fulvestrant safety cohort will be in the US and 
will receive the combination of MLN0128 + fulvestrant, not MLN0128 + 
exemestane.

Clarify that MLN0128 should be administered first on an empty stomach, and 
exemestane administered after a meal, between 1 and 6 hours after MLN0128 dosing, 
with the following exception: For patients in the phase 2 PK/Tumor-PD Cohort, 
during Cycle 1 only, MLN0128 and exemestane should be administered at the same 
time, on an empty stomach.


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
Clarify in the Schedule of Events that a confirmatory scan is to be performed 
approximately 4 weeks after a previous scan for all patients with a complete or partial 
response. 

Provide guidance for the management of patients with noninfectious pneumonitis.

Update the vendor and contact information for reporting product complaints.

Correct typographical errors, punctuation, grammar, and formatting.
14.8 Amendment 4 Rationale and Purposes
Rationale for Amendment 4
This amendment modifies the eligibility criteria to expand the pool of potential study 
participants and to clarify disease status confirmation requirements, and decreases the 
number of PK samples required in the phase 2 portion of the study. This amendment also 
revises the excluded medications section of the protocol based on characterization of PK 
from the phase 1 portion of this study and other clinical studies in the MLN0128 
development program. The starting dose for the phase 2 portion of this study has also been 
confirmed as 4 mg (milled) MLN0128 + either exemestane 25 mg or fulvestrant 500 mg, 
based on a safety and tolerability review of patients in Cohort 2 of phase 1b Part 2. It is not 
anticipated that these modifications will affect the scientific integrity of the study or the 
safety of study participants.
Administrative changes have been made such as introducing the new compound code for the 
study drug, adding the suspected unexpected serious adverse reactions (SUSAR) language, 
and revising the product complaints vendor and contact information. Additional minor 
clarifications or corrections have been made as necessary.
Purposes for Amendment 4
The purposes of this amendment are to:

Expand eligibility criteria to:

Allow enrollment of patients with an Eastern Cooperative Oncology Group 
(ECOG) performance status of 0 to 2 at baseline (previously baseline ECOG 
status must have been 0 to 1; see inclusion criterion #5). 

Remove the requirement that everolimus in combination with exemestane or 
fulvestrant must be the most recent anticancer therapy prior to enrollment 
(see inclusion criterion #13).

Allow prior treatment with PI3K inhibitors, AKT inhibitors, or TORC1 
inhibitors (see exclusion criterion #5).

Clarify the requirements for confirmation of ER+/HER2- status, separate from the 
requirement of metastatic or advanced breast cancer (see inclusion criteria #1 and #2).

Decrease the number of PK samples required of patients in the phase 2 portion:

For patients in the PK/Tumor PD cohort on Cycle 1 Day 15 replace 6 serial 
PK samples (predose, and 0.5, 1, 2, 4, and 8 hours postdose) with a single 


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sample to be collected at the time of the Cycle 1 Day 15 biopsy (2-4 hours 
after the MLN0128 dose).

For all other patients in phase 2 on Cycle 1 Day 15, a single PK sample will 
be collected at 2-hours postdose.

For all patients in phase 2 on Cycle 2 Day 1, replace 3 serial PK samples (0.5, 
2, and 4 hours postdose) with 2 samples that can be collected any time during 
the Cycle 2 Day 15 clinic visit, with the second sample to be collected 1 hour 
after the first. 

For patients in the phase 2 PK/Tumor PD Cohort: 

Remove PK assessment of exemestane. 

Remove requirement for taking exemestane at the same time as MLN0128 
and on an empty stomach during Cycle 1.

Add clinical laboratory testing for fasting lipid profile on Cycle 2 Day 1.

Modify excluded medications based on characterization of PK from the phase 1 portion 
of this study and other clinical studies, and revise text describing the excluded 
medications to align with the other phase 2 protocols in the MLN0128 development 
program:

Do not exclude the concomitant use of a drug needed by patients that has a 
potential to be a moderate CYP2C9 inhibitor, pending follow-up with the 
study investigator and the medical monitor. 

Exclude concomitant PPI therapy on study.

Provide guidelines for use of histamine H2 receptor antagonists, neutralizing 
antacids, and calcium preparations. 

Replace the list of Relevant Cytochrome P450 Inhibitors and Inducers with 
the most current information and revise the source citation.

Confirm that the starting dose of MLN0128 for all phase 2 patients is 4 mg, based on a 
safety and tolerability review of patients in Cohort 2 of phase 1b Part 2.

Add clarification regarding dose modifications depending on starting dose:

The previous recommendation to change from daily dosing to dosing on 
5 consecutive days per week for patients receiving doses ≤4 mg was 
applicable only to patients in the phase 1b Part 1 portion of the study.

The previous recommendation to reduce the dose by 20% also applies only to 
patients in the phase 1b Part 1 portion of the study; new dose reduction 
recommendations (from 4 mg to 3 mg, and then to 2 mg if needed) have been 
added for patients in the phase 2 portion.

Provide more explicit guidance to the investigator when prescribing any concomitant 
strong CYP3A4 and CYP2C19 inducers and/or inhibitors and moderate inhibitors of 
CYP2C9.

Introduce the new compound code “TAK-228” for MLN0128.

Add the suspected unexpected serious adverse reactions (SUSARs) reporting section, 
clarifying the sponsor’s responsibilities for reporting expected and unexpected adverse 
events (AEs).


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
Change the product complaint reporting vendor and contact information.

Modify text for consistency across sections.

Correct typographical errors, punctuation, grammar, and formatting.
14.9 Amendment 5 Rationale and Purposes
Rationale for Amendment 5
This amendment updates the instructions for antiemetic therapy, updates the definition of the 
Response-Evaluable population, and removes the Pharmacokinetic/Tumor-
Pharmacodynamic Cohort.
Purposes for Amendment 5
The purposes of this amendment are to:

Allow the use of ondansetron and granisetron for antiemetic therapy and prophylaxis. 

This change was made to relax the constraints on antiemetic therapy and 
prophylaxis permitted in the study.

Update the definition of the Response-Evaluable population.

This change was made to allow patients without a postbaseline scan to count 
as evaluable.

Remove the Pharmacokinetic/Tumor-Pharmacodynamic Cohort.

This change was made because data from the planned analyses for this cohort 
were not needed to support development of the study drug.


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14.10
Amendment 6 Detailed Summary of Changes
Change 1: Remove the exclusion criterion relating to treatment with strong CYP inhibitors 
or inducers.
The primary change occurs in Section 5.2 Exclusion Criteria:
Amended 
or new 
wording:
3. Treatment with strong inhibitors and/or inducers of CYP3A4, CYP2C19, and 
CYP2C9 must be discontinued at least 1 week before administration of the first 
dose of MLN0128. Exclusion criterion 3 was removed as of Protocol 
Amendment 6.
Rationale for Change:
This change, which removes enrollment restrictions for patients taking CYP3A4, CYP2C9, 
or CYP2C19 inhibitors and/or inducers in this study, was made on the basis of updated data 
on MLN0128 metabolism by specific CYP isoforms.
Change 2: Update the list of concomitant medications prohibited during the study.
The primary change occurs in Section 6.4 Excluded Concomitant Medications and 
Procedures:
Initial 
wording:

Strong CYP3A4 and CYP2C19 inducers and/or inhibitors and moderate 
inhibitors of CYP2C9 should be administered with caution and at the 
discretion of the investigator only if no other reasonable alternatives 
without such CYP inhibitory properties are available within the 
pharmacotherapeutic class and considered suitable for the patient. (Refer to 
Section 14.4 for a list of strong inhibitors and strong inducers of CYP2C9, 
CYP2C19, and CYP3A4.)
….

[….]Examples of histamine H2 receptor antagonists include ranitidine, 
famotidine, nizatidine, and cimetidine.
Amended 
or new 
wording:

Strong CYP3A4 and CYP2C19CYP1A2 inducers and/or inhibitors and 
moderate inhibitors of CYP2C9 CYP inducers should be avoided during 
Cycle 1 and administered with caution and at the discretion of the 
investigator only if no other reasonable alternatives without such CYP 
inhibitory properties are available within the pharmacotherapeutic class and 
considered suitable for the patient. (Refer to See Section 14.4 for a list of 
these agents.).
…

… Examples of histamine H2 receptor antagonists include ranitidine, 
famotidine, and nizatidine., and cCimetidine, a moderate CYP1A2 
inhibitor, is not recommended as a first choice H2 receptor antagonist 
(see Section 14.4).


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Rationale for Change:
This change was made to update the recommendations on concomitant medication use 
during the study on the basis of updated data on MLN0128 metabolism by specific CYP 
isoforms. 
Change 3: Update the list of relevant CYP inhibitors and inducers.
The primary change occurs in Section 14.4 List of Relevant CYP Inhibitors and Inducers:
Description 
of change:
The list of relevant CYP inhibitors and inducers was updated to remove 
sections listing strong CYP2C19 inhibitors and strong and moderate CYP3A4 
inhibitors; to add sections listing strong and moderate CYP1A2 inhibitors; and 
to update the section listing clinically significant enzyme inducers.
Rationale for Change:
This change was made for consistency with updated data on MLN0128 metabolism by 
specific CYP isoforms.
Change 4: Remove dietary restrictions related to CYP inhibitors and inducers.
The primary change occurs in Section 6.4 Excluded Concomitant Medications and 
Procedures:
Deleted 
text
In addition to the above medications, consumption of grapefruit or grapefruit 
juice is not permitted during the study. Patients should not consume food or 
beverages containing the fruit or juice of grapefruits or Seville oranges within 
7 days before the first dose of study drug and throughout the study (See 
Section 14.4).
Rationale for Change:
This change was made for consistency with new data that removes the necessity for 
restrictions concerning CYP2C9 and 2C19.
The following sections also contain this change:

Section 6.6 Precautions and Restrictions.

Section 14.4 List of Relevant CYP Inhibitors and Inducers.
Change 5: Clarify language surrounding the use of contrast with MRI.
The primary change occurs in Section 7.4.17 Disease Assessment:
Initial 
wording:
Patients will undergo CT (with contrast) as appropriate to monitor and assess 
disease progression, using RECIST guidelines (version 1.1), where measureable 
disease is defined as at least 1 extraosseous lesion that can be accurately 
measured in at least 1 dimension.[42] Specific disease sites that cannot be 
adequately imaged by CT may be documented by MRI. Anatomical 
measurements (summed across target lesions) will be collected at Baseline and at 
each subsequent evaluation using an imaging modality consistent with that used 
at Screening. Objective assessments will be performed at each time point 
specified in the Schedule of Events. When possible, the same qualified physician 
will interpret results to reduce variability.


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Amended 
or new 
wording:
Patients will undergo contrast-enhanced imaging (CT (with contrast or MRI)
as appropriate to monitor and assess the overall disease progression, burden 
unless contraindicated for a particular patient using in accordance with
RECIST guidelines (version 1.1) [25], where measureable disease is defined as 
at least 1 extraosseous lesion that can be accurately measured in at least 1 
dimension.[42] Specific disease sites that cannot be adequately imaged by CT 
may be documented by MRI. Anatomical measurements (summed across target 
lesions) will be collected at Baseline and at each subsequent evaluation using an 
imaging modality consistent with that used at Screening. 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 specified in the Schedule of 
Events. When possible, the same qualified physician will interpret results to 
reduce variability. 
Rationale for Change:
This language was changed to clarify that if an MRI is used for imaging, contrast is 
preferred unless contraindicated.
The following sections also contain this change:

Schedule of Events footnotes f and g.

Section 4.1.2 Phase 2.

Section 4.3 Duration of Study.

Section 7.10 Posttreatment Follow-up Assessments (PFS and OS).

Section 8.1.6 Efficacy Analysis.
Change 6: Update the description of potential drug-drug interactions between MLN0128 
and exemestane..
The primary change occurs in Section 1.4.1 Mutual DDI Assessment:
Initial 
wording:
In-vitro, MLN0128 is metabolized by various cytochrome P450 (CYP) enzymes, 
including 2C19 (35%), 3A4 (28%), and 2C9 (28%); MLN0128 neither inhibited 
nor induced any of the major CYP enzymes. Additionally, MLN0128 did not 
inhibit P-glycoprotein but did inhibit breast cancer resistance protein at a 
relatively high concentration not expected at the dose of 5 mg QD proposed for 
administration to patients in this study.
Amended 
or new 
wording:
Recently completed in vitro metabolism experiments in human hepatocytes 
using 14C-labeled MLN0128 suggest that MLN0128 is metabolized primarily 
via cytochrome P450 (CYP) 1A2 (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 non–uridine diphosphate glucuronosyltransferase 


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pathway (approximately 18%). The new data differ from the 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.
In-vitro, MLN0128 is metabolized by various cytochrome P450 (CYP) enzymes, 
including 2C19 (35%), 3A4 (28%), and 2C9 (28%); MLN0128 neither inhibited 
nor induced any of the major CYP enzymes. Additionally, MLN0128 did not 
inhibit P-glycoprotein but did inhibit breast cancer resistance protein at a 
relatively high concentration not expected at the dose of 5 mg QD proposed for 
administration to patients in this study. 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 (see Section 14.4) should be administered only with caution 
and at the discretion of the investigator during the study.
Rationale for Change:
This paragraph was amended to describe updated data on MLN0128 metabolism by specific 
CYP isoforms.
Change 7: Update the signature page.
The primary change occurs on the signature page of the amendment.
Deleted 
text
Amended 
or new 
wording
Rationale for Change:
This change was made to reflect changes in staffing for this project.
PPD
PPD


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PPD

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 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in 
Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With ER+/
HER2 Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With 
Everolimus in Combination With Exemestane or Fulvestrant
NCT Number: NCT02049957
SAP Approve Date: 23 July 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.


iTITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C31001
A Phase 1b/2 Study of Safety and Efficacy of MLN0128 (Dual TORC1/2 Inhibitor) in 
Combination With Exemestane or Fulvestrant Therapy in Postmenopausal Women With 
ER+/HER2- Advanced or Metastatic Breast Cancer That Has Progressed on Treatment With 
Everolimus in Combination With Exemestane or Fulvestrant
PHASE 1/2
Version: Final
Date: 23 July 2018
Prepared by:
Based on:
Protocol Version: Amendment 5
Protocol Date: 12 May 2017
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
PPD


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Statistical Analysis Plan Final
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CONFIDENTIAL
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.


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2.0
TABLE OF CONTENTS
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
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
4.4.1
Phase 1b...............................................................................................................8
4.4.2
Phase 2.................................................................................................................9
5.0
ANALYSIS ENDPOINTS.............................................................................................11
5.1
Secondary Endpoints ...............................................................................................11
5.2
Exploratory Endpoints .............................................................................................11
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................13
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................14
7.1
General Principles....................................................................................................14
7.1.1
Data Presentation ...............................................................................................14
7.1.2
Definition of Study Days....................................................................................15
7.1.3
Conventions for Partial Adverse Event/Concomitant Medication Dates..............15
7.1.4
Conventions for Other Partial Dates...................................................................15
7.2
Analysis Sets ...........................................................................................................16
7.2.1
Safety Population...............................................................................................16
7.2.2
Response-Evaluable Population .........................................................................16
7.2.3
Pharmacokinetics Population .............................................................................16
7.3
Disposition of Subjects ............................................................................................16
7.4
Demographic and Other Baseline Characteristics.....................................................16
7.5
Medical History and Concurrent Medical Conditions...............................................17
7.6
Medication History and Concomitant Medications...................................................17
7.6.1
Prior Therapies...................................................................................................18
7.7
Study Drug Exposure and Compliance.....................................................................18
7.8
Efficacy Analysis.....................................................................................................19
7.8.1
Primary Efficacy Endpoint(s).............................................................................19
7.8.2
Secondary Efficacy Endpoint(s).........................................................................20


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CONFIDENTIAL
7.8.3
Additional Efficacy Endpoint(s).........................................................................22
7.8.4
Exploratory Efficacy Endpoints .........................................................................23
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................24
7.9.1
Pharmacokinetic Analysis ..................................................................................24
7.9.2
Pharmacodynamic Analysis ...............................................................................27
7.10
Other Outcomes.......................................................................................................27
7.11
Safety Analysis........................................................................................................28
7.11.1 Adverse Events ..................................................................................................28
7.11.2 Clinical Laboratory Evaluations .........................................................................30
7.11.3 Vital Signs .........................................................................................................30
7.11.4 12-Lead ECGs ...................................................................................................31
7.11.5 Other Observations Related to Safety.................................................................31
7.12
Interim Analysis ......................................................................................................31
7.13
Changes in the Statistical Analysis Plan...................................................................32
8.0
REFERENCES..............................................................................................................33
9.0
DATA LISTINGS .........................................................................................................34


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3.0
LIST OF ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
API
active pharmaceutical ingredient
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC24
area under the plasma concentration versus time curve from zero to 24 hours
AUCt
area under the plasma concentration versus time curve from zero to the last measurable 
concentration
CBR
clinical benefit rate
CBR-16
clinical benefit rate at 16 weeks
CBR-24
clinical benefit rate at 24 weeks
CI
confidence interval
Cmax
single-dose maximum (peak) concentration
CR
complete response
CT
computed tomography
CTC
circulating tumor cell
DDI
drug-drug interaction
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EOT
End of Treatment (visit)
ER
estrogen receptor
ER/HER2
estrogen receptor positive/human epidermal growth factor receptor-2 negative
HER2
human epidermal growth factor receptor 2
IM
intramuscular; intramuscularly
IV
intravenous; intravenously
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
ORR
overall response rate
OS
overall survival
PFS
progression-free survival
PK
pharmacokinetic(s)
PR
progesterone receptor
PT/INR
prothrombin time/international normalized ratio
QD
quaque die; each day; once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
RECIST
Response Evaluation Criteria in Solid Tumors


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SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SLD
sum [of] longest diameters
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse events
Tmax
single-dose first time of occurrence of maximum (peak) concentration
US
United States
WHO
World Health Organization


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4.0
OBJECTIVES
4.1
Primary Objectives
Phase 1b
#
To evaluate the safety and tolerability of MLN0128 in combination with either exemestane 
or fulvestrant.
Phase 2
#
To evaluate the antitumor activity by CBR at 16 weeks (CBR-16 is defined as the proportion 
of patients who achieve CR or partial response of any duration or have SD at 16 weeks) of 
treatment with MLN0128 in combination with either exemestane or fulvestrant.
4.2
Secondary Objectives
#
To further evaluate the antitumor activity of MLN0128 in combination with either 
exemestane or fulvestrant.
#
To evaluate the pharmacokinetics of MLN0128 and exemestane when administered in 
combination and to evaluate the pharmacokinetics of MLN0128 when administered in 
combination with fulvestrant.
#
To assess the safety and tolerability of MLN0128 in combination with either exemestane or 
fulvestrant.
4.3
Exploratory Objectives
4.4
Study Design
This is a phase 1b/2 study of the safety and efficacy of MLN0128 in combination with 
exemestane or fulvestrant therapy in women with ER+/HER2∀advanced or metastatic breast
cancer that has progressed on treatment with everolimus in combination with exemestane (any
country) or fulvestrant (US only). Patients enrolled in this study will continue taking the same 
CCI


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CONFIDENTIAL
prior therapy (either exemestane or fulvestrant) at their established dose, in combination with
MLN0128.
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. MLN0128 will be administered in 28-day 
treatment cycles.
4.4.1
Phase 1b
In the phase 1b portion of the study, the safety and tolerability of MLN0128 using a capsule 
formulation based on unmilled (Part 1) and milled (Part 2) active pharmaceutical ingredient 
(API) in combination with either exemestane (any country) or fulvestrant (US only) will be 
evaluated. Patients enrolled in Part 1 will remain on MLN0128 capsules based on unmilled API. 
Patients will be enrolled as follows:
Part 1 (Capsules Based on Unmilled API):
MLN0128 + Exemestane Safety Cohort: Six patients will receive MLN0128 capsule
formulation based on unmilled API (5 mg QD) in combination with exemestane (administered 
per prior therapy for the patient). Steady-state serial PK samples will be collected to quantify
both MLN0128 and exemestane to characterize the PK of MLN0128 and exemestane when 
administered in combination.
MLN0128 + Fulvestrant Safety Cohort (US Only): Six patients will receive MLN0128 
capsule formulation based on unmilled API (5 mg QD) in combination with high-dose 
fulvestrant (500 mg IM every month). After completing 2 cycles of treatment with MLN0128 
(Cycle 2, Day 28) in combination with fulvestrant, a safety and tolerability assessment will be 
performed. If ≥2 DLTs occur in either treatment group (exemestane or fulvestrant) after 
completing 2 cycles of treatment with MLN0128 (5 mg QD), the dose of MLN0128 will be
reduced in that treatment group (MLN0128 in combination with exemestane or MLN0128 in 
combination with fulvestrant) to 4 mg QD for patients subsequently enrolled in the phase 2 
portion study.
Part 2 (Capsules Based on Milled API):
MLN0128 + Exemestane (Any Country)/Fulvestrant (US Only) Safety Cohort 1: Six 
patients will receive MLN0128 capsule formulation based on milled API (3 mg once daily [QD]) 
in combination with either exemestane or fulvestrant. Serial blood samples will be collected to 
evaluate the PK of MLN0128 when administered in combination with either exemestane or 
fulvestrant. After the last patient completes Cycle 1, a safety and tolerability assessment will be 
performed. If 2 dose-limiting toxicities (DLTs) occur in these 6 patients, the dose of MLN0128 
will be reduced to 2 mg QD for patients subsequently enrolled in Cohort 2 of Part 2 of the phase 
1b portion of this study. If ≤1 DLT occurs in Cohort 1, the dose of MLN0128 will be escalated to 
4 mg QD for patients entering Cohort 2.


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MLN0128 + Exemestane (Any Country)/Fulvestrant (US Only) Safety Cohort 2: Six 
patients will receive MLN0128 capsule formulation based on milled API, either 4 or 2 mg QD 
based on the safety observed in Cohort 1, in combination with either exemestane or fulvestrant.
Serial PK samples will be collected as outlined for Cohort 1. After the last patient completes 
Cycle 1, a safety and tolerability assessment will be performed.
4.4.2
Phase 2
In the phase 2 portion of the study, the safety and efficacy of MLN0128 in combination with 
either exemestane (any country) or fulvestrant (US only) will be evaluated. Patients will be 
administered MLN0128 at either 4, 3, or 2 mg QD in combination with either exemestane (any 
country) or fulvestrant (US only), depending on the outcome of the safety and tolerability 
analysis performed in the phase 1b portion of the study. 
Another safety and tolerability assessment will be performed during the phase 2 portion of the 
study where the first 6 patients treated with MLN0128 (either 4 mg, 3, mg, or 2 mg QD) in 
combination with exemestane or fulvestrant who have completed 2 cycles of treatment with 
MLN0128 will be evaluated for TEAEs. Enrollment of patients into the study will continue 
during this safety and tolerability assessment.
Patients will be enrolled into one of 2 parallel cohorts, depending on the quality and/or duration 
of their prior response to everolimus in combination with either exemestane (any country) or 
fulvestrant (US only) as follows:
Everolimus-Resistant Cohort: This is a cohort of 56 response-evaluable patients who have 
progressed on treatment with everolimus in combination with either exemestane (any country) or 
fulvestrant (US only) without achieving an objective response (CR or partial response) or after 
achieving SD for 6 months as their best response. Patients will receive MLN0128 in 
combination with the same dose of the previously administered treatment (exemestane [any 
country] or fulvestrant [US only]).
Everolimus-Sensitive Cohort: This is a cohort of 48 response-evaluable patients who have 
progressed on treatment after achieving a CR or partial response of any duration, or SD
≥6 months with prior everolimus treatment in combination with either exemestane (any country) 
or fulvestrant (US only). Patients will receive MLN0128 in combination with the same dose of 
the previously administered treatment (exemestane [any country] or fulvestrant [US only]).
Sparse PK samples will be collected from all patients enrolled in the study (regardless of whether 
they are administered MLN0128 in combination with exemestane or fulvestrant) for plasma PK 
analysis of MLN0128 only. Data generated in this study will be combined with data from other 
studies in which the PK of MLN0128 is characterized for population PK analysis. 


C31001
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Radiological tumor evaluations (CT scan with intravenous [IV] contrast or magnetic resonance 
imaging [MRI] as clinically indicated) of the chest, abdomen, and pelvis) will be used to 
evaluate disease response according to Response Evaluation Criteria in Solid Tumors (RECIST)
guidelines (Version 1.1). Throughout the study, toxicity will be evaluated according to National 
Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 
4.03, effective date 14 June 2010. Adverse events will be assessed, clinical laboratory values, 
vital signs, and ECGs will be obtained to evaluate the safety and tolerability of MLN0128 in 
combination with either exemestane or fulvestrant. 


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5.0
ANALYSIS ENDPOINTS
The primary endpoints include:
Phase 1b 
#
Adverse events, SAEs, assessments of clinical laboratory values, vital sign measurements, 
physical examination findings, and electrocardiograms (ECGs).
Phase 2
#
CBR-16.
5.1
Secondary Endpoints
The secondary endpoints include:
#
Clinical benefit rate at 24 weeks (CBR-24 is defined as the proportion of patients who 
achieve CR or partial response of any duration or have SD at 24 weeks).
#
Overall response rate (ORR; defined as best response of CR or partial response).
#
Progression-free survival (PFS).
#
Overall survival (OS).
#
Change in tumor size from baseline.
#
Steady-state PK parameters of MLN0128 and exemestane including, but not limited to, 
single-dose maximum (peak) concentration (Cmax), Tmax, area under the plasma 
concentration versus time curve from zero to 24 hours (AUC24h), area under the plasma 
concentration versus time curve from zero to the last measurable concentration (AUCt), and 
t1/2.
#
Adverse events, SAEs, assessments of clinical laboratory values, vital sign measurements, 
physical examination findings, and ECGs.
5.2
Exploratory Endpoints
The exploratory endpoints include:
CCI


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CCI


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6.0
DETERMINATION OF SAMPLE SIZE
Phase 1b
The safety and tolerability of MLN0128 in combination with either exemestane or fulvestrant 
will be evaluated. Patients will be enrolled as follows:

In Part 1 of the phase 1b portion of the study, up to 6 patients will be enrolled into the 
MLN0128 + Exemestane Safety Cohort and up to 6 patients will be enrolled into the 
MLN0128 + Fulvestrant Safety Cohort. The number of patients is based on clinical 
considerations.

In Part 2 of the phase 1b portion of the study, 6 patients will be enrolled into MLN0128 + 
Exemestane/Fulvestrant Safety Cohort 1, and 6 patients will be enrolled into MLN0128 + 
Exemestane/Fulvestrant Safety Cohort 2. The number of patients is based on clinical 
considerations.
Phase 2
The sample size for each cohort in the phase 2 portion of the study is based on a standard Simon 
two-stage design. A Bayesian predictive probability design was used to allow multiple interim 
analyses to stop early for futility [1]. See Section 6.0 for sample size assumptions. Up to 
56 response-evaluable patients will be enrolled in the Everolimus-Resistant Cohort. In the
Everolimus-Sensitive Cohort, up to 48 response-evaluable patients will be enrolled.


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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.
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of study drug administration. Cycle 1 day 1 values are considered 
pre-dose. Screening values are used for baseline values if a cycle 1 day value is unavailable.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
For the categorical variables, the count and proportions of each possible value will be tabulated. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be tabulated.
Additional statistics will be tabulated for pharmacokinetic data (see Section 7.9.1).
A month is operationally defined to be 30.4375 days. 
7.1.1
Data Presentation
Results from the phase 1b and phase 2 portions of the study will be presented separately as 
follows (unless specified elsewhere):
Phase 1b: 
1. Baseline tables (demographics, disease characteristics, prior therapies)
Part 1 MLN0128 Unmilled API
Part 2 MLN0128 Milled API
Phase 1b Total
N=24
MLN0128
5 mg QD + 
Exemestane
N=6
MLN0128
5 mg QD+ 
Fulvestrant
N=6
Total
N=12
MLN0128 
3 mg QD +
Exemestane/
Fulvestrant
N=6
MLN0128 
4 mg QD +
Exemestane/
Fulvestrant
N=6
Total
N=12
2. Disposition, Safety
Part 1 MLN0128 Unmilled API
Part 2 MLN0128 Milled API
Phase 
1b 
Total
N=24
MLN0128
5 mg QD + 
Exemestane
N=6
MLN0128
5 mg QD+ 
Fulvestrant
N=6
Total
N=12
MLN0128 
3 mg QD 
+Exemestane
N=3
MLN0128
3 mg QD + 
Fulvestrant
N=3
Total
MLN0128
3 mg QD
N=6
MLN0128
4 mg QD+
Exemestane
N=6
Total 
N=12
Phase 2:
1. Disposition, Baseline and Demographic Characteristics, and Efficacy (no total needed)


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Everolimus Sensitive Cohort
Everolimus Resistant Cohort
Total (except 
efficacy)
MLN0128 4 
mg QD 
+ Exemestane
MLN0128 4 
mg QD 
+ Fulvestrant
Sensitive 
Total
MLN0128 4 
mg QD + 
Exemestane
MLN0128 4 
mg QD
+ Fulvestrant
Resistant
Total
2. Safety
MLN0128 4 mg QD + Exemestane
MLN0128 4 mg QD + Fulvestrant
Total
Everolimus 
Sensitive 
Cohort
Everolimus 
Resistant
Cohort
Total
Everolimus 
Sensitive 
Cohort
Everolimus 
Resistant
Cohort
Total
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
7.1.3
Conventions for Partial Adverse Event/Concomitant Medication Dates
Missing or incomplete start dates will be imputed based on the algorithm described below:
If the start date has month and year but day is missing, the adverse event will be considered 
treatment-emergent or the therapy concomitant if both the month and year of the start date are on 
or after the month and year of the date of the first dose of MLN0128 and on or before the month 
and year of the date of the last dose of MLN0128 plus 30 days.

If the start date has year, but day and month are missing, the adverse event will be considered 
treatment -emergent or the therapy concomitant if the year of the start date is on or after the 
year of the date of the first dose of MLN0128 and on or before the year of the date of the last 
dose of MLN0128 plus 30 days.
7.1.4
Conventions for Other Partial Dates 
Missing or incomplete dates recorded during the screening visits (e.g date of initial diagnosis)
will be imputed based on the algorithm described below:

If only the day-component is missing, the first day of the month will be used if the year and 
the month are the same as those for the first dose of study drug. Otherwise, the fifteenth will 
be used. 

If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the date of 
the 15th of January will be used. 


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
If only the year is present, and it is not the same as the year of the first dose of study drug, the 
fifteenth of June will be used, unless other data indicates that the date is earlier.
7.2
Analysis Sets
7.2.1
Safety Population
Safety population: patients who receive at least 1 dose of study drug. All safety analyses will be 
performed using the safety population.
7.2.2
Response-Evaluable Population
Response-evaluable population (phase 2 only): patients who receive at least 1 dose of study drug 
and have measurable disease at baseline. 
7.2.3
Pharmacokinetics Population
Pharmacokinetic population: patients with sufficient dosing and PK data to reliably estimate PK 
parameters. PK analyses will be performed using the PK population.
7.3
Disposition of Subjects
The date first subject signed ICF, date of last subject’s last visit/contact, date of last subject’s last 
procedure for collection of data for primary endpoint, MedDRA Version, WHODrug Version, 
and SAS Version will be generated in a summary table.
For the phase 1 portion the number of patients in the safety population, in the pharmacokinetics 
population, and the reason study drug was discontinued will be summarized. 
For the phase 2 portion the number of patients in the safety population, in the response-evaluable 
population, the dose level of exemestane or fulvestrant at study entry, the reason study drug was 
discontinued, and the end of study reasons will be summarized.
All percentages will be based on the number of patients in the safety population. 
The number of subjects enrolled by region, country and site will be summarized:
North America
- United States
Europe
- Belgium
- France 
7.4
Demographic and Other Baseline Characteristics
Summaries of demographic and baseline characteristics will be presented for subjects in the 
safety population.


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The demographic characteristics consist of:

Age at date of informed consent (continuous)

Age category 1.
–
<65 years.
–
≥65 years.

Age category 2.
–
Adults (18-64 years).
–
From 65 to 84 years.
–
85 years and over.

Height (cm).

Weight (kg) [at screening if available, otherwise use C1D1].

Ethnicity.

Race.
Baseline characteristics consist of:

Baseline ECOG performance status.

Histological subtype (Basal, Luminal A, Luminal B, Normal Breast-like).

Time since initial diagnosis (months) [(date of first dose – date of initial diagnosis)/30.4375].

Stage of disease at initial diagnosis.

Number and percent positive for each marker: PR, C-myc amplification, BRCA1, BRCA2,
and EGFR.

Number and percent positive for PTEN (from tumor samples).
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 medication history.
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. The number and percentage of patients taking concomitant medications will be 
tabulated by WHO standardized medication name (generic name).


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7.6.1
Prior Therapies
The number and percentage of patients with prior surgery, prior radiation, and prior 
antineoplastic therapies will be summarized. The following will be summarized for those 
patients with prior antineoplastic therapies:

Prior therapy received (PTDECOD in PT dataset).

Number of prior therapy regimens (PTGRPID in PT dataset).

Best response to most recent prior therapy.
7.7
Study Drug Exposure and Compliance
7.7.2
Extent of Exposure
The overall treatment duration in weeks (date of last dose – date of first dose + 1/ 7), number of 
treated cycles (distribution and summary statistics), cumulative dose for each study drug, average 
daily dose in mg/day [cumulative dose in mg / duration of treatment in days] for MLN0128 and 
exemestane, planned cumulative dose for each study drug, and the relative dose intensity for 
each study drug will be summarized for patients in the safety population.
A treated cycle is defined as a cycle in which the patient receives any amount of MLN0128 
(actual dose greater than zero for at least one of the dosing days in the cycle). 
The cumulative dose for MLN0128 and exemestane in (mg) is the sum of all doses (mg) 
administered to a subject during the treatment period.
Relative dose intensity = [cumulative dose / planned cumulative dose] * 100.
For MLN0128 and exemestane the relative dose intensity is calculated as:
[cumulative dose in mg / assigned dose level (mg) at the start of the study * duration of treatment 
in days] * 100.
For fulvestrant the relative dose intensity is calculated as:
[cumulative dose in mg / assigned dose level (mg) at the start of the study * number of treatment 
cycles] * 100.
7.7.3
Action on Study Drug
The number and percentage of patients for the following actions on study drug for MLN0128, 
exemestane, and fulvestrant:

Dose Reduced at Least Once.

Dose Held at Least Once.

Dose Missed at Least Once.

Discontinued Permanently.
Action on study drug will be summarized by cycle (cycles 1-6) and overall for the safety 
population.


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7.8
Efficacy Analysis
Phase 1b
Data listings will present the tumor measurements from CT or MRI, the sum of the long diameter 
(SLD), percent change from baseline in the SLD, percent change from nadir in the SLD, non-
target disease assessment, new lesion assessment, disease response assessment by the 
investigator based on RECIST criteria, and if symptomatic deterioration occurred at each 
response assessment. In addition, the best overall response (unconfirmed and confirmed),
duration of stable disease (SD), and duration of response will be presented in a data listing.
See Section 7.8.3 Additional Efficacy Endpoints for the definition of duration of stable disease 
and the duration of response. 
7.8.1
Primary Efficacy Endpoint(s)
Phase 2
The primary efficacy endpoint for the phase 2 portion of the study is the clinical benefit rate at 
16 weeks (CBR-16) and is defined as the proportion of patients who achieve CR or partial 
response of any duration, or have stable disease [SD] at 16 weeks. 
The number and percentage of patients achieving clinical benefit at 16 weeks will be 
summarized by cohort and combination partner (Exemestane or Fulvestrant) within each cohort. 
The estimate of the CBR-16 will be presented with a 2-sided 95% exact binomial confidence 
interval. CBR-16 will be determined based on both unconfirmed and confirmed response (see 
Section 7.8.3 Additional Efficacy Endpoints for definitions) for the response-evaluable 
population.
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 (see exception below).
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
CR/PR (unconfirmed)
SD
SD
CR/PR (unconfirmed)


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7.8.2
Secondary Efficacy Endpoint(s)
Phase 2
Clinical benefit rate at 24 weeks (CBR-24)
The CBR-24 is defined as the proportion of patients who achieve CR or partial response of any 
duration, or have SD at 24 weeks. 
The number and percentage of patients achieving CBR-24 will be summarized by cohort and 
combination partner (Exemestane or Fulvestrant) within each cohort. The estimate of the 
CBR-24 will be presented with a 2-sided 95% exact binomial confidence interval. The CBR-24
will be determined based on both unconfirmed and confirmed best overall response (see 
Section 7.8.3 Additional Efficacy Endpoints for definitions) for the response-evaluable 
population.
SD for at least 24 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, Cycle 4, and Cycle 6 (see exception below).
CBR at 24 weeks (unconfirmed) is defined as the number of patients who achieve CR or PR at 
any time or have SD for at least 24 weeks.
CBR at 24 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 24 weeks or meet the following criteria:
Overall response at end of Cycle 2
Overall response at end of Cycle 4
Overall Response at the end of 
Cycle 6
CR/PR (unconfirmed)
SD
SD
SD
CR/PR (unconfirmed)
SD
SD
SD
CR/PR (unconfirmed)
Overall response rate (ORR)
The ORR is defined as the proportion of patients with a best response of CR or partial response. 
The number and percentage of patients achieving an ORR will be summarized by cohort and 
combination partner (Exemestane or Fulvestrant) within each cohort. The estimate of the ORR
will be presented with a 2-sided 95% exact binomial confidence interval. The ORR will be 
determined based on both unconfirmed and confirmed best overall response (see Section 7.8.3
Additional Efficacy Endpoints for definitions) for the response-evaluable population.
Progression-free survival (PFS)
Progression-free survival is defined as the time from the date of first MLN0128 administration to 
the date of first documentation of disease 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: 
(earliest date of progression or death – date of first dose of MLN0128+ 1)/30.4375


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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 in 
Table 7.a.
Table 7.a
Handling of Missing Response Assessment and Censoring
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 Assessment: investigator response assessment other than Unable to Assess, unknown or missing (i.e. CR, 
PR, SD or PD).
PFS Analysis
The Kaplan-Meier method will be used to analyze the distribution of PFS for the Safety 
Population. 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, 12 and 18 and 24 months will be presented. 
The source of PFS (death or progressive disease) and the status of subjects who are censored in 
the PFS Kaplan-Meier analysis [no post baseline tumor assessment and no death, on-study (on 
treatment, in follow-up), Lost to follow-up, and received subsequent anti-cancer therapy] will be 
tabulated.
PFS will be summarized by cohort and combination partner (Exemestane or Fulvestrant) within 
each cohort.
Overall survival (OS)
Overall survival in months is defined as: (date of death – date of first dose of MLN0128 + 1) / 
30.4375. Patients without documentation of death at the time of analysis will be censored at the 


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date last known to be alive. The number and percentage of patients experiencing an event, the 
number and percentage of patients who are censored, the 25th, 50th (median), and 75th 
percentiles (and 95% CIs), and Kaplan-Meier estimates at 6 and 12 months (or other appropriate 
time points) will be presented for each cohort and combination partner.
OS will be summarized by cohort and combination partner (Exemestane or Fulvestrant) within 
each cohort.
Change in tumor size from baseline
Waterfall plots of the best percent of change from baseline in the sum of the longest diameter 
(SLD) of the target lesions will be generated for each cohort (legend for combination partner).
7.8.3
Additional Efficacy Endpoint(s)
Best Overall Response
Best Overall Response (unconfirmed): The best response after the first dose of study drug until 
subsequent therapy ordered from best to worst: Complete Response, Partial Response, Stable 
Disease, Progressive Disease. The best response can also be Unable to Assess, Unknown, or No 
assessment performed if this is the only investigator assessment of objective response available 
for the patient.
Best Overall Response (confirmed): The best response after the first dose of study drug until 
subsequent therapy ordered from best to worst: Complete Response, Partial Response, Stable 
Disease, Progressive Disease. The best response can also be Unable to Assess, Unknown, or No 
assessment performed if this is the only investigator assessment of objective response available 
for the patient.
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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Confirmation Derivation Rules
Overall response 1st time point
Overall response subsequent time 
point
BEST overall response
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 minimum criteria for SD is needed as the first protocol scan is at the end of cycle 2, 
approximately 8 weeks from first dose.
The number and percentage of patients in each response category (CR, PR, SD, SD-16, SD-24,
Progressive Disease, Unable to Assess, Unknown, or no post baseline response assessment) will 
be summarized by cohort and combination partner (Exemestane or Fulvestrant) within each 
cohort.
Duration of Response (DOR)
The duration of objective response will be calculated for those patients with a best response of 
CR or PR, and is defined as the number of days from the start date of CR, or PR (whichever 
response is achieved first) until progressive disease or until the last response assessment if there 
is no progressive disease. For phase 2 the Kaplan-Meier method will be used to analyze the 
DOR. 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 will be 
presented. 
Duration of Stable Disease
The duration of stable disease will be calculated for those patients with a best response of SD. 
The duration of SD is the number of days from cycle 1 day 1 until progressive disease or until 
the last response assessment if there is no progressive disease (listing).
7.8.4
Exploratory Efficacy Endpoints
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7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
The PK of MLN0128 on Cycle 1 Day 15 and Cycle 2 Day 1 obtained during the phase 1b (Parts 
1 and 2) will be assessed based on evaluable patients. The MLN0128 plasma concentrations 
collected during the phase 2 will be included in data listings in the clinical study report.
The exemestane plasma concentrations obtained in the phase 1b (Parts 1 and 2) will be presented
in data listings in the clinical study report; however, no exemestane PK parameters will be 
estimated and/or reported, due to the limited amount of PK evaluable data. 
For the purposes of assessing a potential DDI between MLN0128 and exemestane on MLN0128, 
plasma concentration-time data and relevant PK parameters (such as Cmax, AUC24h, and t1/2) of 
MLN0128 will be compared against historical single-agent PK data. The results of this PK 
evaluation will not be part of the clinical study report.
In addition, PK data generated during the phase 1b and phase 2 in this study may be combined 
with data from other studies in which the PK of MLN0128 is characterized for population PK 
analysis. The results of population PK analysis will be presented in a separate report. This will 
include the sparse PK data collected during the phase 2 portion of the study. 
PK data from the phase 1b portion of the study will be summarized as described below.
Pharmacokinetic Concentrations
Descriptive statistics (number of patients, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of variation, geometric mean, geometric coefficient of variation, median, 
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minimum, and maximum) will be used to summarize the MLN0128 plasma concentrations. For 
the estimation of mean concentration in plots and tabular summaries, BLQ values will always be 
replaced by zero.
Linear and semi-logarithmic plots of the mean (+SD) MLN0128 plasma concentrations versus 
scheduled sampling times will be provided for each intense sampling study visit (Cycle 1 Day 15 
and Cycle 2 Day 1) segregated by treatment group, as follows: 
1. MLN0128 5 mg QD [unmilled API, light meal] + Exemestane.
2. MLN0128 5 mg QD [unmilled API, light meal] + Fulvestrant.
3. MLN0128 3 mg QD [milled API, empty stomach] + Exemestane.
4. MLN0128 3 mg QD [milled API, empty stomach] + Fulvestrant.
5. MLN0128 4 mg QD [milled API, empty stomach] + Exemestane.
Linear and semi-logarithmic plots of individual MLN0128 plasma concentrations versus actual 
sampling time will be provided for each treatment group and segregated by study visit (Cycle 1 
Day 15 and Cycle 2 Day 1) eg, for MLN0128 the Cycle 1 Day15 and Cycle 2 Day 1 will be 
overlayed on the same plot. 
In all Cycle 1 Day 15 MLN0128 plasma concentration versus time plots, pre-dose concentrations 
will be duplicated and the replicate value will then be imputed as the 24-hour post-dose 
concentration, thereby extending the PK profile from 8 hours to 24 hours. 
All individual patient plasma MLN0128 and exemestane concentration data will be presented in 
a data listing. MLN0128 imputed 24-hour concentration values will be flagged in listings and 
will be accompanied by an appropriate footnote.
Pharmacokinetic Parameters
PK parameters will be estimated using non-compartmental methods with WinNonlin®
Professional Version 7.0 or higher (Certara USA, Inc., Princeton, NJ). The plasma PK 
parameters will be estimated from the concentration-time profiles for all PK population patients. 
In estimating the PK parameters, BQL values at the beginning of the profile will be set to zero. 
BQL values that occur after the first quantifiable point will be considered missing. Values that 
are embedded between BQLs, or quantifiable values occurring after two or more BQLs, will be 
set to missing at the discretion of the pharmacokineticist. Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times. If an actual 
time is missing the nominal time may be used. 
In addition, for the estimation of the Cycle 1 Day 15 MLN0128 plasma PK parameters, pre-dose 
concentrations will be duplicated and the replicate value will then be imputed as the 24-hour 
post-dose concentration, thereby extending the PK profile from 0 to 8 hours to 0 to 24 hours. 
Hence, all Cycle 1 Day 15 PK parameters will be derived over a period of 24 hours.
All individual patient PK parameter data will be in a data listing. Descriptive statistics (number 
of patients, arithmetic mean, arithmetic standard deviation, arithmetic coefficient of variation, 


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median, minimum value, and maximum value) will be used to summarize the calculated PK 
parameters. Additionally, geometric mean and geometric coefficient of variation will be
calculated for concentration parameters (such as Cmax and Ctrough) and AUC parameters (such as 
AUCt and AUC24h), clearance parameters (CL/F), and volume parameters (Vz/F). For Tmax, only 
median, minimum value, and maximum value will be presented.
Descriptive statistics reported in the main body of the CSR will include sample size, geometric 
mean and geometric coefficient of variation for concentration, AUC, clearance and volume 
parameters; arithmetic mean, coefficient of variation, and sample size will be reported for λz and 
t1/2; and median and range for Tmax.
Data permitting, the following steady-state PK parameters will be calculated for MLN0128
following Cycle 1 Day 15 by noncompartmental analysis:

Observed maximum plasma concentration (Cmax).

Time to observed maximum plasma concentration (Tmax).

Area under the plasma concentration-time curve from time 0 to time of last measurable
concentration (AUCt).

Area under the plasma concentration versus time curve from zero to 24 hours (AUC24h).

Area under the plasma concentration-time curve from time 0 to 4 hr (AUC4h).

Area under the plasma concentration-time curve from time 0 to 8 hr (AUC8h).

End of dosing interval (trough) concentration (Ctrough).

Terminal disposition half-life (t1/2).

Apparent oral clearance (CL/F).

Apparent terminal phase volume of distribution (Vz/F).
The following Cycle 1 Day 15 PK parameters will also be reported in a separate listing of 
supplementary PK parameters:

Terminal phase number of data points (Number).

Upper time for calculation of terminal elimination rate constant (λz upper).

Lower time for calculation of terminal elimination rate constant (λz lower).

Terminal disposition phase rate constant (λz).

Terminal phase regression adjusted R2 (R2
adj).
Data permitting, the following steady-state PK parameters will be calculated for MLN0128
following Cycle 2 Day 1 by noncompartmental analysis:

Cmax.

Tmax.


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#
AUCt.
#
AUC4h.
Descriptive statistics will be presented for the MLN0128 plasma PK parameters on Cycle 1, Day 
15 and Cycle 2, Day 1 for the following groups:
1. MLN0128 5 mg QD [unmilled API, light meal] + Exemestane.
2. MLN0128 5 mg QD [unmilled API, light meal] + Fulvestrant.
3. MLN0128 3 mg QD [milled API, empty stomach] + Exemestane.
4. MLN0128 3 mg QD [milled API, empty stomach] + Fulvestrant.
5. MLN0128 4 mg QD [milled API, empty stomach] + Exemestane.
Dot plots of selected PK parameters vs treatment group will be generated for Cycle 1 Day 15 
(Cmax, AUC4h, AUC8h and AUC24h) and Cycle 2 Day 1 (Cmax, AUC4h).
7.9.2
Pharmacodynamic Analysis
7.10
Other Outcomes
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7.11
Safety Analysis
7.11.1 Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 20.0 or later (based on version at time of database lock). Treatment-emergent AEs are 
defined as: AEs that occur after the first dose of MLN0128 and within 30 days after the last dose 
of MLN0128. 
Treatment-emergent AEs will be tabulated by MedDRA system organ class and preferred term 
and will include the following categories 
#
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 TEAEs.
#
Serious drug-related TEAEs.
#
The most commonly reported treatment-emergent AEs by preferred term (at least 10% of
patients).
#
Most frequent non-serious TEAEs (>5% of patients in both cohorts sorted by preferred term).
Patients reporting the same event more than once will have that event counted only once within 
each system organ class, and once within each preferred term.
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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 pigmentation
Mucosal inflammation
Mucosal roughness
Mucosal membrane hyperplasia
Mucosal toxicity
Mucosal necrosis
Mucosal ulceration
Mucosal pain
Mucous membrane disorder
Oedema mucosal
Leukoplakia
Mucosal infection
Drug eruption
Mucosal excoriation
Fixed eruption
Erythroplasia
Mucocutaneous haemorrhage
Burning sensation mucosal
Paraesthesia mucosal
Rash
Mucocutaneous rash
Rash papular
Nodular rash
Rash rubelliform
Rash
Rash scarlatiniform
Rash erythematous
Rash vesicular
Rash generalised
Rash maculovesicular
Rash macular
Rash morbilliform
Rash maculo-papular
For the phase 1 portion a by-subject listing of DLTs in Cycle 1 will be generated.
The number and percentage of subjects experiencing treatment emergent AEs resulting in 
discontinuation of study drug (action on study drug=DISCONTINUED FROM STUDY) will be 
summarized by MedDRA system organ class, and preferred term.


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A by-subject listing of treatment-emergent AEs resulting in discontinuation of study drug and 
treatment-emergent AEs resulting in dose modifications (held or reduced) will be generated.
A by-subject listing of the deaths will be presented. An on-study death is defined as a death that 
occurs between the first dose of study drug and within 30 days of the last dose of study drug.
7.11.2 Clinical Laboratory Evaluations
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
version 4.03. The number and proportion of patients with shifts in NCI CTCAE toxicity grades 
from baseline to the worst post 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, Calcium - decreased, 
Calcium – increased, Glucose – decreased, Glucose – increased, Potassium – decreased, 
potassium – increased, magnesium – decreased, magnesium – increased, sodium – decreased, 
sodium – increased, triglycerides – increased, albumin –decreased, phosphaste – decreased, 
amylase – increased.
For phase 2 the actual values and change from baseline in clinical laboratory parameters (in SI 
units) will be summarized for Neutrophils (ANC), Aspartate aminotransferase (AST), Alanine 
aminotransferase (ALT), Glucose, Hemoglobin A1c, Cholesterol (total), Triglycerides, 
High-density lipoprotein cholesterol (HDL-C) and Low-density lipoprotein cholesterol (LDL-C) 
at each scheduled visit up to 6 cycles. Figures of mean actual values at each scheduled visit up to 
6 cycles will also be generated for these clinical laboratory parameters (in SI units).
7.11.3 Vital Signs
For phase 1 descriptive statistics for vital sign results (diastolic and systolic blood pressure, heart 
rate and body weight) will be summarized as follows:

Baseline value (C1D1 or screening if C1D1 is not available).

Minimum post-baseline value.

Change to Minimum post-baseline value.

Maximum post-baseline value.

Change to Maximum post-baseline value.
Changes to the minimum and maximum post-baseline values will be calculated relative to the 
baseline value.


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In addition to the above for phase 2 the actual values and change from baseline will be 
summarized over time for each cohort up to 6 cycles.
7.11.4 12-Lead ECGs
For phase 1 descriptive statistics for ECG parameters (ventricular rate, PR, QRS, QT, and QTc 
(Fridericia) will be summarized as follows:

Baseline value (C1D1 or screening if C1D1 is not available).

Minimum post-baseline value.

Change to Minimum post-baseline value.

Maximum post-baseline value.

Change to Maximum post-baseline value.
The number and percent of subjects with increases >30 ms and >60 ms from pre-dose in QTcF
will be summarized.
In addition, for phase 2 the actual values and change from baseline will be summarized over time 
for each cohort up to 6 cycles (including 2H and 4H post-dose values at Cycle 1 Day 1 and 
Cycle 1 Day 15 visits). 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 = 60 seconds/ventricular rate in beats/minute]
7.11.5 Other Observations Related to Safety
Not Applicable
7.12
Interim Analysis
There will be 3 interim analyses for futility in the Everolimus-Resistant Cohort and 2 interim 
analyses for futility in the Everolimus-Sensitive Cohort. The investigator-assessed CBR-16 rate 
will be used as the endpoint for the interim analysis. The interim analysis will be based on 
response-evaluable patients who have had the opportunity to complete a minimum of 4 cycles of 
treatment with MLN0128 or have discontinued treatment with MLN0128 before the end of 
Cycle 4.
In the Everolimus-Resistant Cohort, there will be 3 interim analyses based on the following 
assumptions:

Ineffective CBR-16 rate (Ho): 10%.


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Statistical Analysis Plan Final
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CONFIDENTIAL

Effective CBR-16 rate (Ha): 20%.

Alpha = 10%; power = 80%.

Prior Beta Distribution Parameters: ao = 0.10, b0 = 0.90.

Probability of early termination under Ho: 68%.
Timing of Interim Analyses in the Everolimus-Resistant Cohort
Stage
No. of Patients 
Evaluated
Number of Patients With CBR-16 to Proceed or Declare Active
1
29
≥3
2
39
≥4
3
49
≥6
Final
56
≥9
Abbreviations: CBR-16 = defined as the proportion of patients who achieve complete response or partial response of 
any duration, or stable disease) 16 weeks; No. = number.
In the Everolimus-Sensitive Cohort, there will be 2 interim analyses based on the following 
assumptions:

Ineffective CBR-16 rate (Ho): 15%.

Effective CBR-16 rate (Ha): 30%.

Alpha = 5%; power = 80%.

Prior Beta Distribution Parameters: ao = 0.15, b0 = 0.85.

Probability of early termination under Ho: 71%.
Timing of Interim Analyses in the Everolimus-Sensitive Cohort
Stage
No. of Patients
Evaluated
Number of Patients With CBR-16 to Proceed or Declare Active
1
23
≥4
2
38
≥7
Final
48
≥12
Abbreviations: CBR-16 = defined as the proportion of patients who achieve complete response or partial response of 
any duration, or stable disease) 16 weeks; No. = number.
7.13
Changes in the Statistical Analysis Plan 
The exemestane concentrations will not be summarized and exemestane PK parameters will not 
be estimated and/or reported due to the limited amount of PK evaluable data.


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Statistical Analysis Plan Final
23 July 2018
CONFIDENTIAL
8.0
REFERENCES
1. Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin Trials 
2008;5(2):93-106.


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Statistical Analysis Plan Final
23 July 2018
CONFIDENTIAL
9.0
DATA LISTINGS
The below subject-level listings will be generated:
#
Disposition (date of first dose, date of last dose, number of cycles, reason for discontinuation
of study treatment).
#
Populations (can be included with disposition listing).
#
Demographics.
#
Baseline characteristics.
#
Prior therapy.
#
Study drug exposure.
#
TEAEs leading to study drug discontinuation.
#
TEAEs resulting in dose modifications.
#
Serious AEs.
#
On-study deaths.
#
DLTs during Cycle 1 (Phase 1b).
#
Pharmacokinetic concentrations (including sampling times) for MLN0128 and Exemestane.
#
Pharmacokinetic parameters for MLN0128.
#
#
#
Efficacy (target lesions, non-target lesions, investigator assessment of response, best
response (confirmed and unconfirmed), duration of response, duration of stable disease).
CCI
CCI


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