Clinical trial NCT02725268
Conditions: Endometrial Neoplasms
Keywords: Drug Therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2016-04-01; Completion date: 2020-10-30
Enrollment: 241 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary purpose of this study is to determine if sapanisertib in combination with weekly paclitaxel improves progression-free survival (PFS) compared to weekly paclitaxel alone.

Detailed description:
The drugs being evaluated in this study are sapanisertib and MLN1117. Sapanisertib is being evaluated as a single agent and in combination with paclitaxel or MLN1117 to treat women with advanced, recurrent, or persistent endometrial cancer. This study will evaluate the efficacy and safety of each drug or drug combination.

The study will enroll approximately 241 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of 4 treatment groups:

* Paclitaxel 80 mg/m\^2
* Paclitaxel 80 mg/m\^2 + Sapanisertib 4 mg
* Sapanisertib 30 mg
* Sapanisertib 4 mg + MLN1117 200 mg

Participants will receive either paclitaxel intravenous (IV) weekly, Paclitaxel IV along with sapanisertib orally, sapanisertib orally, or sapanisertib and MLN1117 orally.

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

Arms: arm 1: Paclitaxel 80 milligrams per square meter (mg/m\^2), IV, weekly on Days 1, 8, and 15 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 13 weeks). arm 2: Paclitaxel 80 mg/m\^2, IV, weekly on Days 1, 8, and 15 of a 28-day cycle along with sapanisertib 4 milligrams (mg), capsule, orally on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 20 weeks). arm 3: Sapanisertib 30 mg, capsule, orally, once weekly on Days 1, 8, 15, and 22 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 6 weeks). arm 4: Sapanisertib 4 mg, capsule, orally and MLN1117 200 mg, capsule, orally on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day cycle until disease progression, unacceptable toxicity, or withdraw consent (the median exposure was up to approximately 8 weeks).
Interventions: intervention 1: Paclitaxel intervention 2: Sapanisertib intervention 3: MLN1117
Intervention descriptions: intervention 1: Paclitaxel intravenous solution. intervention 2: Sapanisertib capsules. intervention 3: MLN1117 capsules.

Protocol documents:
Prot_001.pdf: 



Title: A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), 
MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly 
Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial 
Cancer
NCT Number: NCT02725268
Protocol Approve Date: 02 March 2020
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
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
1
CLINICAL STUDY PROTOCOL C31004 Amendment 06
MLN0128
A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), 
MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly 
Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial 
Cancer
Protocol Number:
C31004
Indication:
Advanced solid malignancies
Phase:
2
Sponsor:
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA 02139 USA
Telephone: +1 (617) 679-7000
EudraCT Number:
2014-005394-37
Therapeutic Area:
Oncology
Protocol History
Original
26 May 2015
Amendment 01
09 February 2016
Amendment 02
19 May 2016
Amendment 03
17 April 2017
Amendment 04
25 September 2017
Amendment 05
23 January 2018
Amendment 06
02 March 2020
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company 
Limited, may be referred to in this protocol as “Millennium,” “Sponsor,” or “Takeda.”
Approved by:
Note: If this document was approved electronically, the electronic approval signatures may be 
found at the end of the document.
Signature
Date DD Month YYYY
Signature
Date DD Month YYYY
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metria
PPD


MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
2
Rationale for Amendment 06
This document describes the changes in reference to the protocol incorporating Amendment 06. 
The primary purpose of this amendment is to remove long-term follow up (progression-free 
survival [PFS] and/or overall survival [OS]), clarify study closure, and remove in-home fasting 
glucose monitoring.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see Section 14.12.
Changes in Amendment 06
1. Removed long-term follow up (PFS follow up and/or OS follow up) for patients after end of
treatment.
2. Update to the Global Clinical Lead for the study.
3. Removed in-home glucose monitoring.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
3
PROTOCOL SUMMARY
Study Title: A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), 
MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly Paclitaxel 
and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial Cancer
Number of Patients: Approximately 242 patients will be randomized into this study from approximately 
75 study centers in North America, Europe, and Asia-Pacific.
Study Objectives
Primary
!
To determine if MLN0128 in combination with weekly paclitaxel improves progression-free 
survival (PFS) compared to weekly paclitaxel alone.
Secondary
!
To determine if single-agent MLN0128 improves PFS compared to weekly paclitaxel alone.
!
To determine if MLN0128+MLN1117 improves PFS compared to weekly paclitaxel alone.
!
To assess the safety and tolerability of single-agent MLN0128, MLN0128 in combination 
with paclitaxel, and MLN0128+MLN1117.
!
To evaluate improvement in efficacy measures (endpoints other than PFS) of MLN0128 in 
combination with weekly paclitaxel, single-agent MLN0128, and MLN0128+MLN1117 to 
weekly paclitaxel alone.
!
To collect plasma concentration-time data with sparse pharmacokinetic (PK) sampling to 
contribute to future population PK analysis.
Quality of Life (QOL)
!
To assess the QOL and symptoms in patients treated with MLN0128 in combination with 
weekly paclitaxel, single-agent MLN0128, and MLN0128+MLN1117 to weekly paclitaxel 
alone.
Exploratory
 
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MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
4
Overview of Study Design: This is a phase 2, open-label, randomized, multicenter, 4-arm study of the 
safety and efficacy of MLN0128 in combination with paclitaxel, single-agent MLN0128, single-agent 
paclitaxel, and MLN0128 in combination with MLN1117 in adult women with advanced endometrial 
cancer. The patient population will consist of women with histologic or cytologic diagnosis of 
endometrial carcinoma (including endometrioid, serous, mixed adenocarcinoma, clear-cell carcinoma, or 
carcinosarcoma) that is advanced, recurrent, or persistent, and has relapsed or is refractory to curative 
therapy or established treatments. Patients must have had 1 prior platinum-based chemotherapeutic 
regimen but not more than 2 prior systemic chemotherapy regimens.
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. Study drug will be administered in 28-day treatment cycles.
Approximately 242 patients will be randomized at a ratio of 1:1:1:1 to receive study drug in one of 
4 treatment arms:
!
Arm A: paclitaxel 80 mg/m2 weekly on Days 1, 8, and 15 of a 28-day cycle.
!
Arm B: paclitaxel 80 mg/m2 weekly on Days 1, 8, and 15 of a 28-day cycle+MLN0128 4 mg on 
Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle.
!
Arm C: MLN0128 30 mg once weekly (QW) on Days 1, 8, 15, and 22 of a 28-day cycle.
!
Arm D: MLN0128 4 mg+MLN1117 200 mg on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day 
cycle.
In the event that enrollment into a treatment arm(s) is closed, patients will be randomized 1:1 into the 
remaining treatment arms. Paclitaxel will be administered intravenously (IV), whereas MLN0128 and 
MLN1117 will be administered by mouth (PO) throughout the study. Patients in Arm A and Arm B will 
receive paclitaxel alone or paclitaxel+MLN0128 until they experience disease progression, unacceptable 
toxicity, or withdraw consent. Patients in Arm B who discontinue paclitaxel before disease progression 
may continue to receive MLN0128 alone until they experience disease progression, unacceptable toxicity, 
or withdraw consent. In addition, patients will receive MLN0128 (in Arm C) or MLN0128+MLN1117 (in 
Arm D) continuously until they experience disease progression, unacceptable toxicity, or withdraw 
consent. 
Patients will attend the EOT visit 30 to 40 days after receiving their last dose of study drug.
Sparse PK samples will be collected from patients enrolled in Arms B, C, and D for determination of the 
plasma concentration of MLN0128 and/or MLN1117 during Cycle 1 at prespecified time points. 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. For correlative biomarker analysis, fresh and archival tumor 
samples will be obtained during Screening, 
 at prespecified time 
points. In addition, fresh tumor samples will be obtained on Cycle 1 Day 22 from patients in Arms C and 
D to identify adaptive response mechanisms to treatment of MLN0128 or MLN0128+MLN1117.
Radiological tumor evaluations (computed tomography [CT] scan with contrast or magnetic resonance 
imaging [MRI] with contrast, 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).
Changes in QOL disease-specific symptoms will be assessed using the European Organization for 
Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) and the 
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MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
5
Endometrial Cancer Module (EORTC QLQ-EN24).
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for 
Adverse Events. Adverse events will be assessed, and laboratory values, vital signs, and 
electrocardiograms will be obtained to evaluate the safety and tolerability of MLN0128 in combination 
with paclitaxel, single-agent MLN0128, and MLN0128+MLN1117.
There will be 2 interim analyses with early stopping rules for futility in the single-agent MLN0128 arm 
(Arm C) and MLN0128+MLN1117 arm (Arm D).
Study Population: Female patients must be 18 years of age or older before the Screening visit to be
enrolled in the study. Patients must have histologic or cytologic diagnosis of endometrial carcinoma 
(including endometrioid, serous, mixed adenocarcinoma, clear-cell carcinoma, or carcinosarcoma), and 
the cancer is advanced, recurrent, or persistent and has relapsed or is refractory to curative therapy or 
established treatments. Patients must have had 1 but no more than 2 prior lines of chemotherapy. Patients 
must have an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate clinical 
laboratory values. Patients are required to undergo a fresh tumor biopsy at Screening before beginning 
study treatment.
Patients must have measurable disease by RECIST 1.1 criteria, defined as at least 1 lesion that can be 
accurately measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be 
≥10 mm in long axis when measured by CT, MRI, or caliper measurement by clinical exam. Lymph 
nodes must be ≥15 mm in short axis when measured by CT or MRI.
Duration of Study: Patients in Arm A and Arm B will receive paclitaxel alone or paclitaxel+MLN0128 
until they experience disease progression, unacceptable toxicity, or withdraw consent. Patients in Arm B 
who discontinue paclitaxel before disease progression may continue to receive MLN0128 alone until they 
experience disease progression, unacceptable toxicity, or withdraw consent. In addition, patients will 
receive MLN0128 (in Arm C) or MLN0128+MLN1117 (in Arm D) continuously until they experience 
disease progression, unacceptable toxicity, or withdraw consent. Patients will discontinue treatment if 
they have an unacceptable drug-related toxicity. The study will be closed approximately 5 months after 
the last patient is randomized, or when the last patient discontinues study treatment.
Patients will attend an EOT visit 30 to 40 days after receiving their last dose of study drug or at the start 
of subsequent anticancer therapy. Up until Amendment 06, after EOT, patients were to be followed for 
PFS and OS, during the Posttreatment follow-up Period. 
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MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
6
STUDY OVERVIEW DIAGRAM
Please Note: Up until Amendment 06, after EOT, patients were to be followed for PFS and OS, during the 
Posttreatment follow-up period.
IV=intravenous(ly), OS=overall survival, PFS=progression-free survival, PO=by mouth, QW=once weekly.
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MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
Confidential
7
SCHEDULE OF EVENTS
Screening (a)
TREATMENT CYCLES
EOT (d)
Cycles 1-8
Cycles 9 and 
Beyond
Day -28 
to Day -1
Day 1 Day 3 (b) Day 8 Day 15 Day 22 (c) Day 28 Day 1
Day 28 
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Height
X
Weight
X
X
X
X
X
Physical examination
X
X
X
X
X
Vital signs (e)
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
Single, 12-lead ECG
X
X (f)
X (f)
X (f)
Histological subtyping
X
Radiographic tumor evaluation (g)
X
X (g)
X (g)
X (g)
EORTC QLQ-C30 (h)
X
X
X
X
EORTC QLQ-EN24 (h)
X
X
X
X
Monitoring of concomitant medications and 
procedures
Recorded from the first dose of study drug through 30 days after the last dose of study drug
Adverse event reporting
Recorded from the first dose of study drug through 30 days after the last dose of study drug
Serious adverse events (i) will be reported from signing of the informed consent form through 30 days after 
the last dose of study drug.
Dosing (patients will be randomized to one of the following 4 arms) (j):
Arm A
Paclitaxel 80 mg/m2 IV weekly on Days 1, 8, and 15 of a 28-day cycle
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MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
Confidential
8
Screening (a)
TREATMENT CYCLES
EOT (d)
Cycles 1-8
Cycles 9 and 
Beyond
Day -28 
to Day -1
Day 1 Day 3 (b) Day 8 Day 15 Day 22 (c) Day 28 Day 1
Day 28 
Arm B
Paclitaxel 80 mg/m2 IV weekly on Days 1, 8, and 15 of a 28-day 
cycle+MLN0128 4 mg PO on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day 
cycle
Arm C
MLN0128 30 mg QW PO
Arm D
MLN0128 4 mg PO+MLN1117 200 mg PO on Days 1-3, 8-10, 15-17, and 
22-24 of a 28-day cycle
Samples/Laboratory Assessments
Hematology/chemistry (k)
X1
X1 (l)
X1
X1
X1 (l)
X1
Urinalysis
X1 (m)
X1 (l)
X1 (l)
X1
Pregnancy test (n)
X1
X1 (n)
X1 (n)
Coagulation (PT/INR, aPTT)
X1
X1 (l)
X1 (l)
X1
Fasting serum glucose (o)
X1
X1
X1
X1
Fasting lipid profile
X1
X1 (p)
X1
X1
HbA1c
X1
X1 (q)
Q3C (q)
Blood sample for PK analysis (r)
See the Pharmacokinetic Sample Breakdown table
Archival (banked) tumor tissue (u)
X1 (u)
Fresh tumor biopsy (v)
X1 (v)
X1 (c)
aPTT=activated partial thromboplastin time, CT=computed axial tomography, ECG=electrocardiogram, ECOG=Eastern Cooperative Oncology Group, EORTC 
QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, EORTC QLQ-EN24=European Organization 
for Research and Treatment of Cancer Quality of Life Questionnaire Endometrial Cancer Module, EOT=end of treatment, HbA1c=glycosylated hemoglobin, 
INR=international normalized ratio, IV=intravenous(ly), MRI=magnetic resonance imaging, OS=overall survival, OSFU=overall survival follow up, 
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MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
Confidential
9
Screening (a)
TREATMENT CYCLES
EOT (d)
Cycles 1-8
Cycles 9 and 
Beyond
Day -28 
to Day -1
Day 1 Day 3 (b) Day 8 Day 15 Day 22 (c) Day 28 Day 1
Day 28 
PFS=progression-free survival, PFSFU=progression-free survival follow up, PK=pharmacokinetic(s), PO=by mouth, PT=prothrombin time, Q=every, 
QW=once weekly, RECIST=Response Evaluation Criteria in Solid Tumors, X#=the number of samples required (eg, 2 samples=X2).
Tests and procedures should be performed on schedule, but occasional changes are allowable (±2 days unless otherwise specified) for holidays, vacations, and 
other administrative reasons, starting after the completion of Cycle 2 Day 1.
(a) Screening assessments are performed within 28 days before the Cycle 1 Day 1 dose. The informed consent form may be signed more than 28 days before 
Cycle 1 Day 1. Screening assessments performed no more than 3 days before Day 1 will qualify as baseline assessments and need not be repeated, unless 
otherwise specified.
(b) The Day 3 visit occurs on Cycle 1 only for PK sample collection from patients in Arm B (MLN0128+paclitaxel) (see the Pharmacokinetic Sample 
Breakdown table).
(c) The Day 22 visit occurs within Cycle 1 only to obtain fresh, post-dose tumor biopsies from patients in Arm C (single-agent MLN0128) and Arm D 
(MLN0128+MLN1117) only (see Section 7.4.16 for additional details). The biopsy should be obtained 2-4 hours after study drug dosing. 
(d) Patients will attend an EOT visit 30-40 days after receiving their last dose of study drug 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 visit should be conducted before
the initiation of subsequent anticancer therapy. The study will be closed when the last patient discontinues treatment.
Up until Amendment 06, after EOT, patients were to be followed for PFS and OS, during the Posttreatment follow-up period.
(e) Vital sign measurements include blood pressure (diastolic and systolic), heart rate, and temperature.
(f) Single, 12-lead ECGs will be collected predose. When the timing of an ECG coincides with blood samples, the ECG should be completed first.
(g) All CT and MRI scans should be acquired with contrast unless contraindicated for a particular patient. Baseline CT or MRI scans of the chest, abdomen, and 
pelvis must be obtained within 4 weeks before the first dose of study drug. The same imaging modality (CT or MRI) will be used throughout the study. CT 
or MRI scans will be obtained every 2 cycles from Cycles 2-8 (ie, Cycle 2 Day 28, Cycle 4 Day 28, Cycle 6 Day 28, and Cycle 8 Day 28 [3 days]) and then 
every 3 cycles thereafter (ie, Cycle 11 Day 28, Cycle 14 Day 28, Cycle 17 Day 28 [5 days], etc), and all Day 28 response assessments should be completed 
before Day 1 of the subsequent cycle. Up until Amendment 06, a confirmatory scan was to be performed at approximately 4 weeks from the previous scan 
for all patients with an objective or partial response. A CT or MRI scan is not required at the EOT visit for patients with documented radiographic disease 
progression. 
(h) All questionnaires should be completed before any other study procedures are performed.
(i) Including serious pretreatment events; see Section 9.1.1.
(j) The first dose of study drug must be administered within 5 days after randomization on study. For calculating the appropriate dose of paclitaxel, body surface 
area should be capped at 2.0 m2 for all patients receiving paclitaxel in Arm A or Arm B. In Arms B and D, MLN0128 will be administered on an empty 
stomach; in Arm C, weekly MLN0128 will be administered with a light meal (see Section 6.1).
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MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
Confidential
10
Screening (a)
TREATMENT CYCLES
EOT (d)
Cycles 1-8
Cycles 9 and 
Beyond
Day -28 
to Day -1
Day 1 Day 3 (b) Day 8 Day 15 Day 22 (c) Day 28 Day 1
Day 28 
(k) Results of hematology and chemistry safety laboratory testing must be available and reviewed by the investigator before enrollment and initial administration 
of any study drug. For patients randomized to receive paclitaxel (Arms A and B), hematology and chemistry panels are to be tested and reviewed by the 
investigator or appropriate designee before administering paclitaxel.
(l) May be assessed up to 24 hours before the study visit.
(m) At Screening, creatinine clearance must be ≥50 mL/min based either on Cockroft-Gault estimate or based on a 12- or 24-hour urine collection.
(n) A serum pregnancy test will be performed for women of childbearing potential at Screening. A urine pregnancy test must be performed predose on Day 1 of 
every cycle with negative results available before the first dose may be administered in that cycle. A serum pregnancy test may also be performed within 
3 days before dosing in place of the Day 1 urine test.
(o) Fasting serum glucose will be measured in the clinic. Patients are required to fast overnight (nothing except water and/or medications after midnight or for a 
minimum of 8 hours before the assessment) for each of these measurements. For patients in Arm A (single-agent paclitaxel), Arm B (paclitaxel+MLN0128), 
and Arm C (single-agent MLN0128), the sample will be collected predose; after predose blood draws are complete, patients receiving single-agent 
MLN0128 QW in Arm C should consume a light meal before dosing (Section 6.1). For patients Arm D (MLN0128+MLN1117), the sample should be taken 
approximately 2 hours after study drug administration with the patient continuing to fast until the sample is taken.
(p) Fasting lipid profile will be collected at Screening, at Day 1 (predose) of every cycle starting with Cycle 2, and at EOT. A sample is not required at Cycle 1 
Day 1.
(q) HbA1c will be evaluated on Day 1 of every 3 cycles (ie, Cycle 3 Day 1, Cycle 6 Day 1, Cycle 9 Day 1, etc).
(r) Blood samples for PK analysis for patients in Arms B, C, and D will be performed according to the schedule presented in the Pharmacokinetic Sample 
Breakdown table.
(s) 
(t) 
.
(u) Archived tumor tissue from either paraffin blocks or a minimum of 20 unstained slides (paraffin blocks preferred) should be obtained from a previous 
resection or biopsy that was done as part of the patient’s standard care. These samples will be evaluated for candidate biomarkers predictive of response. The 
archival tumor tissue is to be collected only from enrolled patients and may be collected and sent to the sponsor after initiation of protocol treatment. See 
Section 7.4.16 for requirements.
(v) Fresh tumor biopsies are required for all patients at Screening. The screening biopsy must be obtained within 14 days before dosing on Cycle 1 Day 1 and 
should be obtained on a separate visit from the other screening requirements. See Section 7.4.16 for additional details regarding the requirements for tumor 
biopsies.
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MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
11
PHARMACOKINETIC SAMPLE BREAKDOWN
Treatment Arms B, C, and D Only
Arm B (Paclitaxel+MLN0128) Only
Cycle 1 Day 3
Predose
X1
1-2 hours after dose of MLN0128 (a)
X1
3-6 hours after dose of MLN0128 (a)
X1
PK=pharmacokinetic(s), X#=the number of samples required (eg, 2 samples=X2).
(a) On Cycle 1 Day 3, PK plasma specimens can be collected at any time during the sampling window. Over the 
course of the study, a distribution of sampling times within the windows is encouraged. The exact time and date 
of MLN0128 dose and the time and date of PK sample collection must be recorded.
Arm C (Single-Agent MLN0128) Only
Cycle 1 Day 1 (a)
Cycle 1 Day 15 (b)
At time of clinic visit (anytime postdose)
X1
Approximately 1 hour after previous PK sample collection
X1
1 to 2 hours postdose (±15 min)
X1
3 to 6 hours postdose (±30 min)
X2 (c)
PK=pharmacokinetic(s), X#=the number of samples required (eg, 2 samples=X2).
(a) Patients should bring a light meal with them to this visit. After completion of fasting serum glucose sampling, 
patients will begin consuming the meal within 30 min before dosing, after which they will take their regularly 
scheduled doses of MLN0128. The exact date/time of meal consumption, MLN0128 dosing, and PK sampling 
must be recorded. Over the course of the study, a distribution sampling times is encouraged.
(b) Patients will take their regularly scheduled doses of MLN0128 at home with a light meal and will record the 
exact date/time of meal consumption and dose administration in their subject diaries. Patients will then report to 
the clinic for the scheduled visit, during which they will provide PK samples. The exact date/time of PK sampling 
must be recorded. Over the course of the study, a distribution of clinic visit/sampling times (eg, morning through 
late afternoon) for this visit is encouraged.
(c) Two samples will be taken no less than 1 hr apart within the specified window.
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Arm D (MLN0128+MLN1117) Only
Cycle 1 Day 1
Cycle 1 Day 15
At time of clinic visit (anytime postdose)
X1 (a)
1 hour (10 min) after previous PK sample collection 
X1
1-2 hours postdose (b)
X1
3-6 hours postdose (b)
X1
PK=pharmacokinetic, X#=the number of samples required (eg, 2 samples=X2).
(a) On Cycle 1 Day 15, patients should take their dose or doses of study drug early in the morning at home and note 
the exact date and time that the dose was taken. Two postdose PK plasma samples will be collected at the clinic. 
The first specimen may be collected after arrival at the clinic and the second specimen collected approximately 
1 hour after the first. Over the course of the study, a distribution of clinic visit/sampling times (eg, morning 
through late afternoon) for this visit is encouraged. The exact time and date of MLN0128 and MLN1117 dose and 
the time and date of PK sample collection must be recorded.
(b) On Cycle 1 Day 1, PK plasma samples can be collected at any time during the sampling window. Over the 
course of the study, a distribution of sampling times within the windows is encouraged. The exact time and date 
of MLN0128 dose and the time and date of PK sample collection must be recorded.
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TABLE OF CONTENTS
1. BACKGROUND AND STUDY RATIONALE ....................................................................21
1.1 Disease Under Treatment...............................................................................................21
1.2 MLN0128......................................................................................................................22
1.2.1 Nonclinical Experience .........................................................................................22
1.2.2 Clinical Experience...............................................................................................25
1.3 MLN0128 in Combination With MLN1117...................................................................25
1.3.1 Nonclinical Experience .........................................................................................25
1.3.2 Clinical Experience...............................................................................................27
1.4 Study Rationale .............................................................................................................27
1.4.1 Rationale for the Proposed Dose and Schedule in Arm B ......................................28
1.4.2 Rationale for the Proposed Dose and Schedule in Arm C ......................................29
1.4.3 Rationale for the Proposed Dose and Schedule in Arm D ......................................30
1.4.4 Rationale for Fresh Tumor Biopsies to Study Adaptive Response .........................31
1.5 Potential Risks and Benefits ..........................................................................................31
2. STUDY OBJECTIVES.........................................................................................................33
2.1 Primary Objectives ........................................................................................................33
2.2 Secondary Objectives ....................................................................................................33
2.3 Quality of Life Objective...............................................................................................33
2.4 Exploratory Objectives ..................................................................................................34
3. STUDY ENDPOINTS ..........................................................................................................34
3.1 Primary Endpoint ..........................................................................................................34
3.2 Secondary Endpoints .....................................................................................................34
3.3 QOL Endpoints .............................................................................................................35
3.4 Exploratory Endpoints...................................................................................................35
4. STUDY DESIGN..................................................................................................................36
4.1 Overview of Study Design.............................................................................................36
4.2 Number of Patients........................................................................................................38
4.3 Duration of Study..........................................................................................................38
5. STUDY POPULATION........................................................................................................39
5.1 Inclusion Criteria...........................................................................................................39
5.2 Exclusion Criteria..........................................................................................................41
6. STUDY DRUG.....................................................................................................................43
6.1 Study Drug Administration............................................................................................43
6.2 Dose Modification Guidelines .......................................................................................45
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6.3 Excluded Concomitant Medications and Procedures......................................................53
6.3.1 Excluded Concomitant Medications for all Patients...............................................53
6.3.2 Excluded Concomitant Medications for MLN0128 Single-Agent and 
Combination Treatment Arms (Arms B, C, and D).............................................54
6.3.3 Potential Drug-Drug Interactions in Arm D (MLN0128+MLN1117).....................54
6.4 Permitted Concomitant Medications and Procedures......................................................55
6.5 Precautions and Restrictions ..........................................................................................56
6.5.1 All Treatment Arms..............................................................................................56
6.5.2 Paclitaxel (Arm A) and Paclitaxel+MLN0128 (Arm B) Treatment Arms Only......57
6.6 Management of Clinical Events.....................................................................................57
6.6.1 Management of Hyperglycemia ............................................................................57
6.6.2 Management of Hyperlipidemia............................................................................59
6.6.3 Management of Oral Mucositis .............................................................................60
6.6.4 Management of Rash ............................................................................................61
6.6.5 Management of Nausea and/or Vomiting ..............................................................62
6.6.6 Management of Cardiac Abnormalities .................................................................63
6.6.7 Management of Other Nonhematologic Toxicities ................................................65
6.6.8 Management of AST/ALT Elevations ...................................................................66
6.6.9 Management of Noninfectious Pneumonitis ..........................................................67
6.6.10 Management of Clinical Events: Paclitaxel .........................................................68
6.7 Blinding and Unblinding ...............................................................................................68
6.8 Description of Investigational Agents ............................................................................68
6.9 Preparation, Reconstitution, and Dispensation ...............................................................69
6.10 Packaging and Labeling...............................................................................................69
6.11 Storage, Handling, and Accountability.........................................................................70
7. STUDY CONDUCT .............................................................................................................71
7.1 Study Personnel and Organizations................................................................................71
7.2 Arrangements for Recruitment of Patients .....................................................................71
7.3 Treatment Group Assignments.......................................................................................71
7.4 Study Procedures...........................................................................................................72
7.4.1 Informed Consent .................................................................................................72
7.4.2 Patient Demographics ...........................................................................................72
7.4.3 Medical History....................................................................................................72
7.4.4 Physical Examination............................................................................................72
7.4.5 Patient Height and Weight ....................................................................................72
7.4.6 Vital Signs ............................................................................................................72
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7.4.7 Pregnancy Test .....................................................................................................73
7.4.8 ECOG Performance Status....................................................................................73
7.4.9 Concomitant Medications and Procedures.............................................................73
7.4.10 Adverse Events...................................................................................................73
7.4.11 Enrollment ..........................................................................................................73
7.4.12 ECG....................................................................................................................73
7.4.13 Clinical Laboratory Evaluations..........................................................................73
7.4.14 Fasting Serum Glucose .......................................................................................75
7.4.15 Disease Assessment ............................................................................................76
7.4.16 Tumor Biopsies and Archival Tumor Samples ....................................................76
7.4.17 PK Measurements (Arms B, C, and D only)........................................................77
7.4.18 QOL Assessment ................................................................................................77
7.4.19 DNA Measurements............................................................................................78
7.5 Completion of Treatment...............................................................................................78
7.6 Completion of Study......................................................................................................78
7.7 Discontinuation of Treatment With Study Drug.............................................................78
7.8 Withdrawal of Patients From Study ...............................................................................79
7.9 Study Compliance .........................................................................................................80
8. STATISTICAL AND QUANTITATIVE ANALYSES .........................................................80
8.1 Statistical Methods ........................................................................................................80
8.1.1 Determination of Sample Size...............................................................................80
8.1.2 Randomization and Stratification ..........................................................................81
8.1.3 Populations for Analysis .......................................................................................81
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data..............................82
8.1.5 Demographic and Baseline Characteristics............................................................82
8.1.6 Efficacy Analysis..................................................................................................82
8.1.7 Analyses of Patient-Reported Outcomes ...............................................................83
8.1.8 PK/Pharmacodynamics/Biomarkers ......................................................................84
8.1.9 Safety Analysis .....................................................................................................84
8.1.10 Interim Analysis..................................................................................................86
9. ADVERSE EVENTS............................................................................................................86
9.1 Definitions.....................................................................................................................86
9.1.1 Pretreatment Event Definition...............................................................................86
9.1.2 AE Definition .......................................................................................................87
9.1.3 SAE Event Definition ...........................................................................................87
9.2 Procedures for Recording and Reporting AEs and SAEs................................................88
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9.3 Monitoring of AEs and Period of Observation ...............................................................89
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events...............90
10. ADMINISTRATIVE REQUIREMENTS............................................................................90
10.1 GCP.............................................................................................................................90
10.2 Data Quality Assurance ...............................................................................................90
10.3 Electronic Case Report Form Completion....................................................................91
10.4 Study Monitoring.........................................................................................................91
10.5 Ethical Considerations .................................................................................................92
10.6 Patient Information and Informed Consent...................................................................92
10.7 Patient Confidentiality.................................................................................................92
10.8 Investigator Compliance ..............................................................................................92
10.9 On-site Audits .............................................................................................................93
10.10 Investigator and Site Responsibility for Drug Accountability.....................................93
10.11 Product Complaints ...................................................................................................93
10.12 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities.............94
10.13 Closure of the Study ..................................................................................................94
10.14 Record Retention.......................................................................................................95
11. USE OF INFORMATION...................................................................................................95
11.1 Clinical Trial Registration............................................................................................96
11.2 Clinical Trial Results Disclosure..................................................................................96
12. INVESTIGATOR AGREEMENT.......................................................................................97
13. REFERENCES....................................................................................................................98
14. APPENDICES ..................................................................................................................102
14.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status............102
14.2 Methods of Contraception Considered to be Effective................................................103
14.3 Cockcroft-Gault Equation..........................................................................................104
14.4 New York Heart Association Classification of Cardiac Disease .................................104
14.5 List of Relevant CYP Inhibitors and Inducers ............................................................105
14.6 List of BCRP, OCT1, and OCT2 Substrates...............................................................105
14.7 Rationale for Amendment 01.....................................................................................106
14.8 Rationale for Amendment 02.....................................................................................109
14.9 Rationale for Amendment 03.....................................................................................110
14.10 Rationale for Amendment 04...................................................................................111
14.11 Rationale for Amendment 05...................................................................................112
14.12 Detailed Description of Amendments to Text...........................................................113
6.6.1
Management of Hyperglycemia .......................................................................115
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LIST OF TABLES
Table 1.a
DLT Observed with MLN0128 (3 Days Per Week)+Weekly Paclitaxel in 
Study MLN0128-1004 .......................................................................................29
Table 1.b
DLT Observed with Weekly MLN0128 in Study MLN0128-1004 .....................30
Table 1.c
DLT Observed with MLN0128+MLN1117 (3 Days Per Week) in Study 
C32001 ..............................................................................................................31
Table 6.a
Examples of a Light Meal ..................................................................................44
Table 6.b
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay..............47
Table 6.c
Dose Reduction Schedule for MLN0128 and MLN1117 ....................................53
Table 6.d
Management of Hyperglycemia .........................................................................58
Table 6.e
Management of Hyperlipidemia .........................................................................60
Table 6.f
Management of Oral Mucositis ..........................................................................61
Table 6.g
Management of Rash .........................................................................................62
Table 6.h
Management of Nausea and/or Vomiting ...........................................................63
Table 6.i
Management of Left Ventricular Dysfunction ....................................................64
Table 6.j
Management of QTc Prolongation......................................................................65
Table 6.k
Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue)......................................................................................66
Table 6.l
Management of AST/ALT Elevations ................................................................67
Table 6.m
Management of Noninfectious Pneumonitis .......................................................68
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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
4E-BP1
eukaryotic initiation factor 4-binding protein
AE
adverse event
AKT
serine/threonine-specific protein kinase (also known as protein kinase B)
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
BCRP
breast cancer resistance protein
BSA
body surface area
CBR
clinical benefit rate
CNS
central nervous system
CR
complete response
CRF
case report form
CT
computed tomography
CYP
cytochrome P450
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EORTC QLQ-EN24
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Endometrial Cancer Module
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire
EOT
end of treatment (visit)
HER2
estrogen receptor positive/human epidermal growth factor receptor-2
ER
estrogen receptor
FBG
fasting blood glucose
GCP
Good Clinical Practice
HbA1c
glycosylated hemoglobin, hemoglobin A1c
HDPE
high-density polyethylene
IB
Investigator’s Brochure
IC50
50% inhibitory concentration
ICF
informed consent form
ICH
International Conference for Harmonisation
IEC
independent ethics committee
INR
international normalized ratio
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Abbreviation
Term
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous(ly)
IXRS
Interactive Voice/Web Response System
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MLN0128
also known as TAK-228
MLN1117
also known as TAK-117
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTOR
mammalian (or mechanistic) target of rapamycin
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OCT1
organic cation transporter protein 1
OCT2
organic cation transporter protein 2
ORR
overall response rate
OS
overall survival
PFS
progression-free survival
PI3K
phosphoinositide 3-kinase
PIK3CA
phosphoinositide-3-kinase, catalytic alpha polypeptide
PK
pharmacokinetic(s)
PO
by mouth (oral)
PPI
proton pump inhibitor
PR
partial response
PRO
patient-reported outcome
PTEN
phosphatase and tensin homolog
PT
prothrombin time 
QD
quaque die; each day; once daily
QD×3 QW
once daily for 3 days each week
QOL
quality of life
QTc
rate-corrected QT interval (msec)
QTcF
QT interval (msec) with Fridericia correction
QW
once weekly
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
S473
serine 473
S6K
ribosomal protein S6 kinase
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
SmPC
Summary of Product Characteristics
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Abbreviation
Term
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse events
TORC1
mammalian (or mechanistic) target of rapamycin complex 1
TORC2
mammalian (or mechanistic) target of rapamycin complex 2
TTP
time to progression
ULN
upper limit of the normal range
US
United States
USPI
United States Prescribing Information
WBC
white blood cell
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1.
BACKGROUND AND STUDY RATIONALE
1.1
Disease Under Treatment
Endometrial cancer is the most common gynecological malignancy with an estimated 
287,000 new cases per year worldwide.[1] It is the fourth most common malignancy among 
women in the United States (US), with an estimated 52,000 new cases and 8,600 deaths in 
2013.[2]
Endometrial carcinomas are classified into 2 major types (I and II), based upon light microscopic 
appearance, clinical behavior, and epidemiology. Type I carcinomas include tumors of 
endometrioid histology that are Grade 1 or 2. These comprise approximately 80% of endometrial 
carcinomas and typically have a favorable prognosis, are estrogen responsive, and may be 
preceded by an intraepithelial neoplasm. Type II tumors account for 10% to 20% of endometrial 
carcinomas and include Grade 3 endometrioid tumors as well as tumors of nonendometrioid 
histology (serous, clear-cell, mucinous, squamous, transitional cell, mesonephric, 
carcinosarcoma, and undifferentiated). These tumors are often high grade, have a poor prognosis, 
and are not clearly associated with estrogen stimulation. A precursor lesion in type II tumors is 
rarely identified.
Systemic treatment for metastatic and relapsed endometrial cancer consists of endocrine therapy 
or cytotoxic chemotherapy. In nonrandomized trials, paclitaxel with carboplatin or cisplatin 
demonstrated a response rate >60% and a possibly prolonged survival compared with historical 
experience with other nonpaclitaxel-containing regimens. Results from randomized trials showed 
a similar response when paclitaxel was added to first-line platinum-containing regimens.[3]
Based on these results, paclitaxel-based combination regimens are preferred for first-line 
chemotherapy of advanced and recurrent endometrial cancer.[4] According to the European 
Society for Medical Oncology guidelines, endometrial cancer recurring after first-line 
chemotherapy is largely a chemoresistant disease. Various agents have been tested in a number 
of small phase 2 trials in patients previously exposed to chemotherapy, but the available options 
and response remain limited.[5] Only high-dose paclitaxel has consistently shown a response rate 
greater than 20%.
Dose-dense weekly administration of paclitaxel is a proven strategy to further enhance antitumor 
activity, especially in the re-treatment setting. Preclinical and clinical studies have proven that 
the duration of paclitaxel exposure is an important determinant of its cytotoxic effect. Thus, 
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cytotoxicity can be enhanced at fairly low concentrations of paclitaxel provided that the exposure 
is extended, eg, through weekly administration.[6-8]
1.2
MLN0128
1.2.1
Nonclinical Experience
The mammalian (or mechanistic) target of rapamycin (mTOR) serine/threonine kinase has a 
central role in regulating cellular growth and metabolism in response to external environmental 
factors.[9,10] The mTOR kinase binds with other proteins to form 2 distinct multiprotein 
complexes, mTOR complex 1 (TORC1) and mTOR complex 2 (TORC2). The TORC1 complex 
is stimulated by growth factors and amino acids and regulates cell growth by controlling the 
activity of the ribosomal protein S6 kinase (S6K) and eukaryotic initiation factor 4-binding 
protein (4E-BP1).[11] The TORC2 complex is activated by growth factors and promotes cell 
survival, proliferation, and actin cytoskeleton organization by phosphorylating and activating 
kinases, such as serine/threonine-specific protein kinase (AKT) kinase (also known as protein 
kinase B), which is a regulator of apoptosis.[12,13]
Two major classes of mTOR inhibitors are under development, allosteric inhibitors and 
adenosine triphosphate (ATP)-competitive inhibitors. The first-generation, or allosteric, 
inhibitors include rapamycin and the related analogs or rapalogs temsirolimus, everolimus, and 
ridaforolimus. The rapalogs effectively inhibit phosphorylation of S6K but only partially inhibit 
the phosphorylation of 4E-BP1, which regulates cap-dependent translation of transcripts for cell 
survival, proliferation, and angiogenesis.[10] Thus, rapamycin and the rapalogs are only partial 
inhibitors of TORC1.[10]
The ATP-competitive inhibitors (also known as mTOR kinase inhibitors or TORKinibs), such as 
MLN0128, 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.[14-16]
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), 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 
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targeted pathway (such as phosphorylation of 4E-BP1 as discussed previously) or loss of 
S6K-mediated feedback inhibition of growth factor receptor signaling leading to paradoxical 
hyperactive signaling. The normal feedback loop involves activated S6K, which phosphorylates 
and inactivates insulin receptor substrate-1 and inhibits signaling through the phosphoinositide 
3-kinase (PI3K) pathway.[13,17] 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.[10,13,17]
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 mTORC1 in a dose- and schedule-dependent manner with near complete inhibition of 
S6K.[18] Half the paired tumor samples had a post-treatment increase in the phosphorylation of 
AKT at S473.[18] 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.
MLN0128, also known as TAK-228 and INK128, is an orally available, potent, and highly 
selective ATP competitive inhibitor of mTOR kinase that exhibits dual specificity against both 
the TORC1 and TORC2 (TORC1/2) complexes. 
In vitro studies have demonstrated that MLN0128 selectively and potently inhibits the mTOR 
kinase (the concentration inhibiting 50% of enzyme activity [IC50] is 1.1 nM). Relative to mTOR 
inhibition, MLN0128 has >100-fold less potency on class I (PI3K isoforms α, β, γ, δ), class II 
(PI3KC2α and PI3K2Cβ), and class III (VPS34) PI3K family members. MLN0128 inhibited 
ligand binding of 10 receptor and intracellular protein kinases (ACVR1, BMPR1B, CSF1R, 
CSNK1D, CSNK1E, DDR1, MEK1, MEK2, PDGFRB, and RIPK2) out of a panel of 
402 distinct kinases. MLN0128 also inhibited the biochemical activity of 5 kinases (mTOR, 
DNA-PK, PDGFRα, Flt3, and CK1 epsilon kinases) out of a panel of 222 protein kinases by 
>80% at 1 M. MLN0128 also displays potent cellular inhibition of both the TORC1 and 
TORC2 pathway with cellular pharmacodynamically active concentrations at IC50 values of less 
than 10 nM. 
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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.[19] 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.[19-21] Dual TORC1/2 inhibition mitigates the feedback 
activation of AKT, which is known to facilitate resistance to TORC1-only inhibitors such as 
rapamycin.[22] 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.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN0128 may 
be found in the MLN0128 Investigator’s Brochure (IB).
Clinical Background of the Use of mTOR Inhibitors in Endometrial Cancer
Women with recurrent or metastatic endometrial cancer responded to mTOR inhibition with 
weekly intravenous (IV) administration of temsirolimus.[23] Response was higher in 
chemotherapy-naïve patients than those who were chemotherapy-treated. In addition, everolimus 
showed efficacy as second- or third-line therapy in women with chemotherapy-refractory 
advanced or metastatic endometrial cancer.[24,25] Also, ridaforolimus showed antitumor activity 
as second-or third-line therapy in patients with advanced or recurrent endometrial 
cancer.[23,26,27]
MLN0128 in Combination With Paclitaxel
The mTORC1 inhibitor rapamycin was reported to synergistically enhance the activity of 
paclitaxel in breast cancer cells.[28] In an AN3-CA endometrial tumor xenograft model, 
MLN0128 in combination with paclitaxel exhibited stronger antitumor efficacy compared to 
paclitaxel alone (BIOL-09-011). MLN0128 has been shown to induce G1 cell cycle arrest. 
Paclitaxel is known to block the progression of cells through G2 into mitosis and this G2-M 
arrest has been proposed to be a prerequisite step for apoptosis induced by paclitaxel.[29]
Pretreatment of mTOR inhibitors will arrest cells in G1 phase and may potentially antagonize the 
toxic effect of paclitaxel.[30] Therefore, MLN0128 should be given after paclitaxel 
administration in order not to interfere with the mechanism of paclitaxel. 
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1.2.2
Clinical Experience
Single-agent MLN0128 is in clinical development with 3 phase 1 studies in patients with either 
advanced nonhematologic tumors (Studies INK128-001 and C31002) or hematologic 
malignancies (relapsed or refractory multiple myeloma or Waldenström macroglobulinemia; 
Study INK128-002). In addition, MLN0128 is being investigated in combination with paclitaxel 
with or without trastuzumab in a phase 1 study in patients with advanced solid tumors 
(INK128-003).
Milled MLN0128 is being investigated either as a single agent or in combination with paclitaxel 
in an additional phase 1 study in patients with advanced solid tumors (Study MLN0128-1004) 
and in a phase 1/2 study in patients with advanced estrogen receptor (ER)-positive, human 
epidermal growth factor receptor-2 (HER2)-negative breast cancer (Study C31001). The 
combination of milled MLN0128 with MLN1117 (an investigational oral PI3Kα inhibitor) is 
being evaluated in a phase 1b study in adult patients with advanced nonhematologic 
malignancies (Study C32001).
Further details on these studies are provided in Section 1.4, and in the MLN0128 and 
MLN0128+MLN1117 IBs.
1.3
MLN0128 in Combination With MLN1117
1.3.1
Nonclinical Experience
Activating somatic missense mutations (eg, E542K, E545K, and H1047R) in the 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic alpha polypeptide (PIK3CA) gene 
encoding the p110catalytic subunit of PI3Khave been identified as a major mechanism for 
PI3K-dependent malignant transformation, proliferation, and survival. PIK3CA mutations have 
been reported to occur in various solid tumors with the highest rates in breast (27%), endometrial 
(24%), bladder (23%), colon (15%), and ovarian (10%) cancers.[31-33] In addition to direct 
mutations of PI3K, the pathway may also be activated by mutations or overexpression of 
upstream effectors such as receptor tyrosine kinases, including HER2, epidermal growth factor 
receptor, and insulin-like growth factor receptor. PIK3CA is also amplified in several tumor 
types including the squamous type of NSCLC.[34] MLN1117, also known as TAK-117, is a 
selective, small molecule inhibitor of PI3K. MLN1117 has demonstrated greatest 
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antiproliferative activity in cell lines harboring PIK3CA activating mutations and/or HER2 
overexpression.
The nonclinical antitumor activity of MLN0128 in combination with MLN1117 has been 
explored in a number of experimental in vitro and in vivo tumor models. To investigate the effect 
of MLN0128+MLN1117 on the downstream cellular signaling of the PI3K/AKT/mTOR 
pathway, Western blot analysis was performed using a diverse group of human tumor cell lines 
treated with MLN0128 and MLN1117 as a single agent or in combination. The treatment of 
MLN0128+MLN1117 resulted in greater inhibition of these targets than either single agent. 
Additionally, treatment with MLN0128+MLN1117 induced greater apoptosis, as indicated by 
decreased levels of total poly-adenosine diphosphate ribose polymerase. Further, the 
antiproliferative effect of MLN0128+MLN1117 was determined against a diverse group of 
human tumor cell lines in vitro and in vivo. The combination exhibited at least additive activity 
in all other cell lines tested (HCC1419, HCC1954, MDA-MB-468, MDA-MB-436 [breast 
tumor], A549, NCI-H460, and NCI-H596 [lung carcinoma]). The level of inhibition observed 
was greater for MLN0128+MLN1117 than either single agent alone. Antitumor activity of 
MLN0128+MLN1117 was assessed in 3 xenograft models in mice, 2 breast cancer cell line 
models, HCC70 (triple negative breast cancer, PTEN null) and MDA-MB-361 (HER2-amplified 
breast cancer with mutated PIK3CA), and 1 colorectal cancer HCT-116 (KRAS and PIK3CA 
mutations) models. MLN0128 and MLN1117 were administered orally (PO) as single agents or 
in combination concurrently using once daily (QD) and intermittent schedules over 21, 28, or 
30 days. The treatment of MLN0128+MLN1117 was tolerated and resulted in a statistically 
significant (p 0.001) increase in antitumor effects when compared with single-agent treatment 
in multiple treatment schedules in mice bearing HCC70 and MDA-MB-361 human breast cancer 
xenografts, in the latter of which substantial tumor growth delay was demonstrated. The 
treatment of MLN0128+MLN1117 was also tolerated and resulted in a statistically significant 
(p=0.003) increase in antitumor effects when compared to single-agent treatment in mice bearing 
HCT-116 human colorectal carcinoma xenografts.
The principal adverse effects associated with the administration of each agent are consistent with 
their respective mechanisms of action. Based on the available single-agent nonclinical and 
clinical safety data for MLN0128 or MLN1117, the expected overlapping nonclinical 
combination toxicities (including bone marrow and lymphoid depletion, effects on 
glucose/insulin homeostasis including hyperglycemia, and potential effects on chloride and 
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cholesterol levels) can be monitored with routine clinical hematology and serum chemistry 
evaluations, and are expected to be reversible and manageable in the clinic. Results from in vitro 
drug metabolism and PK studies suggest that the potential for drug-drug interactions between 
MLN0128 and MLN1117 in humans is low.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN1117 and 
MLN0128+MLN1117 may be found in the current editions of the MLN0128+MLN1117 and 
MLN1117 IBs.
1.3.2
Clinical Experience
MLN1117 is in clinical development for the treatment of advanced nonhematologic tumors both 
as a single agent (Study INK1117-001) or in combination with MLN0128 (Study C32001). 
These studies have been designed to investigate the safety, PK, pharmacodynamics, and 
preliminary efficacy of MLN1117 either as a single agent or in combination with MLN0128. 
Further details are presented in the current editions of the MLN0128+MLN1117 and MLN1117 
IBs.
1.4
Study Rationale
The primary objective of this phase 2 study in patients with advanced endometrial cancer is to 
compare the clinical efficacy of MLN0128+weekly paclitaxel to weekly paclitaxel alone in 
second- or third-line treatment of advanced, recurrent, or persistent endometrial cancer. In 
addition, the clinical efficacy of single-agent MLN0128 and the combination of 
MLN0128+MLN1117 will be compared to weekly paclitaxel alone. 
Molecular studies showed that endometrioid neoplasms have a different genetic profile than 
nonendometrioid neoplasms. Endometrioid carcinomas form 3 subgroups: one with high rates of 
microsatellite instability, one with POLE mutations leading to ultra-high mutation rates, and one 
with relatively low mutation rates and exhibiting a microsatellite stable phenotype.[35] Broadly, 
these tumors are defined by high rate of PTEN mutations and a relative lack of TP53 mutations. 
Specific mutations in FGFR2, ERBB2, PIK3CA, PIK3R1, KRAS, SOX17 and CTNNB1 
(-catenin) genes are also associated with this tumor type.[35,36] In contrast, serous and 
serous-like endometrial carcinomas exhibit extensive somatic copy number alterations. Common 
molecular findings in the serous subtype include p53 and PIK3CA mutations as well as ERBB2 
and KRAS amplifications and PTEN deletions.[35,37] Despite these genetic differences between 
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endometrioid and nonendometrioid carcinomas it is apparent that both histological populations 
show high rates of genomic alterations of the PI3K-AKT-mTOR pathway that may be sensitive 
to treatment with a dual TORC1/TORC2 inhibitor such as MLN0128. In addition, the 
combination of a PI3Kα inhibitor (MLN1117) with a TORC1/2 inhibitor (MLN0128) would be 
expected to provide more robust inhibition of the PI3K-AKT-mTOR pathway than either agent 
alone. The randomized, open-label, 4-arm, phase 2 study of paclitaxel, paclitaxel+MLN0128, 
MLN0128, and MLN0128+MLN1117 will test the following 2 hypotheses: 1) that sequential 
administration of paclitaxel+MLN0128 can potentiate the cytotoxic effects of paclitaxel and 
improve treatment outcomes compared to single-agent paclitaxel and 2) that TORC1/2 inhibition 
either with or without additional PI3Kα inhibition will provide better efficacy compared with the 
single-agent cytotoxic effects of paclitaxel in patients with advanced recurrent endometrial 
cancer and progressive disease after platinum-containing cytotoxic chemotherapy. 
1.4.1
Rationale for the Proposed Dose and Schedule in Arm B
The selected dose and schedule for Arm B of paclitaxel, 80 mg/m2 weekly on Days 1, 8, and 15 
of each 28-day cycle (weekly paclitaxel)+MLN0128, 4 mg on Days 2-4, 9-11, 16-18, and 
23-25 of each 28-day cycle) (QD×3 QW) was determined in 2 designated studies: 
Study INK128-003 and Study MLN0128-1004.
INK128-003 was an open-label study designed to determine the maximum tolerated dose (MTD) 
and to identify dose-limiting toxicities (DLTs) for oral administration of unmilled MLN0128 
paclitaxel, with or without trastuzumab, in patients with advanced solid malignancies. In this 
study, 67 patients with advanced solid tumors received weekly paclitaxel+MLN0128 (6-40 mg 
via 3 dosing schedules) in the dose-escalation phase (n=47), and weekly paclitaxel+MLN0128 
given QD×3 QW with or without trastuzumab 2 mg/kg in the expansion phase (n=20; 5 and 
15 patients, respectively).
A favorable tolerability profile was observed when MLN0128 was administered 24 hours after 
paclitaxel on a QD×3 QW schedule. The MTD for MLN0128 given QD×3 QW in combination 
with weekly paclitaxel was 10 mg. A dose of 8 mg of MLN0128 was further explored in the 
expansion phase. The most common Grade 3 or greater study drug-related toxicities observed 
were neutropenia (21%), diarrhea (12%), and hyperglycemia (12%). Of 54 response-evaluable 
patients, 8 achieved partial response (PR) and 6 had stable disease (SD) lasting ≥6 months. 
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MLN0128 exhibited a dose-dependent increase in exposure, and there were no indications of a 
drug-drug interaction between paclitaxel and MLN0128. 
Scale-up manufacturing of MLN0128 required the introduction of a physical milling step to 
control particle size distribution of MLN0128 drug substance. In order to understand if this 
milling step altered the safety and PK profile of MLN0128, re-evaluation of safety and PK of the 
milled MLN0128 dose with weekly paclitaxel to be used in Arm B of this study was conducted 
in Study MLN0128-1004 under standard phase 1 conditions (see Table 1.a). A total of 22 
patients were enrolled and assigned, sequentially, to 2 dosing cohorts at the QD×3 QW dosing 
schedule for MLN0128+weekly paclitaxel established in Study INK128-003.
Table 1.a
DLT Observed with MLN0128 (3 Days Per Week)+Weekly Paclitaxel in 
Study MLN0128-1004
Dose of Milled MLN0128+Weekly 
paclitaxel
Number of Evaluable 
Patients
DLTs Observed in Cycle 1
6 mg QD×3 QW
12
1 patient experienced DLT of fatigue, nausea, 
dehydration
4 mg QD×3 QW
6
None
While both dose levels were considered safe based on 3+3 rules, the lower dose level of 4 mg 
QD×3 QW+weekly paclitaxel was chosen as the recommended phase 2 dose (RP2D) of milled 
MLN0128 for further development.
1.4.2
Rationale for the Proposed Dose and Schedule in Arm C
The selected dose and schedule for Arm C of 30 mg MLN0128 once weekly (QW) is based on 
the findings from 2 studies: Study INK128-001 and Study MLN0128-1004.
Study INK128-001 was the first-in-human study of MLN0128. Study INK128-001 was an 
open-label study designed to determine the MTD and to identify DLTs for oral administration of 
single-agent unmilled MLN0128 and to characterize the safety and tolerability of escalating 
doses of MLN0128 in patients with advanced solid tumors. In this study, 116 patients with 
advanced solid tumors received single-agent MLN0128 (2–40 mg via 4 dosing schedules) in the 
dose escalation phase. 
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Doses of 40 mg QW, 30 mg QW, and 5 mg QD were further evaluated in an additional 
82 patients in the expansion phase.
Improved tolerability, including a reduced frequency of treatment-emergent adverse events 
(TEAEs) leading to dose interruptions and modifications, respectively (5 mg QD [26% and 67%] 
vs 30 mg QW [24% and 41%] vs 40 mg QW [19% and 77%] as of a data cut on 
09 December 2015), and longer duration of clinical benefit favored 30 mg QW dosing as a RP2D 
and schedule for further development. 
With the introduction of milled MLN0128, the recommended dose to be used in Arm C of this 
study (30 mg milled MLN0128 QW) was further confirmed in Study MLN0128-1004 
(Table 1.b). A total of 14 patients were enrolled and assigned, sequentially, to 2 QW dosing 
cohorts. PK, safety, and tolerability were assessed.
Table 1.b
DLT Observed with Weekly MLN0128 in Study MLN0128-1004
Dose of Milled MLN0128
Number of Evaluable 
Patients
DLTs Observed in Cycle 1
20 mg QW
6
None
30 mg QW
6
None
As none of the patients in either dose cohort experienced DLT in Cycle 1, a dose of 30 mg 
MLN0128 QW was selected for further development. No clinically meaningful differences in PK 
of MLN0128 were noted between the unmilled MLN0128 (Study INK128-001) and milled 
MLN0128 (Study MLN0128-1004) when given QW.
1.4.3
Rationale for the Proposed Dose and Schedule in Arm D
The dose and schedule selected for Arm D of 4 mg MLN0128+200 mg of MLN1117 (both 
QD×3 QW) is based on the results of Study C32001 conducted under IND #117,524. 
Study C32001 is an ongoing open-label study designed to determine the MTD and DLTs for oral 
administration of milled MLN0128 given in combination with MLN1117 and was designed to 
characterize the safety and tolerability of escalating doses of MLN0128 and/or MLN1117 in 
patients with advanced solid tumors. The study features a dose-escalation phase evaluating 
3 dosing schedules. A favorable tolerability profile was observed when increasing doses of 
MLN0128 (3–8 mg) were administered with a fixed dose of MLN1117 (both given QD×3 QW). 
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The MTD for MLN0128 in combination with MLN1117 both given QD×3 QW was 6 mg 
MLN0128+200 mg MLN1117.
Table 1.c
DLT Observed with MLN0128+MLN1117 (3 Days Per Week) in Study 
C32001
Dose of Milled 
MLN0128+MLN1117
Number of Evaluable 
Patients
DLTs Observed in Cycle 1
6 mg+200 mg QD×3 QW
6
1 patient experienced DLT of AST/ALT elevation
4 mg+200 mg QD×3 QW
8
None
AST=aspartate aminotransferase, ALT=alanine aminotransferase.
While both combination dose levels were considered safe based on 3+3 rules, the lower dose 
level of 4 mg+200 mg QD×3 QW was chosen as the RP2D for milled MLN0128+MLN1117 for 
further development.
1.4.4
Rationale for Fresh Tumor Biopsies to Study Adaptive Response
Tumors develop resistance to targeted therapies through various adaptive responses including 
upregulation of pro-survival signaling and activation of “bypass” signaling pathways.[38]
Identifying treatment-induced adaptive response mechanism(s) for a specific therapy has the 
potential to inform new combination strategies to counter drug resistance. For example, 
treatment-induced activation of the PI3K/mTOR pathway has been identified as a resistance 
mechanism for endocrine therapy in breast cancer. Such combination strategy has been tested in 
the clinic; combination of PI3K/mTOR inhibitor everolimus and endocrine therapy has been 
tested in clinical trials and shown to derive greater therapeutic benefit than endocrine therapy 
alone for patients with hormone-receptor positive breast cancer who were previously treated with 
endocrine therapy.[39,40]
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, blood creatinine increased, hyperglycemia, nausea, anorexia, and decreased appetite.
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Potential overlapping toxicities associated with MLN0128 and MLN1117, the identified and 
potential risks of both drugs, including data from nonclinical and clinical studies for each 
product, have been reviewed. More detailed information on the identified and potential risks of 
both drugs is included in the individual single-agent IBs. Class effects of mTOR inhibitors (for 
MLN0128) and PI3K inhibitors (for MLN1117) have also been considered. Potential 
overlapping toxicities for both agents include:

Dermatologic disorders (pruritus, rash).

Gastrointestinal disorders (diarrhea, mucosal inflammation, nausea, stomatitis, vomiting).

Generalized disorders (anorexia, asthenia, decreased appetite, fatigue).

Hematologic disorders (lymphoid, bone marrow depletion).

Metabolic disorders (decreased blood chloride, hypercholesterolemia, hyperglycemia).
On the basis of current clinical experience and the previous list of potential overlapping 
toxicities, hyperglycemia, diarrhea, nausea, vomiting, fatigue, and rash are the most anticipated 
TEAEs associated with the MLN0128+MLN1117 combination regimen. These events are 
expected to be manageable.
During this study, risk mitigation strategies include, but are not limited to, strict application of 
the study inclusion and exclusion criteria, frequent monitoring of clinical and laboratory results, 
guidelines for management and prophylaxis of potential toxicities, criteria for dose modification, 
and regular monitoring of TEAEs and serious adverse events (SAEs) by the sponsor. 
The benefits of MLN0128 and MLN0128+MLN1117 are discussed in Sections 1.2 and 1.3, 
respectively. 
Further details are presented in the current editions of the MLN0128, MLN0128+MLN1117, and 
MLN1117 IBs.
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2.
STUDY OBJECTIVES
2.1
Primary Objectives
The primary objective is:

To determine if MLN0128 in combination with weekly paclitaxel improves 
progression-free survival (PFS) compared to weekly paclitaxel alone.
2.2
Secondary Objectives
The secondary objectives are:

To determine if single-agent MLN0128 improves PFS compared to weekly paclitaxel 
alone.

To determine if MLN0128+MLN1117 improves PFS compared to weekly paclitaxel 
alone.

To assess the safety and tolerability of single-agent MLN0128, MLN0128 in combination 
with paclitaxel, and MLN0128+MLN1117.

To evaluate improvement in efficacy measures (endpoints other than PFS) of MLN0128 
in combination with weekly paclitaxel, single-agent MLN0128, and 
MLN0128+MLN1117 compared to weekly paclitaxel alone.

To collect plasma concentration-time data with sparse PK sampling to contribute to 
future population PK analysis.
2.3
Quality of Life Objective
The quality of life (QOL) objective is:

To assess the QOL and symptoms in patients treated with MLN0128 in combination with 
weekly paclitaxel, single-agent MLN0128, and MLN0128+MLN1117 to weekly 
paclitaxel alone.
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2.4
Exploratory Objectives
3.
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoint is:
!
PFS.
3.2
Secondary Endpoints
The secondary endpoints are:
!
The number and percentage of patients with TEAEs.
!
Overall survival (OS).
!
Time to progression (TTP).
!
Overall response rate (ORR) (complete response [CR]+PR).
!
Clinical benefit rate (CBR) (CR+PR+SD, SD of any duration).
!
CBR at 16 weeks (CBR-16 is defined as the proportion of patients who achieve CR or PR 
of any duration or have SD with a duration of at least 16 weeks).
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3.3
QOL Endpoints
The QOL endpoints are:
!
Change from Baseline in the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health 
status/QOL score to End-of-Study visit.
!
Change from Baseline in the EORTC QLQ-C30 functioning score to End-of-Study visit.
!
Change from Baseline in the EORTC QLQ-C30 symptom score to End-of-Study visit.
!
Change from Baseline in the European Organization for Research and Treatment of 
Cancer Quality of Life Questionnaire Endometrial Cancer Module (EORTC QLQ-EN24) 
score to the End-of-Study visit.
3.4
Exploratory Endpoints
The exploratory endpoints are:
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4.
STUDY DESIGN 
4.1
Overview of Study Design
This study is a phase 2, open-label, randomized, multicenter, 4-arm study of the safety and 
efficacy of MLN0128 in combination with paclitaxel, single-agent MLN0128, single-agent 
paclitaxel, and MLN0128 in combination with MLN1117 in adult women with advanced 
endometrial cancer. The patient population will consist of women with histologic or cytologic 
diagnosis of endometrial carcinoma (including endometrioid, serous, mixed adenocarcinoma, 
clear-cell carcinoma, or carcinosarcoma) that is advanced, recurrent, or persistent, that has
relapsed or is refractory to curative therapy or established treatments. Patients must have had 
1 prior platinum-based chemotherapeutic regimen but not more than 2 prior systemic 
chemotherapy regimens.
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. Study drug will be administered in 28-day 
treatment cycles.
Approximately 242 patients will be randomized at a ratio of 1:1:1:1 to receive study drug in one 
of 4 treatment arms:

Arm A: paclitaxel 80 mg/m2 weekly on Days 1, 8, and 15 of a 28-day cycle. For 
calculation of the paclitaxel dose, body surface area (BSA) is capped at 2.0 m2.

Arm B: paclitaxel 80 mg/m2 weekly on Days 1, 8, and 15 of a 28-day 
cycle+MLN0128 4 mg on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. For 
calculation of the paclitaxel dose, BSA is capped at 2.0 m2.

Arm C: MLN0128 30 mg QW on Days 1, 8, 15, and 22 of a 28-day cycle.

Arm D: MLN0128 4 mg+MLN1117 200 mg on Days 1-3, 8-10, 15-17, and 22-24 of a 
28-day cycle.
In the event that enrollment into a treatment arm(s) is closed, patients will be randomized 1:1 
into the remaining treatment arms. Paclitaxel will be administered IV while MLN0128 and 
MLN1117 will be administered PO throughout the study. Patients in Arm A and Arm B will 
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receive paclitaxel alone or paclitaxel+MLN0128 until they experience disease progression, 
unacceptable toxicity, or withdraw consent. Patients in Arm B who discontinue paclitaxel before 
disease progression may continue to receive MLN0128 alone until they experience disease 
progression, unacceptable toxicity, or withdraw consent. In addition, patients will receive 
MLN0128 (in Arm C) or MLN0128+MLN1117 (in Arm D) continuously until they experience 
disease progression, unacceptable toxicity, or withdraw consent. 
Patients will attend the EOT visit 30 to 40 days after receiving their last dose of study drug.
Sparse PK samples will be collected from patients enrolled in Arms B, C, and D for 
determination of the plasma concentration of MLN0128 and/or MLN1117 during Cycle 1 at 
prespecified time points as described in the Pharmacokinetic 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. For correlative biomarker analysis, fresh 
and archival tumor samples will be obtained during Screening, 
 
 at prespecified time points as described in the Schedule of Events. In addition, fresh 
tumor samples will be obtained 2 to 4 hours after dosing on Cycle 1 Day 22 from patients in 
Arms C and D to identify adaptive response mechanisms to treatment of MLN0128 or 
MLN0128+MLN1117.
Radiological tumor evaluations (computed tomography [CT] scan with contrast or 
contrast-enhanced 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).[41] Radiographic tumor evaluations 
will be performed at the time points specified in the Schedule of Events.
Changes in QOL disease-specific symptoms will be assessed using the EORTC QLQ-C30 and 
the EORTC QLQ-EN24. In addition to assessing selected symptoms, these instruments will 
measure the effects of disease and treatment on physical, role, emotional, cognitive, and social 
functioning.
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.[42]
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Adverse events (AEs) will be assessed, and laboratory values, vital signs, and electrocardiograms 
(ECGs) will be obtained to evaluate the safety and tolerability of MLN0128 in combination with 
paclitaxel, single-agent MLN0128, and MLN0128+MLN1117.
There will be 2 interim analyses with early stopping rules for futility in the single-agent 
MLN0128 arm (Arm C) and MLN0128+MLN1117 arm (Arm D).
4.2
Number of Patients
Approximately 242 patients will be randomized into this study from approximately 75 study 
centers in North America, Europe, and Asia-Pacific. A patient will be considered enrolled in the 
study when they have been randomized into a treatment arm.
4.3
Duration of Study
Patients in Arm A and Arm B will receive paclitaxel alone or paclitaxel+MLN0128 until they 
experience disease progression, unacceptable toxicity, or withdraw consent. Patients in Arm B 
who discontinue paclitaxel before disease progression may continue to receive MLN0128 alone 
until they experience disease progression, unacceptable toxicity, or withdraw consent. In 
addition, patients will receive MLN0128 (in Arm C) or MLN0128+MLN1117 (in Arm D) 
continuously until they experience disease progression, unacceptable toxicity, or withdraw 
consent. Patients will discontinue treatment if they have an unacceptable drug-related toxicity. 
The study will be closed approximately 5 months after the last patient is randomized, or when 
the last patient discontinues study treatment.
Patients will attend an EOT visit 30 to 40 days after receiving their last dose of study drug or 
before the start of subsequent anticancer therapy. Up until Amendment 06, after EOT, patients 
were to be followed for PFS and OS, during the Posttreatment follow-up period.
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5.
STUDY POPULATION
5.1
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Histologic or cytologic diagnosis of endometrial carcinoma (including endometrioid, 
serous, mixed adenocarcinoma, clear-cell carcinoma, or carcinosarcoma). 
2. Evidence that the endometrial cancer is advanced, recurrent, or persistent and has 
relapsed or is refractory to curative therapy or established treatments.
3. At least 1 prior platinum-based chemotherapeutic regimen, but not more than 2 prior 
chemotherapeutic regimens, for management of endometrial carcinoma. Prior treatment 
may include chemotherapy, chemotherapy/radiation therapy, and/or 
consolidation/maintenance therapy. Chemotherapy administered in conjunction with 
primary radiation as a radio-sensitized therapy will be considered a systemic 
chemotherapy regimen.
4. Measurable disease by RECIST 1.1, defined as at least 1 lesion that can be accurately 
measured in at least 1 dimension (longest diameter to be recorded). Each lesion must be 
≥10 mm in long axis when measured by CT, MRI, or caliper measurement by clinical 
exam. Lymph nodes must be ≥15 mm in short axis when measured by CT or MRI.
5. Tumor accessible and patient consents to undergo fresh tumor biopsies.
6. Female patients 18 years or older.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (refer to 
Section 14.1).
8. Female patients who:

Are postmenopausal for at least 1 year before the Screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method (see Section 14.2) at the 
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same time, from the time of signing the informed consent through 90 days (or longer, 
as mandated by local labeling [eg, United States Prescribing Information (USPI), 
Summary of Product Characteristics (SmPC), etc]) after the last dose of study drug, 
OR

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea 
are not acceptable methods of contraception. Female and male condoms should not be 
used together.)
9. Clinical laboratory values as specified below within 4 weeks before the first dose of study 
drug:

Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥1500/L; 
platelet count ≥100,000/L; glycosylated hemoglobin (HbA1c) <6.5%.

Total bilirubin must be 1.5 times the upper limit of the normal range (ULN).

ALT or AST must be 2.5ULN. AST and ALT may be elevated up to 5 times the 
ULN if their elevation can be reasonably ascribed to the presence of metastatic 
disease in liver.

Creatinine clearance ≥50 mL/min/1.73 m2 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.
10. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and 
suitable venous access for the study-required blood sampling.
11. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may be 
withdrawn by the patient at any time without prejudice to future medical care.
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5.2
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
1. Positive serum pregnancy test during the screening period or a positive urine pregnancy 
test on Day 1 before first dose of study drug. Women who are lactating and 
breastfeeding are not eligible.
2. Previous treatment with any weekly taxane regimen.
3. History of severe hypersensitivity reactions to paclitaxel or any of its excipients. 
4. Previous treatment with PI3K, AKT, dual PI3K/mTOR inhibitors, TORC1/2 inhibitors, 
or TORC1 inhibitors.
5. 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 study drug (patients 
already receiving erythropoietin on a chronic basis for ≥4 weeks are eligible).
6. Patients who are taking proton pump inhibitors (PPIs) within 7 days of the first dose of 
study drug or who require treatment with PPIs throughout the trial or those who are 
taking H2 receptor antagonists within 24 hours of the first dose of study drug.
7. A prothrombin time (PT) or activated partial thromboplastin time (aPTT) above the 
ULN or a history of a coagulopathy or bleeding disorder.
8. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C 
infection.
9. Sensory or motor neuropathy ≥Grade 2.
10. Central nervous system (CNS) metastasis, endometrial leiomyosarcoma, or endometrial 
stromal sarcoma.
11. Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal
disease, or for some other reason that may alter the absorption of MLN0128 or 
MLN1117. In addition, patients with enteric stomata are also excluded.
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12. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active CNS disease, active infection, or any other condition that could compromise 
participation of the patient in the study.
13. Known human immunodeficiency virus infection.
14. History of any of the following within the last 6 months before administration of the 
first dose of study drug:

Ischemic myocardial event, including angina requiring therapy and artery 
revascularization procedures.

Ischemic cerebrovascular event, including transient ischemic attack and artery 
revascularization procedures.

Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) 
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or 
ventricular tachycardia).

Placement of a pacemaker for control of rhythm.

New York Heart Association Class III or IV heart failure (see Section 14.4).

Pulmonary embolism.
15. Significant active cardiovascular or pulmonary disease before administration of the first 
dose of study drug, including:

Uncontrolled hypertension (ie, either systolic blood pressure >180 mm Hg or 
diastolic blood pressure >95 mm Hg).

Pulmonary hypertension.

Uncontrolled asthma or oxygen saturation <90% by arterial blood gas analysis or 
pulse oximetry on room air.

Significant valvular disease; severe regurgitation or stenosis by imaging independent 
of symptom control with medical intervention; or history of valve replacement.
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
Medically significant (symptomatic) bradycardia.

History of arrhythmia requiring an implantable cardiac defibrillator.

Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated 
demonstration of QTc interval >480 msec, or history of congenital long QT 
syndrome, or torsades de pointes).
16. Diagnosed or treated for another malignancy within 2 years before administration of the 
first dose of study drug or previously diagnosed with another malignancy and have any
evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in 
situ of any type are not excluded if they have undergone complete resection.
17. Patients with endometrioid histology and histologically confirmed expression of ERs 
and/or progesterone receptors who have not received prior endocrine therapy and for 
whom endocrine therapy is currently indicated.
6.
STUDY DRUG
6.1
Study Drug Administration
All protocol-specific criteria for administration of MLN0128 or MLN1117 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 Arms B and D, MLN0128 and MLN1117 will be administered on an empty stomach. 
Patients should be instructed to refrain from eating and drinking (except for water and prescribed 
medications) for 2 hours before and 1 hour after each dose. Each dose of MLN0128 and 
MLN1117 will be taken orally with 8 ounces (240 mL) of water.
For Arm C, weekly MLN0128 will be administered with a light meal. Examples of a light meal 
are provided in Table 6.a. Patients should begin consuming the light meal no more than 
30 minutes before taking the weekly dose of MLN0128. It is recommended that each dose of 
MLN0128 be given PO with 8 ounces (240 mL) of water.
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Table 6.a
Examples of a Light Meal
Low-Fat Breakfast
Light Snack
Nutritional information
Approximately 330 calories, with 9 g 
of fat
Approximately 100-300 calories, with 1.5 g of 
fat
Example
2 slices of toast with 1 teaspoon of 
low-fat margarine, 1 teaspoon of jelly, 
and 8 oz of skimmed milk
3.63 oz pudding cup or 1 slice of toast with 
1 teaspoon of jelly and 8 oz of skimmed milk
Cycles consist of 28 days for all treatment arms. In Treatment Arm A, paclitaxel will be 
administered QW for 3 consecutive weeks (on Days 1, 8, and 15 of a 28-day treatment cycle). In 
Treatment Arm B, paclitaxel will be administered QW for 3 consecutive weeks (on Days 1, 8, 
and 15 of a 28-day treatment cycle) and MLN0128 will be administered 3 days per week (on 
Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle). In Treatment Arm C, MLN0128 will be 
administered QW (on Days 1, 8, 15, and 22 of a 28-day treatment cycle). In Treatment Arm D, 
MLN0128 and MLN1117 will be administered together, 3 days per week (on Days 1-3, 8-10, 
15-17, and 22-24 of a 28-day treatment cycle).
Paclitaxel will be administered IV per its package insert or SmPC.[43,44] For calculating the 
appropriate dose of paclitaxel, BSA should be capped at 2.0 m2 for all patients receiving 
paclitaxel in Arm A or Arm B.
Patients should be instructed to take their study medication at approximately the same time on 
each scheduled dosing day and not to take more than the prescribed dose at any time. MLN0128 
and MLN1117 should always be taken together, at the same time, when dosed on the same day. 
Patients should swallow the study medication whole and not chew it, open it, or manipulate it in 
any way before swallowing. If a patient does not take their MLN0128 and/or MLN1117 doses 
within 12 hours after the scheduled dosing time (for patients in Arm B or Arm D) or within 
24 hours after the scheduled dosing time (for patients in Arm C), then the dose should be skipped 
and considered a missed dose. Patients should record any missed doses in their diary (see the 
Study Manual) and resume drug administration at the next scheduled time with the prescribed 
dosage.
If severe emesis or mucositis prevents the patient from taking an MLN0128 or MLN1117 dose, 
that dose will be skipped. If emesis occurs within 6 hours after study medication ingestion, the 
dose should be counted as missed and will not be re-administered, and patients should simply 
adhere to the dosing schedule and resume dosing at the next scheduled time with the prescribed 
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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.
6.2
Dose Modification Guidelines
The investigator should try to the best of his/her ability to assess whether an AE is possibly 
related to study drug, and, if so, attribute it to paclitaxel only, MLN0128 only, MLN0128 and 
paclitaxel, or MLN0128 and MLN1117 and treat the subject accordingly. This section and 
Table 6.b provide suggested guidelines for the management of various study drug-related 
toxicities in subjects receiving paclitaxel and MLN0128.
In general, dose modification guidelines when managing hematologic or nonhematologic 
toxicities are intended for use in a similar manner for patients enrolled in all treatment arms. 
Recommendations are to be applied to patients as appropriate to their treatment assignment and 
symptoms.
All patients who continue to experience any toxicity (hematologic or nonhematologic) of a 
severity that requires either >3 dose reductions of MLN0128 or >2 dose reductions of paclitaxel, 
given administration of appropriate supportive care, should discontinue protocol treatment. 
However, if the patient has evidence of clinical benefit and is considered to possibly benefit from 
continued protocol treatment, the patient may continue protocol treatment with further dose 
reductions, upon review by the project clinician. These circumstances should be discussed on a 
case-by-case basis. As a general rule, if a patient requires dose reduction because of a study 
drug-related toxicity, the drug dose may not be re-escalated.
To manage hematologic or nonhematologic toxicities that require dose reductions, the dose 
modifications planned for this protocol will include the following:
Paclitaxel. Paclitaxel dosing may be withheld for ≥Grade 2 paclitaxel-related toxicities and 
resumed at the same dose or at a 20 mg/m2 dose reduction (25% of starting dose) depending on 
the timing of recovery and number of episodes occurred (see Table 6.b). If paclitaxel dosing is 
delayed due to paclitaxel-related toxicities for >21 consecutive days despite supportive treatment 
per standard clinical practice or more than 2 dose reductions of paclitaxel (≤40 mg/m2) are 
required, paclitaxel therapy should be stopped. Please refer to Table 6.b for detailed information 
on paclitaxel dose reduction/delay for specific AEs.
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MLN0128: In general, MLN0128 dosing should be withheld for ≥Grade 3 MLN0128-related 
nonhematologic toxicities. Table 6.b provides suggested guidelines for the investigator to use 
along with his/her best judgment for MLN0128 and/or paclitaxel dose delay and/or reduction 
based on the AE observed. If MLN0128 dosing is delayed because of MLN0128-related 
toxicities for >21 consecutive days despite supportive treatment per standard clinical practice or 
if >3 MLN0128 dose reductions are required, stop MLN0128 (and paclitaxel therapy, if 
applicable), discontinue the subject from the study, and complete the EOT visit within 30 to 
40 days of the last administration of MLN0128 or paclitaxel, whichever is discontinued last.
The decision regarding which study drug requires dose reduction will depend on the toxicity, its 
onset and time course, the investigator’s judgment, and the actual treatment assignment of the 
patient. For example, hematologic toxicities and neuropathy have been related to paclitaxel but 
have not been a frequent or dominant toxicity associated with MLN0128. The dose of paclitaxel 
alone should be adjusted for hematologic toxicities or nonhematologic toxicities such as 
neuropathy, and the dose of MLN0128 should be reduced for nonhematologic toxicities more 
clearly attributed to MLN0128 (such as stomatitis, fatigue, hyperglycemia, and rash) that are not 
due to other comorbidities.
For the paclitaxel+MLN0128 treatment arm (Arm B), as a general approach to manage 
taxane-related hematologic toxicities, paclitaxel should be reduced first (or delayed) before 
modification of MLN0128. To manage neutropenia attributable to paclitaxel or to the 
combination with MLN0128, the general goals include avoiding a reduction of the MLN0128 
dose below a clinically relevant range. Given these considerations, the first intervention will be 
dose reduction of paclitaxel to 60 mg/m2 (depending on the timing of recovery and number of 
episodes occurred). The next intervention would be to add myeloid growth factor, if appropriate. 
Only after interventions that include myeloid growth factor for hematological toxicity, if 
appropriate, would the paclitaxel dose be reduced a second time, to 40 mg/m2.
Myeloid growth factors are not allowed to be used in Cycle 1 but may be administered per 
investigator discretion for supportive care to manage neutropenia events if clinically indicated. In 
such cases, the American Society of Clinical Oncology Guidelines and/or institutional practices 
and the product label should be followed. Thus, the use of myeloid growth factors as prophylaxis 
is not mandated, but as indicated in Table 6.b, is strongly encouraged if appropriate as an 
intervention step at the repeat occurrence of neutropenia requiring dose modification. Short-
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acting myeloid growth factors are preferred, and they should be discontinued for an appropriate 
number of days before restarting protocol treatment (Table 6.b).
For patients in the single-agent MLN0128 arm (Arm C), up to 3 dose reductions may be applied 
as shown in Table 6.c.
MLN0128+MLN1117: The primary principle for dose reduction in the MLN0128+MLN1117 
arm of the study (Arm D) is to maintain the 200 mg dose of MLN1117, which is considered a 
minimally efficacious dose in the combination of MLN0128+MLN1117. Thus, the dose of 
MLN0128 will be reduced if necessary while the dose and schedule of MLN1117 is maintained 
when study drug administration is resumed (Table 6.c). 
If the Grade 3 or greater event that led to dose interruption resolves to Grade 1 or baseline value 
within 3 weeks of interrupting treatment, then the patient may resume combination study 
treatment if treatment with study drug is thought to be beneficial for the patient by the 
investigator and with the sponsor’s approval. In this case, the patient may resume study treatment 
with MLN1117 at 200 mg QD3 days and MLN0128 reduced by 1 dose level.
Table 6.b
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
AE
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
ANC
Grade 2
(<1500 -
1000/mm3) 
No change: Continue MLN0128 at same 
dose and schedule.

Paclitaxel should not be given to patients who 
have neutrophil counts of <1500 cells/mm3 on 
Day 1 of a 28-day treatment cycle.

Repeat treatment with paclitaxel on Day 8 or 
Day 15 of a 28-day treatment cycle should be 
given only if the neutrophil count is 
≥1000 cells/mm3.

If the use of prophylactic myeloid growth 
factors (ie, GCSF) is considered, GCSF is 
preferred over peg-filgrastim because of the 
weekly dosing of paclitaxel in this study.

Growth factor should not be given on the same 
day as paclitaxel infusion. Growth factor 
should not be used in the period from 24 hours 
before through 24 hours after the 
administration of paclitaxel.
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Table 6.b
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
AE
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
Grade 3
(<1000 
500/mm3) 
No change: Continue MLN0128 at same 
dose and schedule.
Consider use of prophylactic myeloid growth 
factor support per guidelines above.
Hold paclitaxel until ANC ≥1000/mm3
Resume paclitaxel based on timing of recovery and 
number of previous episodes:

≤2 weeks of interrupting planned therapy
o First episode: no change to paclitaxel dose.
o ≥Second episode: reduce paclitaxel dose 
by 25% from starting dose (60 mg/m2) for 
all subsequent cycles.

>2 weeks of interrupting planned therapy: stop 
paclitaxel and discontinue subject from study.
Consider use of prophylactic myeloid growth factor 
support per guidelines above.
Grade 4
(<500/mm3)
Hold MLN0128 until ANC >1000/mm3
Resume MLN0128 based on timing of 
recovery:

≤1 week: no change to MLN0128 dose.

>1 but ≤2 weeks: reduce MLN0128 to 
the next lower dose level for all 
subsequent cycles.

>2 weeks: stop MLN0128 and 
discontinue subject from study.
Consider use of prophylactic myeloid growth 
factor support per guidelines above.
Hold paclitaxel until ANC ≥1000/mm3
Resume paclitaxel based on timing of recovery and 
number of previous episodes: 

≤2 weeks of interrupting planned therapy.
o First episode: no change to paclitaxel dose.
o ≥Second episode: reduce paclitaxel dose 
by 25% from starting dose (60 mg/m2) for 
all subsequent cycles.

>2 weeks of interrupting planned therapy: stop 
paclitaxel and discontinue subject from study.
Consider use of prophylactic myeloid growth factor 
support per guidelines above.
Thrombocytopenia
Grade 1
(≥75,000/mm3) 
No change: Continue MLN0128 at same 
dose and schedule.
No change: Continue paclitaxel at same dose and 
schedule.
Grade 2
(50,000–
74,999/mm3)
No change: Continue MLN0128 at same 
dose and schedule.
Hold paclitaxel until platelets >75,000/mm3
Resume paclitaxel based on timing of recovery 
within 2 weeks of interrupting planned therapy:

≤1 week: no change to paclitaxel.

>1 but ≤2 weeks of interrupting planned 
therapy: reduce paclitaxel by 25% from 
starting dose (60 mg/m2) for all subsequent 
cycles.

>2 weeks of interrupting planned therapy: stop 
paclitaxel and discontinue subject from study.
Grade 3
(25,000–
44,999/mm3)
Hold MLN0128 until platelets >75,000/mm3
Resume MLN0128 based on timing of 
recovery within 2 weeks:

≤1 week: no change to MLN0128 dose.

>1 but ≤2 weeks: reduce MLN0128 
dose to the next lower dose level for all 
Hold paclitaxel until platelets >75,000/mm3.
Resume paclitaxel based on timing of recovery 
within 2 weeks of interrupting planned therapy:

≤1 week: no change to paclitaxel.

>1 but ≤2 weeks of interrupting planned 
therapy: reduce paclitaxel dose by 25% from 
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Table 6.b
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
AE
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
subsequent cycles. 

>2 weeks: stop MLN0128 and 
discontinue subject from study.
Platelet transfusions in the absence of 
bleeding should not be administered.
starting dose (60 mg/m2) for all subsequent 
cycles. 

>2 weeks of interrupting planned therapy: stop 
paclitaxel and discontinue subject from study.
Platelet transfusions in the absence of bleeding 
should not be administered.
Grade 4
(<25,000/mm3) 
Hold MLN0128 until platelets ≥75,000/mm3
Resume MLN0128 according to the number 
of episodes that are resolved to Grade ≤1 or 
baseline values within 2 weeks:

First episode: resume MLN0128 at same
dose and schedule.

Second episode: reduce MLN0128 dose 
to the next lower dose level for all 
subsequent cycles.

Third episode: reduce MLN0128 dose to 
the next lower dose level from the first 
reduced dose for all subsequent cycles.

Fourth episode: stop MLN0128 and 
discontinue subject from study. 
Platelet transfusions should be administered 
prophylactically if platelets ≤10,000/mm3 or 
as clinically indicated if there is bleeding.
Hold paclitaxel until platelets ≥75,000/mm3
Resume paclitaxel according to the number of 
episodes that are resolved to Grade ≤1 or baseline 
values within 2 weeks:

First episode: reduce paclitaxel by 25% from 
starting dose (60 mg/m2) for all subsequent 
cycles.

Second episode: resume paclitaxel at the 
reduced dose (60 mg/m2) for all subsequent 
cycles.

Third episode: reduce paclitaxel by 50% from 
starting dose (40 mg/m2) for all subsequent 
cycles.

Fourth episode: stop paclitaxel and discontinue 
subject from study.
Platelet transfusions should be administered 
prophylactically if platelets ≤10,000/mm3 or as 
clinically indicated if there is bleeding.
Hepatic 
Grade 1
No change: Continue MLN0128 at the same 
dose and schedule.
No change: Continue paclitaxel at the same dose 
and schedule.
Grade 2
Hold MLN0128 until LFTs improve to 
≤Grade 1 or baseline values within 2 weeks.
Resume MLN0128 based on timing of 
recovery:

≤1 week: no change to MLN0128 dose.

>1 but ≤2 weeks: reduce MLN0128 
dose to the next lower dose level for all 
subsequent cycles.

>2 weeks: stop MLN0128 and 
discontinue subject from study.
A rise in indirect bilirubin with a normal 
direct bilirubin believed to be attributable to 
Gilbert’s disease does not require a change 
or hold in MLN0128 dosing. Gilbert’s 
disease should be documented in the 
subject’s medical history CRF page. 
Hold paclitaxel until LFTs improve to ≤Grade 1 or 
baseline values within 2 weeks of interrupting 
planned therapy.
Resume paclitaxel based on time of recovery:

≤1 week: no change to paclitaxel dose.

>1 but ≤2 weeks of interrupting planned 
therapy: reduce paclitaxel dose by 25% from 
starting dose (60 mg/m2) for all subsequent 
cycles.

>2 weeks of interrupting planned therapy: stop 
paclitaxel and discontinue subject from study.
A rise in indirect bilirubin with a normal direct 
bilirubin believed to be attributable to Gilbert’s 
disease does not require a change or hold in 
MLN0128 dosing. Gilbert’s disease should be 
documented in the subject’s medical history CRF 
page.
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Table 6.b
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
AE
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
Grade ≥3
Hold MLN0128 until LFTs improve to 
≤Grade 1 or baseline values within 2 weeks.
Resume MLN0128 according to the number 
of episodes that are resolved to ≤Grade 1 or 
baseline values:

First episode: resume MLN0128 at the 
same dose and schedule.

Second episode: reduce MLN0128 dose 
to the next lower dose level for all 
subsequent cycles.

Third episode: reduce MLN0128 dose to 
the next lower dose level from the 
reduced dose for all subsequent cycles.

Fourth episode: stop MLN0128 and 
discontinue subject from study.
Hold paclitaxel until LFTs improve to ≤Grade 1 or 
baseline values within 2 weeks of interrupting 
planned therapy.
Resume paclitaxel according to the number of 
episodes that are resolved to ≤Grade 1 or baseline:

First episode: reduce paclitaxel dose by 25% 
(60 mg/m2) from starting dose for all 
subsequent cycles.

Second episode: resume paclitaxel at the 
reduced dose (60 mg/m2) for all subsequent 
cycles.

Third episode: reduce paclitaxel dose by 50% 
(40 mg/m2) from starting dose for all 
subsequent cycles.

Fourth episode: stop paclitaxel and discontinue 
subject from study.
Renal (Creatinine)
Grade 1
(>ULN-1.5×ULN 
or 
>1-1.5×baseline)
No change: Continue MLN0128 at same 
dose and schedule. Rule out prerenal 
azotemia and consider IV hydration.
Collect the following tests to help identify 
cause of renal dysfunction:

Chemistry.

Urinalysis.

12-hour urine collection. 

Spot urine for electrolytes, protein, and 
creatinine.
No change: Continue paclitaxel at same dose and 
schedule. Rule out prerenal azotemia and consider 
IV hydration.
Collect the following tests to help identify cause of 
renal dysfunction:

Chemistry.

Urinalysis.

12-hour urine collection.

Spot urine for electrolytes, protein, and 
creatinine.
Grade 2 
(>1.5-3×ULN or 
>1.5-3.0×baseline)
Hold MLN0128 until creatinine improves to 
Grade 1 or baseline values in ≤2 weeks.
Collect the following tests to help identify 
cause of renal dysfunction:

Chemistry.

Urinalysis.

12-hour urine collection. 

Spot urine for electrolytes, protein, and 
creatinine.
Consider IV hydration.
Resume MLN0128 based on timing of 
recovery:

≤1 week: no change to MLN0128 dose.

>1 but ≤2 weeks: reduce MLN0128 to 
the next lower dose for all subsequent 
cycles. 
Hold paclitaxel until creatinine improves to 
Grade 1 or baseline values in ≤2 weeks of 
interrupting planned therapy.
Collect the following tests to help identify cause of 
renal dysfunction:

Chemistry.

Urinalysis.

12-hour urine collection.

Spot urine for electrolytes, protein, and 
creatinine.
Consider IV hydration.

Resume paclitaxel at the same dose and 
schedule.
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Table 6.b
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
AE
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay

>2 weeks: stop MLN0128 and 
discontinue patient from study.
≥Grade 3 
(>3-6×ULN/ 
>3 baseline or 
>6×ULN)
Hold MLN0128 until creatinine improves to 
≤Grade 1 or baseline values in ≤2 weeks.
Collect the following tests to help identify 
cause of renal dysfunction:
Chemistry.
Urinalysis.
12-hour urine collection.
Spot urine for electrolytes, protein, and 
creatinine.
Consider IV hydration.
Resume MLN0128 based on timing of 
recovery:
≤1 week: no change to MLN0128 dose.
>1 but ≤2 weeks: reduce MLN0128 to 
the next lower dose for all subsequent 
cycles. 
>2 weeks: stop MLN0128 and 
discontinue patient from study.
Hold paclitaxel until creatinine improves to ≤Grade 
1 or baseline values ≤2 weeks of interrupting 
planned therapy.
Collect the following tests to help identify cause of 
renal dysfunction:

Chemistry.

Urinalysis.

12-hour urine collection.

Spot urine for electrolytes, protein, and 
creatinine.
Consider IV hydration.
Resume paclitaxel based on timing of recovery:

≤1 week: no change to paclitaxel dose.

>1 but ≤2 weeks of interrupting planned 
therapy: reduce paclitaxel dose by 25% from 
starting dose (60 mg/m2) for all subsequent 
cycles. 

>2 weeks of interrupting planned therapy: stop 
paclitaxel and discontinue patient from study.
Peripheral Neuropathy
Grade 2
No change: Continue MLN0128 at same 
dose and schedule.
No change: Continue paclitaxel at same dose and 
schedule.
≥Grade 3
Continue MLN0128 during the first week 
when paclitaxel treatment is interrupted.

If peripheral neuropathy does not 
improve to ≤Grade 2 after 1 week of 
paclitaxel treatment interruption, hold 
MLN0128 for 1 week.

Resume MLN0128 at the next lower 
dose if the event recovers to ≤Grade 2 
after 1 week of MLN0128 interruption 
(2 weeks of paclitaxel interruption).

Stop MLN0128 if the event does not 
recover to ≤Grade 2 after 1 week of
MLN0128 interruption (2 weeks of 
paclitaxel interruption). 
Hold planned paclitaxel for 1 week to see if 
peripheral neuropathy improves to ≤Grade 2.

Reduce paclitaxel dose by 25% from starting 
dose (60 mg/m2) for all subsequent cycles if 
peripheral neuropathy improves to ≤Grade 2 
after 1 week of paclitaxel planned treatment 
interruption.

If peripheral neuropathy does not improve to 
Grade 2 after 1 week of planned paclitaxel 
treatment interruption, continue to hold 
paclitaxel treatment while MLN0128 treatment 
is held.

Resume paclitaxel at 25% dose reduction from 
starting dose (60 mg/m2) for all subsequent 
cycles if event recovers to Grade 2 after 
2 weeks of paclitaxel interruption (1 week of 
MLN0128 interruption).

Stop paclitaxel if the event does not recover to 
≤Grade 2 after 2 weeks of planned paclitaxel 
treatment interruption (1 week of MLN0128 
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Table 6.b
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
AE
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
interruption).
Hyperglycemia
≤Grade 2
(ULN-250 mg/dL)
Continue MLN0128 at same dose and 
schedule. Refer to Section 6.6.1 for 
guidelines on hyperglycemia management.
Continue paclitaxel at same dose and schedule. 
Refer to Section 6.6.1 for guidelines on 
hyperglycemia management.
Grade 3
(>250 mg/dL)
Hold MLN0128 until hyperglycemia 
improves to Grade ≤2. Refer to Section 6.6.1
for guidelines on hyperglycemia 
management.
Optimize hyperglycemia therapy and resume 
MLN0128 based on timing of recovery: 

1 week: resume MLN0128 at same 
dose and schedule.

>1 but 2 weeks: reduce MLN0128 to 
the next lower dose.

>2 weeks: stop MLN0128 and 
discontinue patient from study.
Continue paclitaxel at same dose and schedule. 
Refer to Section 6.6.1 for guidelines on 
hyperglycemia management.
Rash
Grade 2
Continue MLN0128 at same dose and 
schedule. Consider treatment with topical 
steroid cream/ointment and/or oral 
antihistamines.
Continue paclitaxel at same dose and schedule. 
Consider treatment with topical steroid 
cream/ointment and/or oral antihistamines.
Grade 3
Hold MLN0128 until rash improves to Grade 
≤2. Consider treatment with topical steroid 
cream/ointment, oral antihistamines, and/or 
oral pulse steroids. Refer to Section 6.6.4 for 
guidelines on management of rash.
Resume MLN0128 based on timing of 
recovery:

2 weeks: reduce MLN0128 to the next 
lower dose level.

>2 weeks: stop MLN0128 and paclitaxel 
and discontinue patient from study.
Continue paclitaxel at same dose and schedule. 
Consider treatment with topical steroid 
cream/ointment, oral antihistamines, and/or oral 
pulse steroids.
CRF=case report form, GCSF=granulocyte colony stimulating factor, LFT=liver function test.
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Table 6.c
Dose Reduction Schedule for MLN0128 and MLN1117
Dose Level
Dose
MLN0128 Capsules: Number and Strength
MLN0128
MLN1117
For MLN0128 4 mg QD×3 treatment arm (Arm B) only
0
4 mg QD×3
-
One 3 mg capsule and one 1 mg capsule
-1
3 mg QD×3
-
One 3 mg capsules
-2
2 mg QD×3
-
Two 1 mg capsules
-3
1 mg QD×3
-
One 1 mg capsule
For MLN0128 30 mg QW treatment arm (Arm C) only
0
30 mg QW
-
Six 5 mg capsules
-1
20 mg QW
-
Four 5 mg capsules
-2
15 mg QW
-
Three 5 mg capsules
-3
10 mg QW
Two 5 mg capsules
For MLN0128 4 mg QD×3+MLN1117 200 mg treatment arm (Arm D) only
0
4 mg QD×3
200 mg
One 3 mg capsule and one 1 mg capsule
-1
3 mg QD×3
200 mg
One 3 mg capsules
-2
2 mg QD×3
200 mg
Two 1 mg capsules
-3
1 mg QD×3
200 mg
One 1 mg capsule
6.3
Excluded Concomitant Medications and Procedures
All prescription and over-the-counter medications, including influenza vaccines, taken by a 
patient as of the first study drug administration through 30 days from the last dose will be 
recorded on the designated CRF.
6.3.1
Excluded Concomitant Medications for all Patients 
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). Palliative therapy for target 
lesions is not allowed.
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6.3.2
Excluded Concomitant Medications for MLN0128 Single-Agent and 
Combination Treatment Arms (Arms B, C, and D)
The following medications/therapies are prohibited during the study:

Systemic corticosteroids (either IV or oral steroids, excluding inhalers), unless necessary 
for treatment of an MLN0128-related AE (eg, rash). Premedication with dexamethasone 
before paclitaxel administration in this study is allowed. Use of low-dose glucocorticoids 
for replacement therapy is also allowed.

Strong and moderate cytochrome P450 (CYP) 1A2 inhibitors, strong CYP3A4 inhibitors, 
and clinically significant CYP1A2 and CYP3A4 inducers should be administered with 
caution and at the discretion of the investigator (see Section 14.5 for a list of these 
agents). Alternative treatments, if available, should be considered.

Concomitant administration of any PPI is not permitted during the study. Patients 
receiving PPI therapy before randomization must stop using the PPI for 7 days before 
their first dose of MLN0128. Examples of PPIs include omeprazole, esomeprazole, 
pantoprazole, lansoprazole, and rabeprazole.

Histamine H2 receptor antagonists are 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 14.5).

Administration of neutralizing antacids and calcium preparations is permitted except 
from 4 hours before until 2 hours after MLN0128 or MLN0128+MLN1117 
administration. Some antigas preparations may also have antacid properties and should 
also not be permitted from 4 hours before until 2 hours after study drug administration.
6.3.3
Potential Drug-Drug Interactions in Arm D (MLN0128+MLN1117)
On the basis of in vitro drug metabolism studies, MLN1117 is primarily metabolized by 
CYP3A4 (72%), with minor contributions from CYPs 1A2 (12%), 2C9 (9%), and 2C8 (6%). 
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Recently completed in vitro metabolism experiments in human hepatocytes using 14C-labeled 
MLN0128 suggest that MLN0128 is metabolized primarily via CYP1A2 (approximately 31%-
40%), with a minor contribution from CYP3A4 (approximately 11%-22%). These data suggest 
that MLN0128 is also metabolized by direct glucuronidation (approximately 22%) and an 
unidentified 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. 
Neither MLN1117 nor MLN0128 inhibits or induces any of the major CYP enzymes. On the 
basis of this information, the risk of a drug-drug interaction between MLN1117 and MLN0128 is 
considered to be low. In addition, physiologically based PK modeling and simulation using the 
new metabolism data for MLN0128 suggest that the risk for a metabolism-based drug-drug 
interaction with MLN0128 appears to be low. Therefore, strong CYP1A2 inhibitors and CYP 
inducers (Section 14.5) should be administered with caution and at the discretion of the 
investigator during the study.
There is potential for MLN1117 to affect the PK of breast cancer resistance protein (BCRP) 
substrates (eg, methotrexate, imatinib, topotecan, lapatinib, rosuvastatin, etc) and organic cation 
transporter protein (OCT) 1 or OCT2 substrates (eg, metformin, cimetidine amantadine, 
famotidine, pindolol, etc; see Section 14.6). If patients require treatment with medications that 
are known substrates of these transporters, then these agents should be administered with caution 
or alternative treatment options should be considered. It is recommended that patients requiring 
metformin for treatment of hyperglycemia resulting from MLN0128+MLN1117 administration 
should begin treatment with the lowest effective dose of metformin and have their blood or 
serum glucose closely monitored.
6.4
Permitted Concomitant Medications and Procedures 
Prophylactic use of antiemetic, antinausea, and antidiarrheal medications is encouraged, and 
these may be administered before the first dose and subsequent doses of study drug, as needed 
throughout the study, and as clinically indicated per standard practice.
Other medications considered necessary for the safety and wellbeing of the patient may be 
administered at the discretion of the investigator. Any concomitant medications added or 
discontinued during the study should be recorded on the electronic case report form (eCRF).
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6.5
Precautions and Restrictions
6.5.1
All Treatment Arms
The use of live vaccines and close contact with those who have received live vaccines should be 
avoided during treatment with study drug. Examples of live vaccines are: intranasal influenza, 
measles, mumps, rubella, oral polio, Bacille Calmette-Guerin, yellow fever, varicella, and TY21a 
typhoid vaccines.
No dietary restrictions will be imposed on study patients (refer to Section 6.3). Patients are 
required to fast for glucose monitoring (refer to Section 7.4.14 and Section 0). Patients receiving 
MLN0128 in Arms B or D should refrain from eating or drinking for 2 hours before and 1 hour 
after each dose (per Section 6.1).
Patients who show evidence of hyperglycemia during the study should be encouraged to follow a 
low-carbohydrate diet.
Patients should be encouraged to drink at least 20 ounces of fluids a day, especially on days 
requiring fasting (per protocol), with administration of IV fluids in the clinic as indicated to 
avoid dehydration.
It is not known what effects MLN0128 or MLN1117 has on human pregnancy or development of 
the embryo or fetus. Therefore, patients participating in this study should avoid becoming 
pregnant. Nonsterilized patients of reproductive age group should use effective methods of 
contraception through defined periods during and after study treatment as specified below.
Patients must meet one of the following:

Postmenopausal for at least 1 year before the Screening visit, OR

Surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception (see Section 14.2), at the same 
time, from the time of signing of the informed consent form (ICF) through 90 days (or 
longer, as mandated by local labeling [eg, USPI, SmPC, etc]) after the last dose of study 
drug, OR
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
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
6.5.2
Paclitaxel (Arm A) and Paclitaxel+MLN0128 (Arm B) Treatment Arms Only
Anaphylaxis and severe hypersensitivity reactions characterized by dyspnea and hypotension 
requiring treatment, angioedema, and generalized urticaria have occurred in 2% to 4% of patients 
receiving paclitaxel in clinical trials. Fatal reactions have occurred in patients despite 
premedication. Premedication to prevent hypersensitivity reactions to paclitaxel should be 
administered per standard practice guidelines and the current paclitaxel USPI or SmPC. Patients 
who experience severe hypersensitivity reactions to paclitaxel should not be rechallenged with 
the drug.
To monitor the occurrence of bone marrow suppression in patients receiving 
paclitaxelprimarily neutropenia, which may be severe and result in infectionit is 
recommended that frequent peripheral blood cell counts be performed on all patients receiving 
paclitaxel. Patients should not be retreated with subsequent cycles unless neutrophils are 
>1500 cells/mm3 and platelets are >100,000 cells/mm3.
Please refer to the most recent paclitaxel USPI or SmPC for additional information on 
precautions and restrictions associated with paclitaxel administration.
6.6
Management of Clinical Events
6.6.1
Management of Hyperglycemia
Fasting serum glucose levels will be obtained at the clinic visits as outlined in the Schedule of 
Events. To aggressively manage the hyperglycemia per standard clinical practice, the following 
guidelines (Table 6.d) are provided to aid the investigator in initiating antiglycemic therapies.
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Table 6.d
Management of Hyperglycemia
Grade
Description
Treatment
Study Drug Dose Modification
1
FBG >ULN-160 mg/dL Continue close monitoring of 
blood glucose. Initiate an 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(s) (a) until Grade 2.
Resume study drug(s) based on timing of 
recovery:

1 week: resume at same dose and 
schedule.

>1 but 2 weeks: reduce the dose of 
MLN0128 to the next lower dose (see 
Section 6.2). (b)

>2 weeks: stop study drug.
Prevention/Prophylaxis

Follow fasting serum glucose levels during clinic visits.

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.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117 (Arm D), 
then both agents should be held.
(b) As described in Section 6.2, dose reduction applies only to MLN0128 treatment. The dose of MLN1117 should 
be maintained at 200 mg when resuming treatment after an interruption of study drug or dose modification of 
MLN0128.
If any fasting serum glucose reading performed at the site indicates hyperglycemia (>ULN or 
≥110 mg/dL), the study staff should first confirm that the patient was fasting at the time of the 
blood draw (ie, nothing by mouth for at least 8 hours before). 
On the basis of the clinical experience in MLN0128 trials, most episodes of hyperglycemia 
observed occurred within the first 60 days after initiation of treatment with MLN0128, 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 
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develop Grade 1 hyperglycemia (FBG >ULN ≤160 mg/dL) or consider initiating treatment with 
an oral hypoglycemic agent, such as metformin. All patients with ≥Grade 2 hyperglycemia (FBG 
>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 for 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. In addition, patients should be encouraged to follow a low-carbohydrate diet once 
hyperglycemia is first observed.
6.6.2
Management of Hyperlipidemia
Guidance on study drug dose modification for patients with hyperlipidemia is provided in 
Table 6.e.
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Table 6.e
Management of Hyperlipidemia
Grade
Description
Treatment
Study Drug Dose Modification
1
Cholesterol:
>ULN-300 mg/dL
Triglycerides:
>150-300 mg/dL
None
None
2
Cholesterol:
>300-400 mg/dL
Triglycerides:
>300-500 mg/dL
Treat hyperlipidemia according to 
standard guidelines. Triglycerides 
≥500 mg/dL should be treated 
urgently because of the risk of 
pancreatitis.
Maintain dose if tolerable. If toxicity 
becomes intolerable, interrupt study 
drug(s) (a) 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 the next lower dose 
of MLN0128. (b)
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).
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117 (Arm D), 
then both agents should be held.
(b) As described in Section 6.2, dose reduction applies only to MLN0128 treatment. The dose of MLN1117 should 
be maintained at 200 mg when resuming treatment after an interruption of study drug or dose modification of 
MLN0128.
6.6.3
Management of Oral Mucositis
Guidance for the management of oral mucositis is provided in Table 6.f.
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Table 6.f
Management of Oral Mucositis
Grade
Description
Treatment
Study Drug 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 study 
drug(s) (a) 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 the next lower 
dose level of MLN0128. (b)
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.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117 (Arm D), 
then both agents should be held.
(b) As described in Section 6.2, dose reduction applies only to MLN0128 treatment. The dose of MLN1117 should 
be maintained at 200 mg when resuming treatment after an interruption of study drug or dose modification of 
MLN0128.
6.6.4
Management of Rash
Patients who develop Grade 4 rash should permanently discontinue study treatment, unless they 
derive clinical benefit, in which case they may be retreated at a reduced dose level after recovery 
to Grade 1 severity. Grade 4 rash is defined as rash acneiform/papulopustular with papules 
and/or pustules covering any percentage of BSA, which may or may not be associated with 
symptoms of pruritus or tenderness, and are associated with extensive superinfection with IV 
antibiotics indicated; life threatening consequences (NCI CTCAE version 4.03, effective date 14 
June 2010[42]).
Guidance for management of rash is provided in Table 6.g.
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Table 6.g
Management of Rash
Grade
Description
Treatment
Study Drug Dose Modification
2
Macules/papules covering 
≤30% BSA with or without 
symptoms. 
Consider treatment with topical 
steroid cream/ointment and/or oral 
antihistamines.
None
3
Macules/papules covering 
30% BSA with or without 
symptoms. 
Consider treatment with topical 
steroid cream/ointment, oral 
antihistamines, and/or pulsed 
steroids.
Hold until Grade 2; resume study 
drug(s) (a) based on timing of 
recovery:

≤3 weeks: reduce dose to the 
next lower dose level of 
MLN0128. (b)

>3 weeks: discontinue 
MLN0128 treatment. 
Patients who develop Grade 4 rash should permanently discontinue study treatment unless they derive clinical 
benefit, in which case they may be retreated at a reduced dose level after recovery to Grade 1 severity. Grade 4 
rash is defined as rash acneiform/papulopustular with papules and/or pustules covering any percentage of BSA, 
which may or may not be associated with symptoms of pruritus or tenderness, and are associated with extensive 
superinfection with IV antibiotics indicated; life threatening consequences.
Prevention/Prophylaxis:

Rash should be managed aggressively. The investigator should consider consulting a dermatologist or other 
specialist, if needed.

A skin biopsy at the site of rash should be considered as soon as possible after the initial episode.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117 (Arm D), 
then both agents should be held.
(b) As described in Section 6.2, dose reduction applies only to MLN0128 treatment. The dose of MLN1117 should 
be maintained at 200 mg when resuming treatment after an interruption of study drug or dose modification of 
MLN0128.
6.6.5
Management of Nausea and/or Vomiting
Guidance for the management of nausea and/or vomiting is provided in Table 6.h.
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Table 6.h
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 study 
drug(s) (a) 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.
(a) Study drug(s) refers to MLN0128 and MLN1117. If a patient is taking both MLN0128 and MLN1117 (Arm D), 
then both agents should be held.
6.6.6
Management of Cardiac Abnormalities
Management of Patients With Possible Cardiac Instability
For patients showing signs of cardiac instability after MLN0128+MLN1117 administration, 
additional monitoring onsite before clinic discharge should be considered.
Management of Patients With Left Ventricular Dysfunction
Guidance for MLN0128+MLN1117 dose adjustment for patients with left ventricular 
dysfunction is provided in Table 6.i.
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Table 6.i
Management of Left Ventricular Dysfunction
Grade
Description
Dose Modification
1
Asymptomatic decline in
LVEF >15% from baseline values, OR
LVEF >10%-15% from baseline values and is 
below institution’s LLN.
No change; continue study drug(s) (a) at the same 
dose and schedule.
2
Symptomatic cardiac dysfunction/congestive heart 
failure.
Discontinue treatment.
LLN=lower limit of normal, LVEF=left ventricular ejection fraction.
(a) Study drug(s) refers to MLN0128 and MLN1117. If study drug(s) are to be held, then both agents should be held 
for patients taking both MLN0128 and MLN1117.
Management of Patients With QTc Prolongation
Guidance for MLN0128+MLN1117 dose adjustment for patients exhibiting a prolonged QTc 
interval is provided in Table 6.j. Patients who experience persistent Grade 3 or Grade 4 QTc 
prolongation without another cause should permanently discontinue study treatment.
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Table 6.j
Management of QTc Prolongation
Grade
Description
Treatment
Dose Modification
2
480 msec
QTc
501 msec
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication, etc)
None; continue study drug(s) (a) at the 
same dose and schedule.
3
QTc 501 msec or 
>60 msec change 
from Baseline
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication). (a)
Consider a formal consult by a 
cardiologist.
Notify the sponsor’s project clinician.
Additional ECGs may be performed at 
intervals that the treating physician deems 
clinically appropriate until repeated QTc 
measurements fall or are below the 
threshold interval that triggered the repeat 
measurement.
Hold study drug(s). (b)
The decision whether to reinitiate study 
drug(s) with or without dose reduction and 
additional monitoring in those patients who 
had asymptomatic prolonged QTc 501 
msec (Grade 3) that has reverted to an 
acceptable interval, have previously 
tolerated study drug(s), and appear to have 
benefitted from treatment with either 
disease control or response, will be agreed 
to by the investigator and the project 
clinician on a case-by-case basis.
Patients who experience persistent Grade 3 
or Grade 4 QTc prolongation without 
another cause should permanently 
discontinue study treatment.
(a) A list of medications known to prolong QTc can be found at torsades.org and QTdrugs.org.
(b) Study drug(s) refers to MLN0128 and MLN1117. If study drug(s) are to be held, then both agents should be held 
for patients taking both MLN0128 and MLN1117.
6.6.7
Management of Other Nonhematologic Toxicities
Guidance on dose adjustment for patients with other nonhematologic toxicities is provided in 
Table 6.k.
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Table 6.k
Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue)
Grade
Description
Treatment
Study Drug Dose Modification
1
Mild; asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention 
not indicated.
Initiate appropriate medical 
therapy and monitor.
If tolerable, then no adjustment is 
required.
2
Moderate; minimal, local or 
noninvasive intervention 
indicated.
Initiate appropriate medical 
therapy and monitor.

If tolerable, no adjustment 
required.

If toxicity becomes intolerable, 
hold study drug(s) (a) until 
recovery to ≤Grade 1 then 
reinitiate at same dose. 
≥3
Severe or medically significant 
but not immediately life-
threatening; hospitalization or 
prolongation of hospitalization 
indicated.
Hold study drug(s) until recovery to 
≤Grade 1. Reinitiate study drug(s) 
with the dose of MLN0128 reduced by 
1 level (Section 6.2). (b)
(a) Study drug(s) refers to MLN0128 and MLN1117. If study drug(s) are to be held, then both agents should be held 
for patients taking both MLN0128 and MLN1117.
(b) As described in Section 6.2, dose reduction applies only to MLN0128 treatment. The dose of MLN1117 should 
be maintained at 200 mg when resuming treatment after an interruption of study drug or dose modification of 
MLN0128.
6.6.8
Management of AST/ALT Elevations
Guidance on dose adjustment for patients with AST/ALT elevations is provided in Table 6.l.
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Table 6.l
Management of AST/ALT Elevations
Grade
Description
Treatment
Study Drug Dose Modification
1
>ULN - 3ULN
None
None
2
Asymptomatic with levels 3 -
5ULN; >3ULN with the 
appearance of worsening 
fatigue, nausea, vomiting, right 
upper quadrant pain or 
tenderness, fever, rash, or 
eosinophilia.

Closely monitor LFTs at least 
weekly or more frequently as 
indicated.

Assess patient for other causes 
of transaminitis (eg, past 
medical history, concomitant 
medications).
None
3
>5 to 20ULN; >5ULN for 
>2 weeks.
Same as for Grade 2.
Hold study drug(s) (a) until 
≤Grade 1; restart MLN0128 and 
MLN1117 at the same doses.
4
>20ULN.
Same as for Grade 2.
Discontinue treatment with study 
drug(s). 
Prevention/Prophylaxis:
Ensure proper screening of patients for study participation.
LFT=liver function test.
(a) Study drug(s) refers to MLN0128 and MLN1117. If study drug(s) are to be held, then both agents should be held 
for patients taking both MLN0128 and MLN1117.
6.6.9
Management of Noninfectious Pneumonitis
Guidance for the management of pneumonitis is provided in Table 6.m.
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Table 6.m
Management of Noninfectious Pneumonitis
Grade
Description 
Treatment
Study Drug Dose Modification
1
Asymptomatic: Radiographic 
findings only.
Rule out infection and closely 
monitor.
None
2
Symptomatic:
Not interfering with 
activities of daily living.
Rule out infection and 
consider treatment with 
corticosteroids until symptoms 
improve to ≤Grade 1.
Interrupt study drug (a) treatment:

When symptoms ≤Grade 1, 
reinitiate study drug(s) (a) treatment 
with a 25% dose reduction in the 
MLN0128. (b)

If no recovery within 4 weeks, then 
discontinue study drug 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 study drug (a) treatment until 
symptoms resolve to ≤Grade 1.

Consider re-initiating MLN0128 
treatment with a 25% dose 
reduction. (b)

If toxicity recurs at Grade 3, 
discontinue study drug treatment.
4
Life-threatening:
Ventilatory support 
indicated.
Rule out infection and 
consider treatment with 
corticosteroids.
Discontinue study drug treatment.
(a) Study drug(s) refers to MLN0128 and MLN1117. If study drug(s) are to be held, then both agents should be held 
for patients taking both MLN0128 and MLN1117.
(b) As described in Section 6.2, dose reduction applies only to MLN0128 treatment. The dose of MLN1117 should 
be maintained at 200 mg when resuming treatment after an interruption of study drug or dose modification of 
MLN0128.
6.6.10
Management of Clinical Events: Paclitaxel
For more information on the management of clinical events in patients receiving paclitaxel, refer 
to the most recent paclitaxel USPI or SmPC.
6.7
Blinding and Unblinding
Not applicable. This is an open-label study.
6.8
Description of Investigational Agents
MLN0128 will be supplied as capsules for oral administration. MLN0128 is available in 3 dose 
strengths—1, 3, and 5 mg—each containing 1, 3, and 5 mg of MLN0128, respectively, in 
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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.

3 mg MLN0128 capsules: Swedish orange opaque color.

5 mg MLN0128 capsules: gray opaque color.
MLN1117 will be supplied as 100 mg capsules for oral administration. Each 100 mg capsule 
contains 100 mg of MLN1117 and the following inactive ingredients: hard gelatin capsule and 
small amount of colloidal silicon dioxide.
Refer to the MLN0128, MLN1117, and MLN0128+MLN1117 IBs for full details.
Paclitaxel is a commercially available drug supplied as a solution for injection and will be 
procured or distributed according to the Pharmacy Manual. Please refer to the most recent 
paclitaxel USPI or SmPC for more information regarding paclitaxel.
6.9
Preparation, Reconstitution, and Dispensation
MLN0128 and MLN1117 dosage forms will be provided in labeled bottles in accordance with all 
applicable regulations. Materials provided by the sponsor should be dispensed to patients with 
clear administration instructions from the investigator.
MLN0128 and MLN1117 are anticancer drugs and, as with other potentially toxic compounds, 
caution should be exercised when handling MLN0128 and MLN1117 capsules.
6.10
Packaging and Labeling
MLN0128 and MLN1117 will be provided by Millennium and will be handled at the 
investigative site as open-label material. 
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MLN0128 will be provided in 30-ct, 60-cc high-density polyethylene (HDPE) bottles with 
polypropylene, child-resistant caps and induction seal. MLN1117 will be provided in 14-ct, 
30-cc HDPE bottles with child-resistant caps and induction seal.
MLN0128 and MLN1117 are packaged and labeled in accordance with all applicable 
regulations.
Paclitaxel may be supplied either by the site from commercial sources (US sites) or provided by 
Millennium (ex-US sites). When provided by Millennium, paclitaxel will be appropriately 
labeled in compliance with local and regional regulations.
6.11
Storage, Handling, and Accountability
Upon receipt at the investigative site, MLN0128 and MLN1117 should be stored in the original 
bottles until use and stored at room temperature from 15C to 30C (59F-86F). All temperature 
excursions will be reported to the sponsor for assessment and authorization for continued use. 
All investigational supplies must be stored in a secure area with controlled access and will be 
stored in original packaging. All MLN0128 and MLN1117 supplies should be used before the 
retest expiry date.
A drug dispensing log, including records of drug received from the sponsor and drug dispensed 
to the patients, will be provided and kept at the study site. Storage area temperature conditions 
must be monitored and recorded daily. A daily temperature log will also be kept at the study site.
Because MLN0128 and MLN1117 are investigational agents, they should be handled with due 
care. In case of contact with broken capsules, raising dust should be avoided during the clean-up 
operation. The product may be harmful if inhaled, ingested, or absorbed through the skin. Gloves 
and protective clothing should be worn during the clean-up operation. The area should be 
ventilated and the spill site washed after material pick-up is complete. The spilled material 
should be disposed of as hazardous medical waste in compliance with federal, state, and local 
regulations. In case of contact with the powder (eg, from a broken capsule), skin should be
washed immediately with soap and copious amounts of water for at least 15 minutes. In case of 
contact with the eyes, copious amounts of water should be used to flush the eyes for at least 
15 minutes. Medical personnel should be notified.
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Patients will receive instructions for home storage and administration of MLN0128 and 
MLN1117.
Patients will be instructed to return any unused study drug in the original packaging along with 
their completed diary cards at the appropriate visits.
Paclitaxel should be stored according to instructions provided in the manufacturer’s package 
insert or SmPC.[43,44]
Please refer to the Study Manual for additional instructions.
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 project clinician for this study, the central laboratory and any 
additional clinical laboratories, and other third-party vendors may be found in the Study Manual. 
A full list of investigators is available in the sponsor’s investigator database.
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
A centralized randomization procedure via Interactive Voice/Web Response System (IXRS) will 
be used to assign treatment. Patients will be randomized strictly sequentially at a center as they 
become eligible for randomization. Randomization will be stratified by histological subtype, 
lines of prior chemotherapy, and prior use of taxanes (see Section 8.1.2). If a patient discontinues 
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from study drug, the randomization code will not be reused, and the patient will not be allowed 
to re-enter the study.
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, ethnicity, and sex 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 it. In addition, concomitant medications will be recorded as 
specified in Section 7.4.9.
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
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at Screening. A 
urine pregnancy test must be performed predose on Day 1 of every cycle with negative results 
available before the first dose may be administered in that cycle. A serum pregnancy test may 
also be performed within 3 days before dosing in place of the Day 1 urine test.
7.4.8
ECOG Performance Status
The ECOG performance status (refer to Section 14.1) will be assessed at the times specified in 
the Schedule of Events.
7.4.9
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 study drug through 30 days after the last dose of study 
drug. See Section 6.3 and Section 6.4 for a list of medications and therapies that are prohibited 
and/or allowed during the study. 
7.4.10
Adverse Events
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.
7.4.11
Enrollment
A patient is considered to be enrolled in the study when they have been randomized to a 
treatment arm. Procedures for completing the enrollment information are described in the Study 
Manual.
7.4.12
ECG
A single, 12-lead ECG will be administered at the time points specified in the Schedule of 
Events. Additional ECGs may be obtained as clinically indicated.
7.4.13
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally. Clinical laboratory evaluations will be 
performed as outlined below.
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Clinical Chemistry, Hematology, 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 any study drug. For patients randomized to 
receive paclitaxel (Arm A and Arm B), results of hematology and chemistry safety laboratory 
testing must be reviewed by the investigator or appropriate designee before administering 
paclitaxel.
Hematology
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 panel includes the following:

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (ANC)
Coagulation
A blood sample for coagulation tests will be obtained at the times specified in the Schedule of 
Events. The coagulation panel includes the following:

aPTT.

PT/international normalized ratio.
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 and 
direct)

Urate

Lactate dehydrogenase

Phosphate

Albumin

Alkaline phosphatase

AST

ALT

Glucose 

Potassium

Calcium (total)

Chloride

Carbon dioxide or 
bicarbonate

Magnesium
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
Gamma glutamyl 
transferase

Sodium

Amylase

HbA1c at the times 
specified in the 
Schedule of Events

Protein (total)
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

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. 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. The fasting lipid profile includes the following:

Cholesterol (total)

Triglycerides

High-density lipoprotein 
cholesterol

Low-density lipoprotein 
cholesterol
7.4.14
Fasting Serum Glucose
Fasting serum glucose will be measured in the clinic at the time points specified in the Schedule 
of Events. Patients are required to fast overnight (nothing except water and/or medications after 
midnight or for a minimum of 8 hours before the assessment) for each of these measurements. 
For patients in Arm A (single-agent paclitaxel), Arm B (paclitaxel+MLN0128), and Arm C 
(single-agent MLN0128), the sample will be collected predose; after predose blood draws are 
complete, patients receiving single-agent MLN0128 QW in Arm C should consume a light meal 
before dosing (Section 6.1). For patients in Arm D (MLN0128+MLN1117), the sample should 
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be taken approximately 2 hours after study drug administration with the patient continuing to fast 
until the sample is taken. 
7.4.15
Disease Assessment
Patients will undergo CT (with contrast) or MRI (with contrast) as appropriate to monitor and 
assess disease progression, using RECIST guidelines (version 1.1), where measurable disease is 
defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest 
diameter to be recorded).[41] Each lesion must be ≥10 mm in long axis when measured by CT, 
MRI, or caliper measurement by clinical exam. Lymph nodes must be ≥15 mm in short axis 
when measured by CT or MRI. Specific disease sites that cannot be adequately imaged by CT 
may be documented by MRI. Anatomical measurements will be collected at Baseline and at each 
subsequent evaluation for each target lesion, using an imaging modality consistent with the one
used at Screening. Objective assessments will be performed at each time point as described in the 
Schedule of Events. When possible, the same qualified physician will interpret results to reduce 
variability.
All images will be collected and quality controlled by a sponsor-specified central imaging 
vendor. Radiographic images will be maintained at the site, and test results and physicians’ 
findings will be filed in patient source documents.
7.4.16
Tumor Biopsies and Archival Tumor Samples
Fresh tumor biopsies and archival tumor samples (banked formalin-fixed, paraffin-embedded 
tumor tissue) should be obtained at Screening. The reason for requiring both archival and fresh 
tumor biopsies is to understand the changes that occur from archival tissue to second-line or 
third-line therapy. These baseline tumor samples will be used for assessment of candidate 
biomarkers predictive of response to single-agent and combination treatment, including but not 
limited to PTEN, PIK3CA, mTOR, KRAS, and microsatellite instability. In addition, fresh tumor 
biopsy samples will also be obtained on Cycle 1 Day 22 for subjects enrolled in Arm C and Arm 
D to identify adaptive response mechanisms to treatment of MLN0128 or MLN0128+MLN1117. 
Fresh tumor biopsies will be obtained as indicated in the Schedule of Events. The tumor biopsy 
procedure will be performed by core needle, under radiological guidance if indicated, or 
surgically, if appropriate.
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Detailed instructions for the collection, processing, and shipment of the fresh and archival tumor 
biopsy samples are provided in the Study Manual.
7.4.17
PK Measurements (Arms B, C, and D only)
PK samples collected in this study will be used to quantify MLN0128 and MLN1117. Patients 
must note in dosing diaries the dates and times when they take their doses of MLN0128 and/or 
MLN1117 before the days when the clinical visits for PK sampling are scheduled. These dates 
and times will be noted in the eCRF. Blood samples will be collected at the time points specified 
in the Pharmacokinetic Sample Breakdown table.
PK data collected in this study is for population PK analysis only and may be combined with 
similar data from other clinical studies of MLN0128 and MLN1117. The results of such analyses 
will be reported at a later point in a separate population PK report and will not be part of the 
clinical study report for this study.
7.4.18
QOL Assessment
The QOL instruments, EORTC QLQ-C30 and EORTC QLQ-EN24, will be administered as 
specified in the Schedule of Events and must be completed before other assessments are 
performed or study drug is administered. 
The EORTC QLQ-C30 incorporates 5 functional scales (physical functioning, role functioning, 
emotional functioning, cognitive functioning, and social functioning), 1 global health status 
scale, 3 symptom scales (fatigue, nausea and vomiting, and pain), and 6 single items (dyspnea, 
insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The time recall period 
for this instrument is 1 week (the past week). It is a reliable and valid measure of health-related 
QOL in patients with cancer and takes about 11 minutes to administer. The instrument consists 
of a brief (30-item) questionnaire that has been validated and used in many countries.
The EORTC QLQ-EN24 endometrial cancer module (24-items) has 13 domains: lymphedema, 
urologic problems, gastro-intestinal problems, body image, sexual/vaginal problems, back/pelvic 
pain, tingling/numbness, muscular/joint pain, hair loss, taste change, sexual interest, sexual 
activity, and sexual enjoyment (disease symptoms and side-effects of treatment). It has been 
validated in patients with endometrial cancer and is available in multiple languages.
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7.4.19
DNA Measurements
7.5
Completion of Treatment
Patients will be considered to have completed treatment if they discontinue treatment with study 
drug 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
Treatment with study drug may be discontinued for any of the following reasons:
!
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
Protocol violation.

Progressive disease.

Study terminated by sponsor.

Withdrawal by subject.

Lost to follow-up.

Other.
Patients must discontinue study drug if they experience disease progression or unacceptable 
toxicity, or if they become pregnant.
Once study drug has been discontinued, all study procedures outlined for the EOT visit will be 
completed as specified in the Schedule of Events. The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Note that some patients may discontinue study drug for reasons other than progressive disease. 
Up until Amendment 06, after EOT, these patients were to remain in the study for posttreatment 
assessments of PFS and OS, during the posttreatment follow-up period.
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 subject.

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.
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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 study drug for each treatment cycle and a diary in 
which to record their dosing. The study center staff will check the patient’s diary versus the 
patient’s supply of remaining study drug at each study visit to ensure proper compliance with 
dosing. Patients who are not compliant with the dosing schedule may be withdrawn from the 
study.
8.
STATISTICAL AND QUANTITATIVE ANALYSES
8.1
Statistical Methods
Summary tabulations will be presented by treatment arm and will display the number of 
observations, mean, standard deviation, median, minimum, and maximum for continuous 
variables, and the number and percentage per category for categorical data.
A formal statistical analysis plan (SAP) will be developed and finalized before database lock. 
The SAP will outline all data handling conventions and specify all statistical methods to be used 
for safety and efficacy data analysis. Deviations from the statistical analyses outlined in this 
protocol will be indicated in the SAP; any further modifications will be noted in the clinical 
study report.
8.1.1
Determination of Sample Size
The primary efficacy endpoint of the study is PFS and the primary comparison is between the 
paclitaxel and the paclitaxel+MLN0128 4 mg QD3 treatment arm. Assuming the median PFS is 
4 months for paclitaxel and paclitaxel+MLN0128 4 mg QD3 can improve the median to 
6.5 months (hazard ratio of 0.615, approximately 38% reduction in the hazard rate) a total of 
134 PFS events and 90 patients per treatment arm are required. The calculations are based on a 
power of 80%, 2-sided alpha of 5%, and a dropout rate of 15% due to lost to follow-up or 
withdrawal of consent. Enrollment to the third treatment arm of single-agent MLN0128 30 mg 
QW and the fourth treatment arm of MLN0128 4 mg QD3 in combination with 200 mg 
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MLN1117 has been closed. The total sample size for the study will be approximately 
242 patients.
The total accrual duration will be approximately 25 months to complete enrollment in the 
paclitaxel and paclitaxel+MLN0128 4 mg QD3 treatment arms. The final analysis for the 
primary comparison of PFS between the paclitaxel treatment arm and the paclitaxel+MLN0128 
4 mg QD3 treatment arm will occur approximately 5 months after the last patient is 
randomized.
8.1.2
Randomization and Stratification
Patients will be randomized in a 1:1:1:1 ratio to the 4 treatment arms:

Arm A: Weekly paclitaxel.

Arm B: Weekly paclitaxel+MLN0128 4 mg QD3.

Arm C: MLN0128 30 mg QW.

Arm D: MLN0128 4 mg+MLN1117 200 mg QD3.
In the event that enrollment into a treatment arm(s) is closed, patients will be randomized 1:1 
into the remaining treatment arms. A centralized randomization using IXRS will be used with the
following stratification factors:

Histological subtype: endometrioid vs nonendometrioid.

Line(s) of prior chemotherapy: 1 vs 2.

Prior taxane therapy (other than weekly): yes vs no.
8.1.3
Populations for Analysis
The populations used for analysis will include the following:

Intent-to-treat (ITT) population: patients who are randomized will be used for analysis of 
PFS, TTP, and OS.
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
Safety population: patients who receive at least 1 dose of study drug will be used for all 
safety analyses.

Response-evaluable population: patients who receive at least 1 dose of study drug, have 
measurable disease at Baseline, and 1 postbaseline disease assessment will be used for 
analyses of response.
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. The relevance of missing sample data 
will be assessed.
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
8.1.5
Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment arm, including 
gender, age, race, weight, height, and other appropriate baseline characteristics. No inferential 
statistics will be carried out.
8.1.6
Efficacy Analysis
The primary endpoint for the study is PFS, defined as the time from the date of randomization to 
the date of first documentation of progression or death due to any cause, whichever occurs first. 
For a patient who has not progressed and is last known to be alive, PFS will be censored at the 
last response assessment that is SD or better. The primary efficacy analysis will be based on the 
ITT population.
The Kaplan-Meier method will be used to analyze the distribution of PFS for each treatment arm, 
as outlined in the study objectives. Kaplan-Meier survival curves, the 25th, 50th (median), and 
75th percentiles along with associated 2-sided 95% CIs, hazard ratio along with associated 
95% CI, and Kaplan-Meier estimates at relevant time points will be presented. The p-value from 
a stratified log-rank test will be presented for the primary comparison of paclitaxel and 
paclitaxel+MLN0128 and the secondary objective comparing paclitaxel to both single-agent 
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MLN0128 and MLN0128+MLN1117. The primary hypothesis is to be tested at the 
0.05 significance level (2-sided).
Secondary efficacy endpoints include OS, ORR, TTP, and CBR (CR+PR+SD).
OS is defined as the time from the date of randomization to the date of death. Patients without 
documentation of death at the time of analysis will be censored at the date last known to be alive. 
OS will be analyzed using similar methods as the primary endpoint of PFS.
ORR is defined as the proportion of patients who achieve a best response of CR or PR. CBR is 
defined as the proportion of patients who achieve a best response of CR, PR, or SD. A stratified 
Cochran-Mantel-Haenszel test will be used to compare ORR and CBR between treatment arms. 
The Mantel-Haenszel estimate of the odds ratio and the associated 95% CIs will be presented.
TTP is defined as the time from the date of randomization to the date of first documentation of 
progression. For a patient who has not progressed, TTP will be censored at the last response 
assessment that is SD or better. TTP will be analyzed using similar methods as the primary 
endpoint of PFS.
Duration of SD is defined as the time from the date of randomization to the date of first 
documentation of disease progression for patients who achieved SD as the best overall response.
Sensitivity analyses for time-to-event endpoints (PFS, TTP) and response endpoints (ORR and 
CBR) may be performed based on results from the central imaging vendor.
8.1.7
Analyses of Patient-Reported Outcomes
Patient-reported outcome (PRO) assessments using the EORTC QLQ-C30 and 
EORTC QLQ-EN24 questionnaires will be analyzed to determine if response to therapy and side 
effects of therapy are accompanied by measurable changes in the PROs. Published scoring 
manual and guidelines will be used to score EORTC QLQ-C30 and EORTC QLQ-EN24 scale 
scores and handle missing data.
Descriptive statistics for baseline values, actual values, and the change from Baseline will be 
presented at each scheduled time point for each of the functional and symptom scores, and the 
global health status/QOL score from the EORTC QLQ-C30 questionnaire and the thirteen 
symptoms scales from the EORTC QLQ-EN24 questionnaire. Differences between treatment 
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arms in the EORTC QLQ-C30 and EORTC QLQ-EN24 scores will be evaluated. Longitudinal 
analysis of PRO scores will be performed using linear mixed models.
8.1.8
PK/Pharmacodynamics/Biomarkers
PK Analysis
Individual plasma concentration-time data will be reported in a by-patient listing. The PK and 
pharmacogenetic data collected in this study are intended to contribute to future population PK 
analysis. These data may be combined with data from other studies in which the PK of 
MLN0128 or MLN1117 is characterized for population PK analysis. The analysis plan for the 
population PK analysis will be separately defined and the results of these analyses will be 
reported in a separate population PK report.
Biomarkers
8.1.9
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
Baseline in the patient’s vital signs, weight, and clinical laboratory results using the safety 
population. Exposure to study drug and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of study drug and through 30 days after 
the last dose of study drug will be tabulated.
TEAEs will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will include the following categories:
!
TEAEs.
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
Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

SAEs.
The most commonly reported TEAEs (ie, those events reported by ≥10% of patients in each 
treatment arm) will be tabulated by the MedDRA preferred term. A listing of deaths within 
30 days of last dose of study drug and TEAEs resulting in study drug discontinuation will be 
provided.
Descriptive statistics for the actual values of clinical laboratory parameters and the change from 
Baseline in clinical laboratory parameters will be presented at each scheduled time point. Mean 
laboratory values over time may be plotted for key laboratory parameters. Shift tables for 
laboratory parameters will be generated based on changes in NCI CTCAE grade from Baseline 
to the worst postbaseline value.
Descriptive statistics for the actual values (and/or the changes from Baseline) of vital signs and 
weight over time will be presented at each scheduled time point.
Concomitant medications will be tabulated by World Health Organization drug dictionary 
generic term.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of MLN0128 in combination with paclitaxel, 
MLN0128+MLN1117, or single-agent MLN0128.
ECG Analysis
A summary of ECG abnormalities will be presented at each scheduled time point. Descriptive 
statistics for ECG intervals (QT interval with Fridericia correction [QTcF], PR, QRS, and 
ventricular rate) and changes from Baseline will be presented at each scheduled time point.
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8.1.10
Interim Analysis
There will be 2 interim analyses with early stopping rules for futility in both the single-agent 
MLN0128 and MLN0128+MLN1117 arms using the Bayesian predictive probability design.[45]
The endpoint for the interim analysis will be based on the number of patients who achieve CR or 
PR of any duration, or SD ≥16 weeks as assessed by the investigator (clinical benefit at 
16 weeks). The decision rule for the interim analyses is derived based on the following
assumptions:

Ineffective CBR-16 rate (Ho): 30%.

Effective CBR-16 rate (Ha): 50%.

Alpha=10%; power=80%.

Prior Beta Distribution Parameters: 0=0.30, 0=0.70.

The probability of early termination under the null hypothesis is 77%.
Each interim analysis will be based on patients who have had the opportunity to complete a 
minimum of 4 cycles or have discontinued study drug before the end of Cycle 4. Based on the 
first 20 patients in each arm, 1 or both arms may be dropped if at most 6 patients experience 
clinical benefit at 16 weeks in each arm. After the first 30 patients in each arm have been 
evaluated following 4 cycles of treatment, 1 or both arms may be dropped if at most 10 patients 
experience clinical benefit at 16 weeks in each arm.
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 medication; it 
does not necessarily have to have a causal relationship with study participation.
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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 study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from Baseline.
9.1.3
SAE Event Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of 
the event. It does not refer to an event which hypothetically might have caused death if it 
were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph 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. Examples of such 
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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.[42] Clarification should be made 
between a SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a WBC 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 
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or serious pretreatment event may be requested by Millennium. SAE report information must be 
consistent with the data provided on the eCRF.
SAE Reporting Contact Information
Planned hospital admissions or surgical procedures for an illness or disease that existed before 
study drug was given are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. For serious 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.[42] 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:
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
AEs will be reported from the first dose of study drug through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs.

Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first dose of 
study drug, but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of
Pharmacovigilance or designee from the first dose of study drug through 30 days after 
administration of the last dose of study drug and recorded in the eCRF. After this period, 
only related SAEs must be reported to the 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
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, 
she must inform the investigator immediately and permanently discontinue study drug. The 
sponsor must also be contacted immediately by faxing a completed Pregnancy Form to the 
Millennium Department of Pharmacovigilance or designee (see Section 9.2). The pregnancy 
must be followed for the final pregnancy outcome.
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 study 
drug 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 
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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
Electronic Case Report Form 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 randomized subject. 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.
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 
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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, study drug 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.
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.
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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 study drug 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 study drug 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 Medical 
Information Call Center/
and report the complaint. The contact 
information is as follows:
Medical Information Center:
Phone:
Fax:
Email:
Hours:
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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
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the European 
Medicines Agency, investigators, and IRBs or IECs, as applicable, in accordance with national 
regulations in the countries where the study is conducted. Relative to the first awareness of the 
event by/or further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to 
the regulatory authorities as an expedited report within 7 calendar days for fatal and 
life-threatening events and 15 calendar days for other serious events, unless otherwise required 
by national regulations. The sponsor will also prepare an expedited report for other safety issues 
where these might materially alter the current benefit-risk assessment of an investigational 
medicinal product or that would be sufficient to consider changes in the investigational 
medicinal product’s administration or in the overall conduct of the trial. The investigational site 
also will forward a copy of all expedited reports to his or her IRB or IEC in accordance with 
national regulations.
10.13
Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and the 
IECs in all member states where the study is being carried out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical trial results will be submitted to 
the competent authorities and IECs in all member states involved in the study.
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:
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
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.
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.
Within 15 days of premature closure, Millennium must notify the competent authorities and IECs 
of any member state where the study is being conducted, providing the reasons for study closure.
10.14
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 and MLN1117 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 
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during the study. The information obtained from the clinical study will be used toward the 
development of MLN0128 and MLN1117 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.
11.1
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum, register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, 
and recruiting status will be registered and available for public viewing. 
For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to Takeda providing this information to callers must provide 
Takeda with a written notice requesting that their information not be listed on the registry site.
11.2
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
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12.
INVESTIGATOR AGREEMENT
I have read Protocol C31004 Amendment 05: A Phase 2, Randomized Study of MLN0128 (a 
Dual TORC1/2 Inhibitor), MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the 
Combination of Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or 
Persistent Endometrial Cancer.
I agree to conduct the study as detailed herein and in compliance with International Conference 
on Harmonisation Guidelines for Good Clinical Practice, the ethical principles that have their 
origin in the last version of the Declaration of Helsinki, 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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13.
REFERENCES
1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA 
Cancer J Clin 2011;61(2):69-90.
2. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin 2014;64(1):9-29.
3. Goldfinger M, Diaz I, Muggia F. Systemic treatment of endometrial cancer: what is 
doxorubicin's role? J Clin Oncol 2014;32(20):2181-2.
4. Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C, et al. Endometrial cancer: 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 
2011;22 Suppl 6:vi35-9.
5. Dizon DS, Blessing JA, McMeekin DS, Sharma SK, Disilvestro P, Alvarez RD. Phase II trial 
of ixabepilone as second-line treatment in advanced endometrial cancer: gynecologic 
oncology group trial 129-P. J Clin Oncol 2009;27(19):3104-8.
6. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, et al. Randomized 
phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast 
cancer, with trastuzumab for all HER-2 overexpressors and random assignment to 
trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group 
B protocol 9840. J Clin Oncol 2008;26(10):1642-9.
7. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, et al. 
Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel 
as first-line therapy for metastatic breast cancer. J Clin Oncol 2009;27(22):3611-9.
8. Katsumata N, Yasuda M, Takahashi F, Isonishi S, Jobo T, Aoki D, et al. Dose-dense 
paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian 
cancer: a phase 3, open-label, randomised controlled trial. Lancet 2009;374(9698):1331-8.
9. Laplante M, Sabatini DM. mTOR Signaling. Cold Spring Harb Perspect Biol 2012;4(2).
10. Laplante M, Sabatini, DM. mTOR Signaling in Growth Control and Disease. Cell 
2012;149(2):274-93.
11. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 
2006;6(9):729-34.
12. Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new generation 
of mTOR inhibitors. Nature Reviews Drug Discovery 2011;10(11):868-80.
13. Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: the 
second generation of inhibitors. Mol Cancer Ther 2011;10(3):395-403.
14. Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-competitive 
mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. 
J Biol Chem 2009;284(12):8023-32.
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Use


MLN0128
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99
15. Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. AZD8055 is 
a potent, selective, and orally bioavailable ATP-competitive mammalian target of rapamycin 
kinase inhibitor with in vitro and in vivo antitumor activity. Cancer Res 2010;70(1):288-98.
16. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel 
E, et al. mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT 
signaling. Cancer Discov 2011;1(3):248-59.
17. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR Inhibition Induces 
Upstream Receptor Tyrosine Kinase Signaling and Activates Akt. Cancer Res 
2006;66(3):1500-8.
18. Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, et al. Dose- and schedule-
dependent inhibition of the mammalian target of rapamycin pathway with everolimus: a 
phase I tumor pharmacodynamic study in patients with advanced solid tumors. J Clin Oncol 
2008;26(10):1603-10.
19. Jessen K, et al. INK128 Is a Potent and Selective TORC1/2 Inhibitor With Broad Oral 
Antitumor Activity. Mol Cancer Therapy 2009;8(12):Abstract B148.
20. Kessler L, Wang S, Xin G, Kucharski J, Staunton J, Lan L, et al. INK128, an orally active 
TORC1/2 kinase inhibitor, shows broad antitumor activity and enhances efficacy of cytotoxic 
as well as targeted agents. Cancer Res 2010;70(8; Supplement 1 Abstract 4496).
21. Hassan B, Akcakanat A, Takafumi S, Evans K, Adkins F, Meric-Bernstam F. Inhibitor 
MLN0128 Has Antitumor Efficacy In Cell Lines With Intrinsic And Acquired Rapamycin-
Resistance. Academic Surgical Congress 2013(Abstract ASC20130420).
22. De P, Sun Y, Wu H, Rommel C, Yi L, Dey N, et al. Pre-clinical potency of INK128, a highly 
potent TORC1/2 kinase inhibitor in the HER2 amplified breast cancer model. Cancer Res 
2012;72(Abstract 2240).
23. Oza AM, Elit L, Tsao MS, Kamel-Reid S, Biagi J, Provencher DM, et al. Phase II study of 
temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC 
Clinical Trials Group. J Clin Oncol 2011;29(24):3278-85.
24. Slomovitz BM, Lu KH, Johnston T, Coleman RL, Munsell M, Broaddus RR, et al. A phase 2 
study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with 
recurrent endometrial carcinoma. Cancer 2010;116(23):5415-9.
25. Ray-Coquard I, Favier L, Weber B, Roemer-Becuwe C, Bougnoux P, Fabbro M, et al. 
Everolimus as second- or third-line treatment of advanced endometrial cancer: ENDORAD, a 
phase II trial of GINECO. Br J Cancer 2013;108(9):1771-7.
26. Colombo N, McMeekin DS, Schwartz PE, Sessa C, Gehrig PA, Holloway R, et al. 
Ridaforolimus as a single agent in advanced endometrial cancer: results of a single-arm, 
phase 2 trial. Br J Cancer 2013;108(5):1021-6.
27. Mackay H, Welch S, Tsao MS, Biagi JJ, Elit L, Ghatage P, et al. Phase II study of oral 
ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial 
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cancer: NCIC CTG IND 192. J Clin Oncol (ASCO Meeting Abstracts) 2011;29(suppl; abstr 
5013).
28. Shafer A, Zhou C, Gehrig PA, Boggess JF, Bae-Jump VL. Rapamycin potentiates the effects 
of paclitaxel in endometrial cancer cells through inhibition of cell proliferation and induction 
of apoptosis. Int J Cancer 2010;126(5):1144-54.
29. Shu CH, Yang WK, Shih YL, Kuo ML, Huang TS. Cell cycle G2/M arrest and activation of 
cyclin-dependent kinases associated with low-dose paclitaxel-induced sub-G1 apoptosis. 
Apoptosis 1997;2(5):463-70.
30. Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, et al. Targeting mammalian 
target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast 
cancer cells. Clin Cancer Res 2004;10(20):7031-42.
31. Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 
2008;27(41):5497-510.
32. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, et al. An 
integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast 
cancer. Cancer Res 2008;68(15):6084-91.
33. Ollikainen M, Gylling A, Puputti M, Nupponen NN, Abdel-Rahman WM, Butzow R, et al. 
Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma. Int J 
Cancer 2007;121(4):915-20.
34. Spoerke JM, O'Brien C, Huw L, Koeppen H, Fridlyand J, Brachmann RK, et al. 
Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes 
and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin 
Cancer Res 2012;18(24):6771-83.
35. Cancer Genome Atlas Research N, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, 
et al. Integrated genomic characterization of endometrial carcinoma. Nature 
2013;497(7447):67-73.
36. Bradford LS, Rauh-Hain A, Clark RM, Groeneweg JW, Zhang L, Borger D, et al. Assessing 
the efficacy of targeting the phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway in 
endometrial cancer. Gynecol Oncol 2014;133(2):346-52.
37. O'Hara AJ, Bell DW. The genomics and genetics of endometrial cancer. Adv Genomics 
Genet 2012;2012(2):33-47.
38. Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an 
evolving paradigm. Nat Rev Cancer 2013;13(10):714-26.
39. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, et al. Randomized 
phase II trial of everolimus in combination with tamoxifen in patients with hormone 
receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast 
cancer with prior exposure to aromatase inhibitors: a GINECO study. J Clin Oncol 
2012;30(22):2718-24.
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Use


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40. Baselga J, Campone M, Piccart M, Burris HA, 3rd, Rugo HS, Sahmoud T, et al. Everolimus 
in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 
2012;366(6):520-9.
41. 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.
42. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. 
Department of Health and Human Services National Cancer Institute. 14 June 2010.
43. Paclitaxel Injection [package insert]. Sellersville, PA: Teva Pharmaceuticals USA, 2012.
44. Paclitaxel medac 6 mg/ml concentrate for solution for infusion [Summary of Product 
Characteristics]. Wedel, Germany: medac Gesellschaft fur klinische Spezialpraparate mbH, 
2015.
45. Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin Trials 
2008;5(2):93-106.
46. 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.
47. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
48. The Criteria Committee of New York Heart Association. Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, Brown & 
Co; 1994.
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14.
APPENDICES
14.1
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity: Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory: Restricted in physically strenuous activity, but ambulatory and able to 
carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed <50% of the time: Ambulatory and capable of all self-care, but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time: Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours.
4
100% bedridden: Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead
Source: Oken MM, et al. 1982.[46]
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14.2
Methods of Contraception Considered to be Effective
Acceptable Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (a):
Oral.
Intravaginal.
Transdermal.
Progestogen-only hormonal contraception associated with inhibition of ovulation (a):
Oral.
Injectable.
Implantable (b).
Intrauterine device (IUD) (b).
Intrauterine hormone-releasing system (IUS) (b).
Bilateral tubal occlusion (b).
Vasectomized partner (b) (c).
Sexual abstinence (d).
Methods that are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year include:
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action.
Male or female condom with or without spermicide (e).
Cap, diaphragm, or sponge with spermicide (e).
__________________________________________________
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_ 
CTFG_Contraception.pdf
(a) Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.
(b) Contraception methods that in the context of this guidance are considered to have low user dependency.
(c) Vasectomized partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the woman of childbearing potential participant of the study and that the vasectomized partner has received 
medical assessment of the surgical success.
(d) In the context of this guidance sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject.
(e) A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods)
are also considered acceptable, but not highly effective, birth control methods.
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14.3
Cockcroft-Gault Equation
For women only:
Creatinine Clearance =
0.85 (140-age [years])weight [kg]
72(serum creatinine [mg/dL])
OR
Creatinine Clearance =
0.85 (140-age [years])weight [kg]
0.81(serum creatinine [µmol/L])
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.[47]
14.4
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.[48]
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14.5
List of Relevant CYP Inhibitors and Inducers
Moderate CYP1A2 Inhibitors
Cimetidine
Mexiletine
Oral contraceptives
Methoxsalen
Strong CYP1A2 Inhibitors
Fluvoxamine
Ciprofloxacin
Enoxacin
Zafirlukast
Clinically Significant Enzyme Inducers (Moderate [a] CYP1A2 and Strong CYP3A4)
Phenytoin
Rifampin
Ritonavir
Teriflunomide
Carbamazepine
Enzalutamide
Mitotane
St. John’s wort
Source: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractions
Labeling/ucm093664.htm#table3-2.
Note: This list is not meant to be exhaustive. Please refer to the above link for further information and examples of 
other CYP inhibitors/inducers.
(a) There are no known strong inducers of CYP1A2 at this time.
14.6
List of BCRP, OCT1, and OCT2 Substrates
BCRP, OCT1, and OCT2 Substrates
BCRP Substrates
OCT1 and OCT2 Substrates
Methotrexate
Metformin
Imatinib
Cimetidine
Topotecan
Amantadine
Lapatinib
Famotidine
Rosuvastatin
Pindolol
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14.7
Rationale for Amendment 01
The primary purposes of this amendment are to revise dosing regimens for MLN0128, increase 
the maximum dose reductions from 2 to 3 for MLN0128, and clarify management of treatment-
emergent adverse events. In addition, this amendment reduces the cardiac monitoring 
requirements based on results of a dedicated QT study (Study C31002), which indicated that 
treatment with MLN0128 is not associated with clinically meaningful effects on the overall 
electrocardiographic safety profile.
Purposes for Amendment 01
The purposes of this amendment are:
!
Added EudraCT number and Millennium corporate identification to Title Page.
!
Study Overview Diagram: Clarified description of which groups will continue treatment 
until disease progression, toxicity, or withdrawal of consent.
!
Schedule of Events: Changed general study visit window to align with other phase 2 
protocols (allow ±2 day window for holidays, vacations, or other administrative reasons 
after Cycle 2 Day 1, without permission from the medical monitor). 
!
Schedule of Events: Removed Screening ECHO/MUGA. 
!
Schedule of Events: Aligned ECG collection with other phase 2 protocols (Screening, Day 
1 of every cycle, and EOT).
!
Schedule of Events: Increased pregnancy testing requirements for women of childbearing 
potential to every cycle.
!
Schedule of Events: Aligned fasting lipid profile collection with other phase 2 protocols 
(Screening, Day 1 of every cycle starting with Cycle 2, and EOT) and removed the 
requirement to collect the Screening sample within 14 days before Cycle 1 Day 1. 
!
Schedule of Events: Aligned HbA1c testing with other phase 2 protocols, including 
changing from Day 15 to Day 1 and decreasing from every 2 cycles to every 3 cycles in 
Cycles 1 through 8.
!
Schedule of Events: 
 
 
!
Schedule of Events: Added a visit window for PFS and OS follow up.
!
Schedule of Events: Added footnote k, providing window for time from randomization to 
first dose of study drug.
!
Schedule of Events: Clarified footnote l regarding requirements for safety laboratory 
results to be reviewed relative to first dose and, for patients receiving paclitaxel, before 
each paclitaxel dose. 
!
Schedule of Events: Clarified footnote p regarding fasting requirements relative to fasting 
serum glucose sample collection and added instructions for the fasting serum glucose 
sample to be collected predose for patients receiving paclitaxel.
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
Section 1.2.1 and Section 1.3.1: Added alternative names for MLN0128 and MLN1117.

Section 1.4: Added rationale for proposed doses and schedules in paclitaxel + MLN0128, 
single-agent MLN0128, and MLN0128 + MLN1117 treatment arms.

Section 4.1: Decreased the dose of MLN0128 in Arms B and D from 8 mg to 4 mg.

Section 4.1: Clarified treatment days for single-agent MLN0128 treatment arm (Arm C).

Section 4.1: Clarified description of PFS follow up visits.

Section 4.1: Clarified timing of tumor sampling.

Section 4.2: Clarified definition of enrollment and updated number of study sites.

Section 4.3: Clarified criteria for closing the study.

Section 5.1: Clarified Inclusion Criterion 1 regarding endometrial cancer confirmation and 
requirements for eligibility.

Section 5.1: Clarified Inclusion Criterion 8 regarding use of contraception by female 
patients.

Section 5.1: Deleted Inclusion Criterion 9 regarding LVEF as measured by ECHO or 
MUGA during Screening.

Section 5.2: Clarified description of previous taxane treatment in Exclusion Criterion 1.

Section 5.2: Deleted Exclusion Criterion 6 regarding anticoagulant therapy.

Section 5.2: Revised Exclusion Criterion 13 to consider elevation of either systolic or 
diastolic blood pressure hypertension.

Section 6.1: Clarified instructions for study drug administration.

Section 6.2: Added the combination of MLN0128+MLN117 for the investigator to 
consider when assessing whether an AE is possibly related to study drug.

Section 6.2: Revised maximum dose reductions from 2 to 3 for MLN0128.

Table 6-1: Revised paclitaxel dose reduction guidelines.

Table 6-2: Revised dose reduction schedule for MLN0128.

Section 6.3: Clarified description of excluded concomitant medications and procedures.

Section 6.5.1: Added instruction to avoid exposure to live vaccines.

Section 6.5.1: Added instruction to drink fluids to prevent dehydration.

Section 6.5.2: Clarified heading to include both single-agent paclitaxel and paclitaxel + 
MLN0128 treatment arms.

Section 6.6.1: Clarified instructions for management of hyperglycemia.

Table 6-3: Clarified instructions for dose reductions for management of clinical events to 
include only reductions in MLN0128.

Table 6-6: Clarified instructions for management of rash.

Section 6.6.6: Clarified instructions for management of QTc prolongation.

Table 6-10: Clarified dose modification instructions for Grade 2 toxicity.
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
Table 6-11: Deleted instruction on dose reduction for MLN1117 for ALT/AST elevations.

Section 7.4.9: Revised period for collection of concomitant medications and procedures to 
begin at first dose of study drug.

Section 7.4.13: Aligned clinical laboratory terminology with other phase 2 protocols and 
added protein to chemistry testing.

Section 7.4.15: Revised instructions for in-home daily fasting glucose monitoring.

Section 7.4.16: Added MRI as an optional method of disease assessment.

Section 7.4.17: Revised description of tumor biopsy assessments.

Section 7.4.18: Clarified that PK samples will be collected from patients in Arms B, C, 
and D only.

Section 7.7: Added instruction for patients to discontinue study drug(s) if they experience 
disease progression or unacceptable toxicity, or if they become pregnant.

Section 7.10: Clarified description of duration of follow-up assessments. 

Section 8.1.2: Clarified description of randomization and stratification.

Section 8.1.6: Added description of secondary efficacy endpoint comparison.

Section 10.3: Revised requirement for completed eCRFs to include only randomized 
subjects.

Section 10.11: Updated Product Complaint contact information.

Section 10.12: Added description of suspected unexpected serious adverse events 
reporting.

Section 11: Added new sections on clinical trial registration and clinical trial results 
disclosure.

Section 14.2: Added appendix describing options for acceptable methods of contraception.

Corrected typographical errors, internal inconsistencies, punctuation, grammar, and 
formatting.
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14.8
Rationale for Amendment 02
The primary purposes of this amendment are to revise the study population for Study C31004 to 
exclude patients with a known severe hypersensitivity reaction to prior paclitaxel exposure, to 
exclude patients with active hepatitis B and hepatitis C infections, and to exclude patients who 
are lactating and breastfeeding or have a positive serum pregnancy test. In addition, this 
amendment clarifies language regarding usage of contraception and updates references. 
Purposes for Amendment 02
The purposes of this amendment are to:

Add an exclusion criterion regarding females who are lactating and breastfeeding or have a 
positive pregnancy test.

Add an exclusion criterion regarding history of severe hypersensitivity reactions to 
paclitaxel.

Add an exclusion criterion regarding hepatitis B and hepatitis C infections.

Add an exclusion criterion regarding patients with hormone-positive disease who have not 
received endocrine therapy as part of previous standard therapy.

Clarify contraception language.

Add the current Summary of Product Characteristics to references to the United States 
Prescribing Information for paclitaxel.

Add >60 msec change from baseline to the description of Grade 3 rate-corrected QT 
interval prolongation.

Add reference to Declaration of Helsinki in the Investigator Agreement.

Correct typographical errors, punctuation, grammar, and formatting.
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14.9
Rationale for Amendment 03
The primary purposes of this amendment are to update the dosing conditions for subjects 
receiving weekly MLN0128 in Arm C, to update the pharmacokinetic (PK) sampling schedule to 
reflect the dosing change in Arm C, to clarify the procedures and/or timing for imaging 
collection and clinical laboratory evaluations, to clarify the MLN0128 and paclitaxel dosing 
instructions, to update the window for obtaining informed consent, and to update the procedures 
for reporting drug exposure during pregnancy and birth events.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only.
Changes in Amendment 03
1. Change the dosing conditions for subjects receiving weekly MLN0128 in Arm C, such that 
subjects take their doses with a light meal.
2. Add a PK sample collection at 3 to 6 hours postdose on Cycle 1 Day 1 for subjects receiving 
weekly MLN0128 in Arm C.
3. Clarify that all images will be collected and quality controlled by a sponsor-specified central 
imaging vendor.
4. Replace references relating to QD or QD5D dosing with the appropriate dosing instructions.
5. Clarify the procedures for fasting serum glucose monitoring.
6. Clarify that informed consent may be signed more than 28 days before Cycle 1 Day 1.
7. Clarify the dosing instructions for patients receiving paclitaxel in Arm A or Arm B.
8. Update the procedures for reporting drug exposure during pregnancy and birth events.
9. Clarify that all CT and MRI scans should be acquired with IV contrast unless contraindicated 
for a particular patient.
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14.10
Rationale for Amendment 04
This document describes the changes in reference to the protocol incorporating Amendment04. 
The primary purpose of this amendment is to update those sections affected by new nonclinical 
data for MLN0128 metabolism by specific cytochrome P450 (CYP) isoforms. The study’s 
exclusion criteria, guidelines for paclitaxel dose modification, list of prohibited concomitant 
medications, description of potential drug-drug interactions, list of relevant CYP inhibitors, and 
dietary restrictions related to CYP inhibitors and inducers have been updated accordingly.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only.
For specific descriptions of text changes and where the changes are located, see Section 14.12.
Changes in Amendment 04
1. Remove the exclusion criterion relating to treatment with strong CYP inhibitors or inducers.
2. Clarify the guidelines for paclitaxel dose modification and delay.
3. Update the list of concomitant medications prohibited during the study.
4. Update the description of potential drug-drug interactions in Arm D.
5. Update the list of relevant CYP inhibitors and inducers.
6. Remove dietary restrictions related to CYP inhibitors and inducers.
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14.11
Rationale for Amendment 05
This document describes the changes in reference to the protocol incorporating Amendment 05. 
The primary purpose of this amendment is to update the sample size for the study to reflect 
changes in study design and the closure of enrollment into Arms C and D. In addition, the 
amendment updates administrative information and clarifies the specified study procedures, 
recommendations, or requirements.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only.
Changes in Amendment 05
7. Update the sample size for the study to reflect changes in study design and the closure of 
enrollment into Arms C and D.
8. Update the Global Clinical Lead for the study.
9. Clarify the text regarding image collection for disease assessment.
10. Add that sensitivity analyses of efficacy endpoints may be performed.
11. Clarify the instructions for contrast use in tumor evaluation imaging.
12. Clarify that Screening must occur within 28 days of Cycle 1 Day 1.
13. Clarify the timing for considering doses missed in the case of emesis after study medication 
ingestion.
14. Clarify the guidelines for paclitaxel dose modifications.
15. Update the list of relevant cytochrome P450 inhibitors and inducers.
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14.12
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment 06 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1:  Removed long-term follow up (PFS follow up and/or OS follow up) for patients 
after end of treatment.
The primary change occurs in Section 4.1 Overview of Study Design, Section 4.3 Duration of 
Study, and Section 7.10 Posttreatment Follow-up Assessments (PFS and OS):
Deleted 
Text
Patients who discontinue study treatment for reasons other than progressive disease 
will continue to have PFS follow-up visits every 2 months (±1 week) for the first 6 
months after the End-of-Treatment (EOT) visit, then every 3 months (±1 week) 
until disease progression, death, or start of another anticancer therapy, whichever 
occurs first. After disease progression, patients will be followed for OS every 
3 months (±1 week).
AND
After EOT, patients will be followed for PFS and OS. For those patients who 
discontinue MLN0128 for any reason other than radiographic disease progression, 
CT (with contrast) or MRI scans (with contrast) should be completed to further 
assess disease progression (per RECIST, version 1.1).[41]
AND
7.10
Posttreatment Follow-up Assessments (PFS and OS)
After EOT, patients will be followed for PFS and OS. For those patients who 
discontinue study drug for any reason other than radiographic disease progression, 
CT (with contrast) or MRI scans (with contrast) should be completed to further 
assess disease progression (per RECIST, version 1.1) until the occurrence of 
progression or start of another anticancer therapy.[41] Refer to the Schedule of 
Events for appropriate assessments during posttreatment follow-up.
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.
NOTE: Related SAEs must be reported to the Millennium Department of 
Pharmacovigilance or designee. This includes deaths that the investigator considers 
related to study drug that occur during the posttreatment follow-up. Refer to 
Section 9 for details regarding definitions, documentation, and reporting of SAEs.
Added TextUp until Amendment 06, after EOT, patients were to be followed for PFS and 
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OS, during the Posttreatment follow-up Period.
Rationale for Change:
In July 2019, the study reached its protocol defined data-driven primary endpoint of PFS. After 
database lock and review of Topline results, it was determined that any emerging data will not 
change study conclusions in any meaningful way. Therefore, as of Protocol Amendment 6, 
requirements for long-term follow up (PFS follow up and/or OS follow up) for patients after 
EOT visit were removed. The study will continue until patients discontinue treatment.
The following sections also contain this change:
!
Protocol Summary
!
Study Overview Diagram
!
Schedule of Events
!
Section 7.7 Discontinuation of Treatment With Study Drug
Change 2: Update to the Global Clinical Lead for the study.
The primary change occurs on the Title Page:
Initial
wording
Amended 
wording:
Rationale for Change:
This change was made to update the Global Clinical Lead for the study.
Change 3:  Removed in-home glucose monitoring.
The primary change occurs in Section 6.6.1 Management of Hyperglycemia, and Section 7.4.15 
In-Home Daily Fasting Glucose Monitoring was deleted:
Initial
wording
In addition to obtaining fasting serum glucose levels at the clinic visits as outlined in 
the Schedule of Events, all patients randomized to receive MLN0128 (ie, Arm B, 
Arm C, or Arm D) will be provided with a glucometer and trained in its use to 
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Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
115
monitor their daily predose fasting blood glucose (FBG) levels at home (see Section 
7.4.14). The level should be collected daily, predose on dosing days, and at 
approximately the same time each day. 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 irregularities in the FBG level are observed during a minimum of 2 consecutive 
months, then the frequency of in-home FBG testing can be reduced to a minimum 
frequency of once weekly, depending on the investigator’s judgement and approval. 
Patients will continue to notify the investigator of FBG levels ≥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. To aggressively manage 
the hyperglycemia per standard clinical practice, the following guidelines 
(Table 6.d) are provided to aid the investigator in initiating antiglycemic therapies.
Amended 
wording:
6.6.1
Management of Hyperglycemia
In addition to ing Fasting serum glucose levels will be obtained at the clinic visits 
as outlined in the Schedule of Events and as described in more detail in 
Section 7.4.14. all patients randomized to receive MLN0128 (ie, Arm B, Arm C, or 
Arm D) will be provided with a glucometer and trained in its use to monitor their 
daily predose fasting blood glucose (FBG) levels at home (see Section 7.4.15). The 
level should be collected daily, predose on dosing days, and at approximately the 
same time each day. 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 irregularities
in the FBG level are observed during a minimum of 2 consecutive months, then the 
frequency of in-home FBG testing can be reduced to a minimum frequency of once 
weekly, depending on the investigator’s judgement and approval. Patients will 
continue to notify the investigator of FBG levels ≥150 mg/dL, and if blood glucose 
Property 
Use


MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
116
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. To aggressively manage the hyperglycemia 
per standard clinical practice, the following guidelines (Table 6.d) are provided to 
aid the investigator in initiating antiglycemic therapies.
Deleted 
Text

Monitor home glucometer test results.

FBG levels ≥150 mg/dL by glucometer should be followed by closer monitoring 
of serum glucose and possible intervention.
Deleted 
Text
7.4.15 In-Home Daily Fasting Glucose Monitoring
In addition to obtaining fasting serum glucose levels at the clinic visits as outlined in 
the Schedule of Events, all patients randomized to receive MLN0128 (ie, Arm B, 
Arm C, or Arm D) will be given a glucometer to monitor their daily FBG levels at 
home on days when fasting glucose is not measured in the clinic. The level should 
be collected daily, predose on dosing days, and at approximately the same time each 
day. Before checking their blood glucose levels, patients should fast overnight 
(nothing except water and/or medications after midnight or for a minimum of 8 
hours before the assessment). After fasted testing is complete, patients in Arm C 
should consume a light meal before MLN0128 dosing (Section 6.1).
On Cycle 1 Day 1, the patient will be provided an in-home glucometer. Patients will 
be trained on proper use of the glucometer and instructed to collect a daily (predose 
on dosing days) fasting glucose level every morning. Patients will be instructed to 
bring the glucometer with them to each study visit so that the data collected can be 
reviewed and recorded in the source documents. Investigators will be responsible for 
reviewing the home glucose monitoring logs for hyperglycemia.
The patient will be instructed to contact the site immediately if the value is abnormal 
(ie, 150 mg/dL) for further instructions on the management of their hyperglycemia. 
Hyperglycemia observed during home glucose monitoring should be confirmed in 
the clinic.
Property 
Use


MLN0128
Clinical Study Protocol C31004 Amendment 06, EudraCT: 2014-005394-37
117
If no irregularities in the FBG level are observed during a minimum of 2 consecutive 
months, then the frequency of in-home FBG testing can be reduced to a minimum 
frequency of once weekly, depending on the investigator’s judgement and approval. 
Patients will continue to notify the investigator of FBG levels that exceed 150 
mg/dL and, if blood glucose levels are not well controlled, or if the patient requires 
either oral hypoglycemic agents or insulin to control blood glucose levels, then the 
frequency of in-home testing of FBG levels will be reinstated to daily.
See also Section 6.6.1.
Rationale for Change:
In July 2019, the study reached its protocol defined data-driven primary endpoint of PFS. After 
review of safety data, it was determined that there was no significant difference in incidence of 
hyperglycemia between patients in Arm A (paclitaxel) and Arm B (paclitaxel + TAK-228). 
Therefore, as of amendment 6, requirement for in-home monitoring was removed. Patients will 
continue to be evaluated for fasting blood sugar as per Schedule of Events.
The following sections also contain this change:

Schedule of Events

7.4.14 Fasting Serum Glucose
Property 
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Property 
Use
PPD

SAP_000.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor), 
MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of Weekly 
Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent Endometrial 
Cancer
NCT Number: NCT02725268
SAP Approve Date: 07 September 2018
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C31004
A Phase 2, Randomized Study of MLN0128 (a Dual TORC1/2 Inhibitor),
MLN0128+MLN1117 (a PI3Kα Inhibitor), Weekly Paclitaxel, or the Combination of
Weekly Paclitaxel and MLN0128 in Women With Advanced, Recurrent, or Persistent
Endometrial Cancer
PHASE 2
Version: Final
Date: 07 September 2018
Prepared by:
Based on:
Protocol Version: Protocol Amendment No. 05
Protocol Date: 23 January 2018
Property of Takeda: Fo
mmercial use only and subject to the applicable Terms of Use
TORC1/2
ORC1
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PPD


C31004
Page 2 of 37
Statistical Analysis Plan Final
07 September 2018
1.1
APPROVAL SIGNATURES
Electronic signatures can be found on the last page of this document.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


C31004
Page 3 of 37
Statistical Analysis Plan Final
07 September 2018
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
APPROVAL SIGNATURES.....................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Quality of Life Objectives..........................................................................................7
4.4
Exploratory Objectives ..............................................................................................7
4.5
Study Design .............................................................................................................8
4.5.1
Overview of Study Design ...................................................................................8
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoint.....................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Quality of Life Endpoints.........................................................................................10
5.4
Exploratory Endpoints .............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................12
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................13
7.1
General Principles....................................................................................................13
7.1.1
Methods for Handling Missing Data...................................................................13
7.1.2
Definitions of Baseline Values...........................................................................13
7.1.3
Definition of Study Days....................................................................................14
7.2
Analysis Sets ...........................................................................................................14
7.3
Disposition of Subjects ............................................................................................15
7.4
Demographic and Other Baseline Characteristics.....................................................15
7.5
Medical History and Concurrent Medical Conditions...............................................16
7.6
Medication History and Concomitant Medications...................................................16
7.6.1
Prior Therapies...................................................................................................17
7.6.2
Follow-up Anti-cancer Therapy .........................................................................17
7.7
Study Drug Exposure and Compliance.....................................................................17
7.7.1
Study Treatments ...............................................................................................17
7.7.2
Extent of Exposure.............................................................................................17
7.7.3
Action on Drug ..................................................................................................18
7.8
Efficacy Analysis.....................................................................................................18
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C31004
Page 4 of 37
Statistical Analysis Plan Final
07 September 2018
7.8.1
Primary Efficacy Endpoint(s).............................................................................18
7.8.2
Secondary Efficacy Endpoint(s).........................................................................21
7.8.3
Additional Efficacy Endpoint(s).........................................................................24
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................25
7.9.1
Pharmacokinetic Analysis ..................................................................................25
7.9.2
Pharmacodynamic Analysis ...............................................................................25
7.10
Patient Reported Outcomes......................................................................................26
7.10.1 EORTC QLQ-C30 and EORTC QLQ-EN24 Scores...........................................26
7.10.2 Percentage of Patients Experiencing Improvement or Deterioration ...................26
7.10.3 Time to Deterioration.........................................................................................29
7.11
Safety Analysis........................................................................................................29
7.11.1 Adverse Events ..................................................................................................29
7.11.2 Vital Signs .........................................................................................................32
7.11.3 12-Lead ECGs ...................................................................................................32
7.11.4 ECOG Performance Status.................................................................................33
7.12
Interim Analysis ......................................................................................................33
7.13
Changes in the Statistical Analysis Plan...................................................................34
8.0
REFERENCES..............................................................................................................35
9.0
APPENDIX...................................................................................................................36
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Page 5 of 37
Statistical Analysis Plan Final
07 September 2018
3.0
LIST OF ABBREVIATIONS
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
CBR
clinical benefit rate
CR
complete response
CRF
case report form
CT
computed tomography
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EORTC QLQ-EN24
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Endometrial Cancer Module
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire
EOT
end of treatment
INR
international normalized ratio
IRC
Independent review committee
ITT
intent-to-treat
IRT
Interactive Response Technology
MedDRA
Medical Dictionary for Regulatory Activities
MLN0128
also known as TAK-228
MRI
magnetic resonance imaging
mTOR
mammalian (or mechanistic) target of rapamycin
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)
PO
by mouth (oral)
PPI
proton pump inhibitor
PR
partial response
PRO
patient-reported outcome
PTEN
phosphatase and tensin homolog
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
arch and T
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Page 6 of 37
Statistical Analysis Plan Final
07 September 2018
Abbreviation
Term
PT
prothrombin time 
QD
quaque die; each day; once daily
QD×3 QW
once daily for 3 days each week
QOL
quality of life
QTc
rate-corrected QT interval (msec)
QTcF
QT interval (msec) with Fridericia correction
QW
once weekly
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
TEAE
treatment-emergent adverse events
TORC1
mammalian (or mechanistic) target of rapamycin complex 1
TORC2
mammalian (or mechanistic) target of rapamycin complex 2
TTP
time to progression
ULN
upper limit of the normal range
WBC
white blood cell
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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Statistical Analysis Plan Final
07 September 2018
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective of the study is:
!
To determine if MLN0128 in combination with weekly paclitaxel improves progression free 
survival (PFS) compared to weekly paclitaxel alone.
4.2
Secondary Objectives
The secondary objectives of the study are:
!
To determine if single-agent MLN0128 improves PFS compared to weekly paclitaxel alone.
!
To determine if MLN0128 + MLN1117 improves PFS compared to weekly paclitaxel alone.
!
To assess the safety and tolerability of single-agent MLN0128, MLN0128 in combination 
with paclitaxel, and MLN0128 + MLN1117.
!
To evaluate improvement in efficacy measures (endpoints other than PFS) of MLN0128 in 
combination with weekly paclitaxel, single-agent MLN0128, and MLN0128 + MLN1117 
compared to weekly paclitaxel alone.
!
To collect plasma concentration-time data with sparse PK sampling to contribute to future 
population PK analysis.
4.3
Quality of Life Objectives
The health-related quality of life (HRQL) objective is:
!
To assess the QOL and symptoms in patients treated with MLN0128 in combination with 
weekly paclitaxel, single-agent MLN0128, and MLN0128 + MLN1117 to weekly paclitaxel 
alone.
4.4
Exploratory Objectives
The exploratory objectives of the study are:
Prope
or non-commercial use only and subject to the applicable Terms of Use
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Page 8 of 37
Statistical Analysis Plan Final
07 September 2018
4.5
Study Design
4.5.1
Overview of Study Design
This study is a phase 2, open-label, randomized, multicenter, 4-arm study of the safety and
efficacy of MLN0128 in combination with paclitaxel, single-agent MLN0128, single-agent
paclitaxel, and MLN0128 in combination with MLN1117 in adult women with advanced
endometrial cancer. The patient population will consist of women with histologic or cytologic
diagnosis of endometrial carcinoma (including endometrioid, serous, mixed adenocarcinoma,
clear-cell carcinoma, or carcinosarcoma) that is advanced, recurrent, or persistent, that has
relapsed or is refractory to curative therapy or established treatments. Patients must have had 1 
prior platinum-based chemotherapeutic regimen, but not more than 2 prior systemic
chemotherapy regimens.
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. Study drug will be administered in 28-day
treatment cycles.
Approximately 242 patients will be randomized at a ratio of 1:1:1:1 to receive study drug in 1 of
4 treatment arms:
Arm A: paclitaxel 80 mg/m2 weekly on Days 1, 8, and 15 of a 28-day cycle
Arm B: paclitaxel 80 mg/m2 weekly on Days 1, 8, and 15 of a 28-day cycle
+ MLN0128 4 mg on Days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle
Arm C: MLN0128 30 mg once weekly (QW) on Days 1, 8, 15, and 22 of a 28-day cycle
Arm D: MLN0128 4 mg + MLN1117 200 mg on Days 1-3, 8-10, 15-17, and 22-24 of a 28-day 
cycle
A centralized randomization will be used with the following stratification factors:

Histological subtype: endometrioid vs. nonendometrioid.

Lines(s) of prior chemotherapy: 1 vs. 2.

Prior taxane therapy (other than weekly): yes vs. no.
In the event that enrollment into a treatment arm(s) is closed, patients will be randomized 1:1 
into the remaining treatment arms. Paclitaxel will be administered intravenously (IV) while 
MLN0128 and MLN1117 will be administered PO throughout the study. Patients in Arm A and 
Arm B will receive paclitaxel alone or paclitaxel + MLN0128 until they experience disease 
progression, unacceptable toxicity, or withdraw consent. Patients in Arm B who discontinue 
paclitaxel prior to disease progression may continue to receive MLN0128 alone until they 
experience disease progression, unacceptable toxicity, or withdraw consent. In addition, patients 
will receive MLN0128 (in Arm C) or MLN0128 + MLN1117 (in Arm D) continuously until they 
experience disease progression, unacceptable toxicity, or withdraw consent. Patients who 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


C31004
Page 9 of 37
Statistical Analysis Plan Final
07 September 2018
discontinue study treatment for reasons other than progressive disease will continue to have PFS 
follow-up visits every 2 months (± 1 week) for the first 6 months after the end-of-treatment 
(EOT) visit, then every 3 months (± 1 week) until disease progression, death, or start of another 
anticancer therapy, whichever occurs first. After disease progression, patients will be followed 
for OS every 3 months (± 1 week).
Patients will attend the EOT visit 30 to 40 days after receiving their last dose of study drug.
Sparse PK samples will be collected from patients enrolled in Arms B, C, and D for
determination of the plasma concentration of MLN0128 and/or MLN1117 during Cycle 1 at
prespecified time points as described in the Pharmacokinetic Sample Breakdown table in the 
study protocol. 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. For correlative 
biomarker analysis, fresh and archival tumor samples will be obtained during screening, as well 
as a blood sample for
at prespecified time points as described in the Schedule of Events
in the study protocol. In addition, fresh tumor samples will be obtained 2 to 4 hours after dosing 
on Cycle 1 Day 22 from patients in Arms C and D to identify adaptive response mechanisms to 
treatment of MLN0128 or MLN0128 + MLN1117.
Radiological tumor evaluations (computed tomography [CT] scan with 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). Radiographic tumor evaluations will be performed at the 
time points specified in the Schedule of Events in the study protocol.
Changes in QOL disease-specific symptoms will be assessed using the European Organization
for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and
the Endometrial Cancer Module (EORTC QLQ-EN24). In addition to assessing selected
symptoms, these instruments will measure the effects of disease and treatment on physical, role,
emotional, cognitive, and social functioning.
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, and laboratory values, vital signs, and electrocardiograms will
be obtained to evaluate the safety and tolerability of MLN0128 in combination with paclitaxel,
single-agent MLN0128, and MLN0128 + MLN1117.
There will be 2 interim analyses with early stopping rules for futility in the single-agent 
MLN0128 arm (Arm C) and MLN0128+MLN1117 arm (Arm D).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Page 10 of 37
Statistical Analysis Plan Final
07 September 2018
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint is Progression Free Survival (PFS).
5.2
Secondary Endpoints
The secondary endpoints are:
!
The number and percentage of patients with treatment-emergent adverse events (TEAEs).
!
Overall survival (OS).
!
Time-to-progression (TTP).
!
Objective response rate (ORR; defined as complete response [CR]+partial response [PR] per 
Response Evaluation Criteria in Solid Tumors [RECIST] Version 1.1).
!
Clinical benefit rate (CBR; defined as CR+PR+stable disease (SD)) with SD of any duration.
!
CBR at 16 weeks (CBR-16 is defined as the proportion of patients who achieve CR or PR of 
any duration or have SD with a duration of at least 16 weeks).
5.3
Quality of Life Endpoints
The QOL endpoints are:
!
Change from baseline in the EORTC QLQ-C30 global health status (GHS)/QOL score to end 
of study visit.
!
Change from baseline in the EORTC QLQ-C30 functioning score to end of study visit.
!
Change from baseline in the EORTC QLQ-C30 symptom score to end of study visit.
!
Change from baseline in the EORTC QLQ-EN24 score to the end of study visit.
5.4
Exploratory Endpoints
The exploratory endpoints are:
Prop
For non-commercial use only and subject to the applicable Terms of Use
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C31004
Page 11 of 37
Statistical Analysis Plan Final
07 September 2018
Note: Exploratory endpoints will not be reported in the Clinical Study Report and these
endpoints are not discussed further in the SAP.
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6.0
DETERMINATION OF SAMPLE SIZE
The primary efficacy endpoint of the study is PFS and the primary comparison is between the
paclitaxel and the paclitaxel + MLN0128 4 mg QDx3 treatment arm. Assuming the median PFS 
is 4 months for paclitaxel and paclitaxel + MLN0128 4 mg QDx3 can improve the median to 6.5
months (hazard ratio of 0.615, approximately 38% reduction in the hazard rate) a total of 134
PFS events and 90 patients per treatment arm are required. The calculations are based on a power 
of 80%, 2-sided alpha of 5%, and a dropout rate of 15% due to lost to follow-up or withdrawal of
consent. Enrollment to the third treatment arm of single-agent MLN0128 30 mg QW and the 
fourth treatment arm of MLN0128 4 mg QDx3 in combination with 200 mg MLN1117 has been 
closed. The total sample size for the study will be approximately 242 patients.
The total accrual duration will be approximately 25 months to complete enrollment in the 
paclitaxel and paclitaxel+MLN0128 4 mg QD3 treatment arms. The final analysis for the 
primary comparison of PFS between the paclitaxel treatment arm and the paclitaxel + MLN0128 
4 mg QDx3 treatment arm will occur approximately 5 months after the last patient is 
randomized.
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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4.
Continuous data will be summarized using descriptive statistics (number of observations, mean, 
standard deviation, median, 25th and 75th percentiles (where specified), minimum, and 
maximum). Frequencies and percentages will be used for summarizing categorical (discrete) 
data. For summaries of categorical variables percentages are based on the number of subjects 
with non-missing values unless otherwise specified (e.g. objective response rate, clinical benefit 
rate, CBR at 16 weeks).
Confidence intervals, when presented, will generally be constructed at the 95% level. For 
binomial variables, the normal approximation methods will be employed unless otherwise 
specified.
All statistical tests and resulting p-values will be reported as 2-sided and will be assessed at 
α=0.05 significance level unless otherwise stated. P-values should be presented to 3 decimal 
places, with values less than 0.001 presented as <0.001.
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate. Percentages will be presented to 1 decimal place.
A month is operationally defined to be 30.4375 days. 
Where specified, there will be three pair-wise comparisons between paclitaxel vs. 
paclitaxel+MLN0128, between paclitaxel vs. MLN0128 and between paclitaxel vs. 
MLN0128+MLN1117.
7.1.1
Methods for Handling Missing Data
For efficacy and safety data, no imputation of values for missing data will be performed. For 
patient reported outcomes, handling of missing data is discussed in section 7.10. Data imputation 
rules for incomplete dates are described in Appendix B.
7.1.2
Definitions of Baseline Values
In general, for efficacy endpoints the last observed measurement prior to randomization will be 
considered the baseline measurement. For safety end points the last observation before first dose 
of study drug will be considered the baseline measurement. For patient-reported outcomes the 
last observed measurement on or before the date of first dose of study drug will be considered 
the baseline measurement.
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7.1.3
Definition of Study Days
For the purpose of efficacy data summary, Day 1 is defined as the date of randomization. For 
visits (or events) that occur on or after randomization, Day is defined as (date of visit [event] –
date of randomization + 1). For visits (or events) that occur prior to randomization, Day is 
defined as (date of visit [event] – date of randomization). There is no Day 0.
For the purpose of safety data summary or calculations of time since baseline, Study Day 1 is 
defined as the date on which a subject is administered their first dose of study drug. For visits (or 
events) that occur on or after the first dose of study drug, study day is defined as (date of visit 
[event] – date of first dose of study drug + 1). For visits (or events) that occur prior to Study Day 
1, study day is defined as (date of visit [event] – date of first dose of study drug). There is no 
Study Day 0.
7.2
Analysis Sets

Intent-to-treat (ITT) population: all randomized patients. Patients will be analyzed according 
to the randomization assignment. The ITT population will be used for the primary efficacy 
analysis of PFS, and secondary efficacy endpoints including OS and TTP.

Safety population: patients who receive at least 1 dose of study drug. Patients will be 
analyzed according to the treatment arm actually received. The safety population will be 
used for all safety analyses. In addition, the safety population will be used for a sensitivity 
analysis of secondary efficacy endpoints ORR, CBR and CBR-16 and the best overall 
response and patients will be analyzed according to the randomization assignment.

Response-evaluable population: patients who receive at least 1 dose of study drug, have 
measurable disease at Baseline, and have 1 post-Baseline disease assessment. Patients will be 
analyzed according to the randomization assignment. The response-evaluable population will 
be used for the primary analysis of secondary efficacy endpoints of ORR, CBR and CBR-16, 
and the best overall response.

Per-protocol population: all ITT patients who meet the following criteria:
–
Had at least one adequate post-randomization tumor assessment.
–
Received treatment as randomized.
–
Did not have any major or important protocol deviations that would potentially impact 
the interpretation of the efficacy analyses.
The subset of major/important protocol deviations that would exclude a patient from the 
per protocol population will be based on a review of the protocol deviations in the 
clinical trial management system and will be documented prior to database lock. The per-
protocol population will be used for a sensitivity analysis of PFS, and secondary efficacy 
endpoints including OS and TTP.
The number and percentage of patients in each population will be summarized.
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7.3
Disposition of Subjects
Study information including the date first subject signed ICF, date of last subject’s last 
visit/contact, date of last subject’s last procedure for collection of data for primary endpoint of 
PFS, MedDRA version, WHO Drug version and SAS Version will be generated in a summary 
table. The date of last procedure for PFS is the date of progressive disease or death, otherwise 
use the date of the last response assessment.
The disposition of patients includes the number and percentage of patients for the following 
categories: randomized and not treated, discontinued study drug, primary reason to discontinue
study drug, ongoing (if applicable at the time of DB lock), discontinued from the study, and 
primary reason to discontinue from the study. All percentages will be based on the number of 
patients in the ITT population.
7.4
Demographic and Other Baseline Characteristics
Summaries of demographics, baseline characteristics and stratification factors will be presented 
for subjects in the ITT population.
The demographic characteristics consist of:

Age (continuous)

Age category 1
o
< 65 years
o
≥ 65 years

Age category 2
o
Adults (18-64 years)
o
From 65 to 84 years
o
85 years and over

Height (cm)

Weight (kg) – screening if available otherwise C1D1

Ethnicity

Race

Geographic Region, Country, Site
Australia and New Zealand
North America
  - Canada
   - United States
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Europe
   - Belgium
    - Germany
    - Italy
    - Netherlands
    - Norway
    - Spain
    - United Kingdom
Baseline characteristics consist of:

Time since initial diagnosis (months) [date of first dose – date of initial 
diagnosis/(30.4375))].

Histological classification [Endometrioid adenocarcinoma, NOS; Serous
cystadenocarcinoma, NOS; Mixed cell adenocarcinoma; Clear cell adenocarcinoma, 
NOS; Carcinosarcoma, NOS; Unknown].

Histological grade [Well differentiated (G1); Moderately differentiated (G2); Poorly 
differentiated (G3); Undifferentiated (G4)].

ER status

PR status

Microsatellite stability

ECOG Performance Status (categorical)
Stratification factors consist of:

Histological subtype: endometrioid vs. non-endometrioid

Prior lines of chemotherapy: 1 vs. 2

Prior taxane therapy: yes vs. no.
There will be separate summaries for stratification by original IRT and corrected IRT.
7.5
Medical History and Concurrent Medical Conditions
No summary for medical history and concurrent medical conditions.
7.6
Medication History and Concomitant Medications
No summary for medication history.
The number and percentage of patients taking concomitant medications will be tabulated by 
WHO standardized medication name based on safety population. Concomitant medications are 
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medications ongoing at the time of the first dose of study drug or medications that started after 
first dose and within 30 days of the last dose of study drug. 
7.6.1
Prior Therapies
The number and percentage of patients with prior radiation, and prior anti-cancer therapies will 
be summarized based on safety population. The following will be summarized for those patients 
with prior anti-cancer therapies:

Type of prior anti-cancer therapy (WHO drug standardized medication name).

Best response to most recent prior therapy.

Prior therapy in the adjuvant setting (Y, N).

First systemic chemotherapy for metastatic disease (Y, N).
7.6.2
Follow-up Anti-cancer Therapy
Number and percentage of patients receiving any anti-cancer therapy, and type of anti-cancer 
therapy will be summarized based on safety population.
7.7
Study Drug Exposure and Compliance
7.7.1
Study Treatments
Cycles consist of 28 days for all treatment arms. In Treatment Arm A, paclitaxel will be 
administered weekly on Days 1, 8, 15 of a 28-day cycle. In Treatment Arm B, paclitaxel will be 
administered weekly on Days 1, 8, 15 of a 28-day cycle + MLN0128 administered on Days 2-4, 
9-11, 16-18 and 23-25 of a 28-day cycle. In Treatment Arm C, MLN0128 will be administered 
once weekly on Days 1, 8, 15, and 22 of a 28-day cycle. In Treatment Arm D, MLN0128 and 
MLN1117 will be administered together, 3 consecutive days per week (on Days 1-3, 8-10, 15-17, 
and 22-24 of a 28-day treatment cycle), and should be taken on the same days of each week.
7.7.2
Extent of Exposure
Summaries and descriptive statistics of duration of treatment in weeks ((last dose date – start 
dose date + 1)/7), total number of cycles administered, cumulative dose for each study drug, 
planned cumulative dose for each study drug and relative dose intensity will be summarized by 
treatment arm for patients in the safety population. For patients who discontinued Paclitaxel but 
stayed on MLN0128, number of treatment cycles will be summarized.
Number of cycles administered = A treated cycle is defined as a cycle in which the patient 
received any amount of study drug. This is defined as Actual Dose greater than zero for at least 
one of the dosing day in the cycle for any study drug.
Cumulative dose (mg) = Sum of all doses (mg) administered to a subject during the treatment 
period.
Relative dose intensity = cumulative dose / planned cumulative dose.
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Paclitaxel (weekly on Days 1, 8 and 15 of a 28-day cycle)
Relative dose intensity for Paclitaxel (%) is defined as:
Cumulative dose (mg) / [Number of planned dose from start dose date to last dose date*80mg/
m2] * 100
Number of planned dose = Number of completed 28-day cycle from start dose date to last dose 
date*3 doses per cycle + Number of doses in the uncompleted cycle
MLN0128 QDx3 (Days 2-4, 9-11, 16-18 and 23-25 of a 28-day cycle)
MLN1117 / MLN0128 (Days 1-3, 8-10, 15-17 and 22-24 of a 28-day cycle)
Relative dose intensity (%) presented separately for MLN0128 and MLN1117 is defined as:
{Cumulative dose (mg) / [Number of planned dose from start dose date to last dose date*Starting 
dose]} * 100
Number of planned dose = Number of completed week from start dose date to last dose date*3 
doses per week + Number of doses in the uncompleted week
MLN0128 QW (Days 1, 8, 15 and 22 of a 28-day cycle)
Relative dose intensity for MLN0128 (%) is defined as:
Cumulative dose (mg) / [Number of planned dose from start dose date to last dose date*30mg] * 
100
Number of planned dose = Number of completed 28-day cycle from start dose date to last dose 
date*4 doses per cycle + Number of doses in the uncompleted cycle
7.7.3
Action on Drug
Action on study drug will be summarized by each cycle (Cycles 1-8) and total, for each 
treatment arm in the safety population.
7.8
Efficacy Analysis
The analysis of PFS, OS and TTP will be based on the ITT population and the PP population. 
The analysis of ORR, CBR and CBR-16 will be based on both safety and response-evaluable 
analysis populations. The primary analysis for all efficacy endpoints are based on the 
investigator response assessment per RECIST 1.1 criteria.
7.8.1
Primary Efficacy Endpoint(s)
The primary endpoint is PFS, defined as the time from the date of randomization to the date of 
first documentation of progression or death due to any cause, whichever occurs first. Progression 
is based on the investigator response assessment per RECIST 1.1 criteria. PFS in months is 
defined as:
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PFS (months) = (earliest date of progression or death – date of randomization + 1)/30.4375
In the event of progression, the date of progression is defined as the earliest date among target 
lesions, non-target and new lesions dates at that particular visit.
For a patient whose disease has not progressed and is last known to be alive, PFS will be 
censored at the last response assessment that is SD or better.
The approach for handling of missing response assessments and censoring is presented 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 Assessments
Functionally this corresponds to a response assessment with an investigator’s assessment other 
than not evaluable or missing (i.e. CR, PR, SD or PD).
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PFS Analysis
The primary efficacy analysis will be based on the ITT population. The Kaplan-Meier method 
will be used to analyze the distribution of PFS for each treatment arm. Kaplan-Meier survival 
curves, the 25th, 50th (median), and 75th percentiles, along with associated 2-sided 95% 
confidence intervals (CIs) based on Brookmeyer and Crowley, and Kaplan-Meier estimates with 
95% CIs at 6, 12 and 18 and 24 months will be presented. The primary hypothesis will be tested 
at the 0.1 significance level (1-sided). The p-values from a stratified log-rank test and hazard 
ratios (and 95% CI) estimated from a stratified Cox regression model with treatment arm and 
stratification factors as covariates will be presented for comparison of paclitaxel to
paclitaxel+MLN0128, paclitaxel to MLN0128 and paclitaxel to MLN0128+MLN1117. The 
stratification factors are the histological subtype (endometrioid vs. non-endometrioid), the lines 
of prior chemotherapy (1vs. 2) and prior taxane therapy (yes vs. no). The original IRT 
stratification factors will be used in models.
The source of PFS (death or progressive disease) will be summarized by treatment group.
The reasons for censoring in the PFS Kaplan-Meier analysis will be tabulated for each treatment 
group:

Received subsequent anti-cancer therapy.

No baseline or no post baseline response assessment.

Death or progression after more than 1 missed visit.

Withdrawal of consent.

Lost to follow-up.

No documented death or disease progression.
7.8.1.1
Sensitivity Analyses of the Primary Efficacy Endpoint (PFS)
Sensitivity analyses will be performed in order to explore the robustness of the results of the 
primary analysis.
PFS Sensitivity Analysis 1: account for missing tumor assessment prior to PFS event 
(progression or death).
This analysis will be performed only if at least 20% of events of disease progression were 
documented subsequent to missing 2 or more adequate tumor assessments.

Subjects who miss 2 or more consecutive adequate scheduled tumor assessments 
immediately followed by an event of disease progression will be censored on the date of their 
most-recent adequate tumor assessment prior to the missing/inadequate assessments.

If 2 or more consecutive missing adequate assessments are immediately followed by an 
adequate assessment with an overall response assignment of SD, PR, or CR, this will deemed 
sufficient clinical evidence that progression did not occur during the period of missing data 
and the missing evaluations will be ignored.
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PFS Sensitivity Analysis 2: discrepancy between original stratification in IRT system and
corrected stratification in IRT system
The p-values from a stratified log rank test and the hazard ratio along with its 95% confidence 
interval will be estimated using a stratified Cox regression model with treatment arm and 
stratification factors as covariates. PFS will be compared between treatment groups using the 
corrected IRT strata. This analysis will be performed if at least one stratification variable 
between the original IRT and the corrected IRT disagrees for at least 10% of the randomized 
subjects.
PFS Sensitivity Analysis 3: repeat the primary PFS analysis using the per-protocol 
population
PFS Sensitivity Analysis 4: repeat the primary PFS analysis based on IRC assessment (see 
section 7.8.3)
7.8.1.2
Subgroup Analyses
The analysis of PFS will be repeated in each of the following subgroups. The focus of the 
subgroup analyses is to assess the consistency of treatment effects and to present number of 
patients with events/censored, 25th, median and 75th percentile with HR and 95% CI within each 
subgroup for the 3 comparisons: paclitaxel vs. paclitaxel+MLN0128, paclitaxel vs. MLN0128 
and paclitaxel vs. MLN0128+MLN1117. In addition, number of events/number of patients, HR 
and 95% CI within each subgroup for the 3 treatment comparisons will be presented as part of 
the forest plots and individual Kaplan-Meier survival curves for each subgroup will be presented.

Age (< 65 years, ≥65 years).

Race (white, non-White) – [Not Reported will be excluded].

Region (North America, outside of North America).
Stratification factors per IRT (original):

Histological subtype (endometrioid vs. non-endometrioid).

Lines of prior chemotherapy (1 vs. 2).

Prior taxane therapy (yes vs. no).
7.8.2
Secondary Efficacy Endpoint(s)
Secondary efficacy endpoints include OS, ORR, TTP, CBR with SD of any duration, and CBR
with SD duration of at least 16 weeks. The analyses of OS and TTP will be done for both the ITT 
and the per-protocol populations. The analyses of ORR, CBR and CBR-16 will be done for both 
the safety and response-evaluable populations.
In the event of response (i.e. overall response is PR or better), the date used for start of response 
is defined as the latest of all dates among target lesions or non-target lesions dates at that 
particular visit. 
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Overall survival (OS)
Overall survival in months is defined as the time from the date of randomization to the date of 
death [date of death (OS (months) = (date of death – date of randomization + 1)/30.4375)]. 
Patients without documentation of death at the time of analysis will be censored at the date last 
known to be alive. The Kaplan-Meier method will be used to analyze the distribution of OS for 
each treatment arm. Kaplan-Meier survival curves, the 25th, 50th (median), and 75th percentiles, 
along with associated 2-sided 95% confidence intervals (CIs), and Kaplan-Meier estimates with 
95% CIs at 6, 12 and 18 and 24 months will be presented. A stratified log-rank test and hazard 
ratios (and 95% CI) estimated from a stratified Cox regression model with treatment arm and 
stratification factors as covariates will be presented for comparison of paclitaxel to 
paclitaxel+MLN0128, paclitaxel to MLN0128 and paclitaxel to MLN0128+MLN1117. The 
stratification factors are the histological subtype (endometrioid vs. non-endometrioid), the lines 
of prior chemotherapy (1vs. 2) and prior taxane therapy (yes vs. no). The original IRT 
stratification factors will be used in models.
Best Overall Response
Best overall response is defined as the best response recorded after the first dose of study drug 
until subsequent therapy.
Best Overall Response (unconfirmed): This will be the best response reported by the 
investigator; ordered from best to worst: Complete Response, Partial Response, Stable Disease, 
Progressive Disease. The best response can also be Not Evaluable (NE) or No assessment 
performed if this is the only investigator assessment of objective response available for the 
patient.
Best Overall Response (confirmed): This will be the best response reported by the investigator; 
ordered from best to worst: Complete Response, Partial Response, Stable Disease, Progressive 
Disease. Complete or partial responses may be claimed as best response only if the criteria for 
each are met at a subsequent time. For the best overall response (confirmed), the confirmation 
derivation rules will be as described in the following table.
Overall response 1st time point
Overall response subsequent time point
BEST overall response
CR
CR
CR
CR
PR
PR
CR
SD
SD
CR
PD
SD
CR
NE
SD
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD
PR
NE
SD
NE
NE
NE
Note: No adjustment for a minimum criteria for SD is needed as the first protocol scan is at the 
end of cycle 2, approximately 8 weeks from first dose.
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Overall response rate (ORR) is defined as the proportion of patients among response evaluable 
population who achieve a best overall response of CR or PR based on investigators assessment 
of response following RECIST 1.1. ORR will be summarized by both ORR based on 
unconfirmed best response and ORR based on confirmed best response. A stratified Cochran-
Mantel-Haenszel (CMH) test based on stratification factors will be used to compare ORR 
between treatment arms based on the original IRT (paclitaxel vs. paclitaxel+MLN0128, 
paclitaxel vs. MLN0128 and paclitaxel vs. MLN0128+MLN1117). The Mantel-Haenszel 
estimate of the odds ratio and the associated 95% CIs will be presented for each comparison 
specified above based on original IRT.
Clinical Benefit Rate (CBR)
CBR is defined as the proportion of patients who achieve a best response of CR, PR, or SD of 
any duration. CBR will be presented for both CBR based on unconfirmed best response and CBR 
based on confirmed best response. A stratified Cochran-Mantel-Haenszel (CMH) test based on 
stratification factors will be used to compare CBR between treatment arms (paclitaxel vs. 
paclitaxel+MLN0128, paclitaxel vs. MLN0128 and paclitaxel vs. MLN0128+MLN1117). The 
Mantel-Haenszel estimate of the odds ratio and the associated 95% CIs will be presented for 
each comparison specified above.
Clinical Benefit Rate at 16 weeks (CBR-16)
CBR at 16 weeks (CBR-16) is defined as the proportion of patients who achieve CR or PR of 
any duration or have SD with a duration of at least 16 weeks (see below). CBR-16 will be 
summarized based on unconfirmed best response and confirmed best response. A stratified 
Cochran-Mantel-Haenszel (CMH) test based on stratification factors will be used to compare 
CBR-16 between treatment arms (paclitaxel vs. paclitaxel+MLN0128, paclitaxel vs. MLN0128 
and paclitaxel vs. MLN0128+MLN1117). The Mantel-Haenszel estimate of the odds ratio and 
the associated 95% CIs will be presented for each comparison specified above.
SD for at least 16 weeks is a subset of SD, only calculated for those patients with a best response 
of SD. It is defined as SD at the end of Cycle 2 and at the end of Cycle 4 (see below for 
exceptions).
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 (at the end of Cycle 2 and at the end of Cycle 4).
CBR at 16 weeks (confirmed) is defined as the number of patients who achieve confirmed CR or 
confirmed PR at any time or have SD for at least 16 weeks or meet the following criteria:
Overall response at end of Cycle 2
Overall response at end of Cycle 4
Meet criteria for SD for at least 16 
weeks?
CR/PR (unconfirmed)
SD
YES
SD
CR/PR (unconfirmed)
YES
In addition, the proportion of patients in the following categories will be summarized by 
treatment group: CR, PR, SD, SD at least 16 weeks, overall response (ORR), CBR and CBR-16 
weeks.
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Time to Tumor Progression (TTP)
TTP in months is defined as the time from the date of randomization to the date of first 
documentation of progression [ (date of first documentation of progression – date of 
randomization + 1)/30.4375)]. For a patient whose disease has not progressed, TTP will be 
censored at the last response assessment that is SD or better. 
The Kaplan-Meier method will be used to analyze the distribution of TTP for each treatment 
arm. Kaplan-Meier survival curves, the 25th, 50th (median), and 75th percentiles, along with 
associated 2-sided 95% confidence intervals (CIs), and Kaplan-Meier estimates with 95% CIs at 
6, 12 and 18 and 24 months will be presented. A stratified log-rank test and hazard ratios (and 
95% CI) estimated from a stratified Cox regression model with treatment arm and stratification 
factors as covariates will be presented for comparison of paclitaxel to paclitaxel+MLN0128, 
paclitaxel to MLN0128 and paclitaxel to MLN0128+MLN1117. The stratification factors are the 
histological subtype (endometrioid vs. non-endometrioid), the lines of prior chemotherapy (1vs. 
2) and prior taxane therapy (yes vs. no). The original IRT stratification factors will be used in 
models.
7.8.3
Additional Efficacy Endpoint(s)
The duration of objective response (DOR) will be calculated for those patients with a best 
response of CR or PR (for both unconfirmed and confirmed), and is defined as the number of 
days from the start date of CR, or PR (whichever response is achieved first) until progressive 
disease or until the last adequate response assessment if there is no progressive disease. The 
analysis of duration of response will be descriptive in nature and will be based on response-
evaluable population.
Waterfall plots of the best percentage change from baseline in the sum of the longest diameter
(SLD) of the target lesions will be generated for each treatment group using the response-
evaluable population. If one of the target lesion measurements is missing at a visit then the SLD 
at that visit will not be used for selecting the best percentage change from baseline in SLD for 
the waterfall plot. The sum of longest diameters (SLD) will be calculated based on the following 
rules:
1. If a target lesion at a visit is “too small to measure”, per the CRF completion guidelines the 
value of 5 mm should have been entered as the diameter. This would be used to calculate the 
SLD.
2. If 2 target lesions conjoin into a single lesion (status=”coalesce”), per the CRF completion 
guidelines the LD of the resulting merged lesion is divided by 2 and reported in the CRF for 
each of the previous TL and then would be included in the SLD. 
3. If a target lesion splits into 2 lesions (status=”split”), the LDs of the fragmented portions are 
added up and reported in the CRF and would be included in the SLD.
4. Sum of the target lesions (SLD) [in mm] is defined as the sum of the longest diameters of all 
target lesions at each visit.
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5. SLD change from baseline at visit x [in mm] is defined as the absolute change in the SLD 
from baseline to each visit = “SLD at visit x” – “SLD at baseline”. Baseline SLD 
corresponds to the SLD from the screening visit.
6. Percentage change from baseline in SLD [in %] is defined as “SLD change from baseline at 
visit x” / “SLD at baseline” * 100.
7. Best percentage change in SLD is defined as the percentage change from baseline in SLD at 
the visit with the smallest SLD value among all the post screening visits.
All images will be collected and quality controlled by a sponsor-specified central imaging 
vendor. The independent review committee (IRC) will consist of two independent readers, and 
an adjudicator. For analysis purposes, if the response assessment at a specific timepoint differs 
between the 2 readers, the adjudicated response assessment will be used.
The concordance in the assessment of progressive disease between the investigator (INV) and 
the IRC will be summarized for the ITT population for Arms A (paclitaxel) and B (paclitaxel + 
MLN0128):

Agreement on PD status
o
PD by both IRC and investigator

IRC and investigator agree on timing 

IRC earlier than investigator

IRC later than investigator
o
No PD by either IRC or Investigator

Disagreement on PD status
o
PD by Investigator but not by IRC
o
PD by IRC but not by investigator
Sensitivity analyses for time-to-event endpoints (PFS, TTP) based on the ITT population and 
response endpoints (ORR and CBR both unconfirmed and confirmed) for the safety population
will be generated based on results from the IRC for Arms A (paclitaxel) and B (paclitaxel + 
MLN0128).
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
Sparse PK data for MLN0128 and MLN1117 are being collected to contribute to a future 
population PK analysis. These data may be combined with data from other studies in which the 
PK of MLN0128 or MLN1117 is characterized for population PK analysis. The results of 
population PK analysis will be presented in a separate report.
7.9.2
Pharmacodynamic Analysis
Biomarker analyses will be exploratory in nature and will be summarized in a separate report. 
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7.10
Patient Reported Outcomes
Patient-reported outcome (PRO) assessments will be collected through 2 different instruments: 
EORTC QLQ-C30 and EORTC QLQ-EN24. The ITT population will be used to present patient-
reported outcome analysis. For each treatment group and at each assessment point and overall, 
the number and percentage of compliance for the EORTC QLQ-C30 and EORTC QLQ-EN24
will be summarized. Compliance is defined as the number of questionnaires completed 
(answered at least one question) as a proportion of the number of expected questionnaires per the 
schedule of events (Day 1 of each cycle and End of Treatment). Patients who died will not be 
included in the expected count.
Patient with missing baseline scores are not assessable for baseline description or change from 
baseline and time to deterioration analyses. Patients with baseline scores, but with no follow-up 
scores, are not assessable for change from baseline. For time to deterioration they will be 
censored at Day 1. Published manuals/guidance for EORTC QLQ-C30 will be used for scoring 
and handling missing data. In the case where there is no guidance for handling missing data, 
missing items will be considered missing, they will not be imputed.
7.10.1 EORTC QLQ-C30 and EORTC QLQ-EN24 Scores
Descriptive statistics including the 95% CI around mean for actual values and the change from 
baseline (post – baseline) will be tabulated at each scheduled time point and the EOT visit for 
each of the functional and symptom scores from the EORTC QLQ-C30 and QLQ-EN24 
questionnaires, the global health status/QOL score and summary score from the EORTC QLQ-
C30 questionnaire up to 12 cycles. In addition, the mean and mean change from baseline of the 
EORTC QLQ-C30 subscales, the global health status/QOL score, summary score and the 
EORTC QLQ-EN24 subscales will also be presented over time by treatment group in figures up 
to 12 cycles (including 95% CI around mean). 
The change from baseline of EORTC QLQ-C30 subscales, global health status/QOL, summary 
score and EORTC QLQ-EN24 subscales will be analyzed using linear mixed models, including 
treatment group, visit, the interaction between treatment group and visit, baseline score (and 
other covariates i.e. stratification factors as per original IRT) as covariates. Random-intercept 
only model with appropriate covariance structure will be used based on the following covariance 
structure in order from unstructured, spatial-power and AR(1). The first covariance structure that 
has all the parameter estimates converged for all the subscales will be used. The estimated means 
with 95% CIs will be provided at each time point up to 12 cycles for each treatment arm. The 
mean differences in each score and 95% CIs and p values for the pairwise comparison of 
paclitaxel to paclitaxel+MLN0128, paclitaxel to MLN0128 and paclitaxel to 
MLN0128+MLN1117 will be presented at each time point up to 12 cycles.
7.10.2 Percentage of Patients Experiencing Improvement or Deterioration
The subscale scores based on EORTC QLQ-C30 and EORTC QLQ-EN24 and corresponding 
minimally important differences (MIDs) are defined as shown in Table 7.2. For EORTC QLQ-
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EN24, the MID threshold of 5 is used in the absence of referenced MID, which corresponded to 
the value found in the literature for the other scales of the EORTC questionnaire.
Table 7.b
Definition of Minimally Important Difference (MID) Based on EORTC 
QLQ-C30 and EORTC QLQ-EN24
Subscale
Individual Items
MID
Deterioration from 
Baseline
EORTC QLQ-C30
Functional scales
Physical functioning
1-5
6
Decrease (CFB ≤ -MID)
Role functioning
6-7
7
Decrease (CFB ≤ -MID)
Emotional functioning
21-24
7
Decrease (CFB ≤ -MID)
Cognitive functioning
20, 25
4
Decrease (CFB ≤ -MID)
Social functioning
26-27
6
Decrease (CFB ≤ -MID)
Global health status
Quality of life
29-30
5 and 10
Decrease (CFB ≤ -MID)
Symptom scales/items
Fatigue
10, 12, 18
6
Increase (CFB ≥ MID)
Nausea and vomiting
14-15
4
Increase (CFB ≥ MID)
Pain
9, 19
7
Increase (CFB ≥ MID)
Dyspnoea
8
5
Increase (CFB ≥ MID)
Insomnia
11
5
Increase (CFB ≥ MID)
Appetite loss 
13
6
Increase (CFB ≥ MID)
Constipation 
16
6
Increase (CFB ≥ MID)
Diarrhoea
17
4
Increase (CFB ≥ MID)
Financial difficulties 
EORTC QLQ-EN24
Functional scales
Sexual interest
Sexual activity
28
49
50
4
5
5
Increase (CFB ≥ MID)
Decrease (CFB ≤ -MID)
Decrease (CFB ≤ -MID)
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Table 7.b
Definition of Minimally Important Difference (MID) Based on EORTC 
QLQ-C30 and EORTC QLQ-EN24
Subscale
Individual Items
MID
Deterioration from 
Baseline
Sexual enjoyment
Symptom scales
Lymphoedema
Urological symptoms
Gastrointestinal symptoms
Poor body image
Sexual/vaginal problems
Pain in back and pelvis
Tingling/numbness
Muscular pain
Hair loss
Taste change
54
31-32
34-37
38-42
47-48
51-53                             
33
43
44
45
46
5
5
5
5
5
5
5
5
5
5
5
Decrease (CFB ≤ -MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Increase (CFB ≥ MID)
Note: CFB = change from baseline.
Differences between treatment groups in the EORTC QLQ-C30 subscales, the global health 
status/QOL score and EORTC QLQ-EN24 subscales will be evaluated using published 
minimally important difference (MID) as shown in Table 7.2. At each visit up to cycle 12 and by 
treatment, present the number and percentage of patients for each of the following categories for 
each subscale scores:

Worsened: EORTC QLQ-C30 functional scores, global health status/QOL score, EORTC 
QLQ-EN24 score : change from baseline ≤-MID, for symptom scores: change from baseline
≥MID.

Improved: EORTC QLQ-C30 functional scores, global health status/QOL score, EORTC 
QLQ-EN24 score: change from baseline ≥ MID, symptom scores: change from baseline ≤ -
MID.

Stable: change from baseline within MID.
In addition, at each visit and by treatment, the cumulative number and cumulative percentage 
whose change from baseline of the subscale scores reflects improvement will be summarized.
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7.10.3 Time to Deterioration
Time to deterioration is defined as the time from the date of randomization to the date of first 
detection of deterioration for each EORTC QLQ-C30 subscales, the global health status/QOL 
score, and for each EORTC QLQ-EN24 score [date of first detection of deterioration – date of 
randomization + 1]. Deterioration is defined as a change from baseline ≥ MID for EORTC QLQ-
C30 symptom scores and as a change from baseline ≤ -MID for EORTC QLQ-C30 function 
scores, global health status/QOL score and EORTC QLQ-EN24 score (see Table 7.2). Patients 
without deterioration will be censored at their last quality of life assessment. For patients with no 
post-baseline assessment, time to deterioration will be censored at Day 1.
The Kaplan-Meier method will be used to analyze the distribution of time to deterioration for 
each treatment arm. Kaplan-Meier survival curves, the 25th, 50th (median), and 75th percentiles, 
along with associated 2-sided 95% confidence intervals (CIs), hazard ratio estimated using Cox 
regression model with treatment arm and stratification factors as covariates along with associated 
95% CI for comparison of paclitaxel to paclitaxel+MLN0128, paclitaxel to MLN0128 and
paclitaxel to MLN0128+MLN1117, and Kaplan-Meier estimates at 6, 12, 18 and 24 months will 
be presented. A stratified log-rank test will be performed to compare the time to deterioration 
between treatment arms. The stratification factors are the histological subtype (endometrioid vs. 
non-endometrioid), the lines of prior chemotherapy (1 vs. 2) and prior taxane therapy (yes vs. 
no). The original IRT stratification factors will be used in models.
7.11
Safety Analysis
All safety analyses will be performed using the Safety population.
7.11.1 Adverse Events
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of study drug will be tabulated.
Tabular summaries by MedDRA system organ class and preferred term will be provided for the 
following:

Treatment-emergent adverse events.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

Most commonly reported TEAEs (at least 10% in any arm, sorted by preferred term).

Serious adverse events.

Most frequent non-serious TEAEs (> 5% in any arm).
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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.
Adverse events of interest will be tabulated for the following:
Adverse event of 
interest
MedDRA Preferred Term
Asthenic Conditions
Asthenia, Decreased activity, Fatigue, Malaise, Sluggishness 
(modified HLT)
Mucosal Inflammation
Enanthema
Allergic stomatitis
Mucosa vesicle
Aphthous ulcer
Mucosal atrophy
Lip erosion
Mucosal discolouration
Lip ulceration
Mucosal dryness
Mouth ulceration
Mucosal erosion
Oral mucosa erosion
Mucosal exfoliation
Palatal ulcer
Mucosal haemorrhage
Stomatitis
Mucosal hyperaemia
Stomatitis haemorrhagic
Mucosal hypertrophy
Stomatitis necrotising
Mucosal induration
Mucosal inflammation
Mucosal membrane 
hyperplasia
Mucosal necrosis
Mucosal pain
Mucosal pigmentation
Mucosal roughness
Mucosal toxicity
Mucosal ulceration
Mucous membrane disorder
Oedema mucosal
Mucosal infection
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Adverse event of 
interest
MedDRA Preferred Term
Mucosal excoriation
Erythroplasia
Burning sensation mucosal
Paraesthesia mucosal
Leukoplakia
Drug eruption
Fixed eruption
Mucocutaneous haemorrhage
Rash
Mucocutaneous rash
Nodular rash
Rash
Rash erythematous
Rash generalised
Rash macular
Rash maculo-papular
Rash maculovesicular
Rash morbilliform
Rash papular
Rash rubelliform
Rash scarlatiniform
Rash vesicular
7.11.1.1 Deaths
All deaths occurring on-study and during follow-up will be displayed (regardless of treatment-
emergent AE status). On-study death is defined as death that occurs between the first dose of 
study drug and 30 days after the last dose of study drug (adverse events with an outcome of 
death).
All cause mortality will be tabulated, which includes death of all causes, deaths related to disease 
under study, and deaths due to other reasons. On-study deaths will be tabulated, which includes 
deaths related to disease under study, deaths due to other reasons, and deaths within 30 and 60
days of first dose.
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7.11.1.2 Clinical Laboratory Evaluations
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
version 4.03. The number and proportion of patients with shifts in NCI CTCAE toxicity grades
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, Corrected Calcium -
decreased, Corrected Calcium – increased, Glucose – decreased, Glucose – increased, 
Potassium – decreased, Potassium – increased, Magnesium – decreased, Magnesium –
increased, Sodium – decreased, Sodium – increased, Triglycerides – increased, Albumin –
decreased, Phosphate – decreased, Amylase – increased
The shift from baseline to worst post baseline will include scheduled and unscheduled visits.
For fasting glucose, the shifts from baseline to the worse post baseline (2 hours only) will be 
summarized for MLN0128 QW and MLN0128 + MLN1117 arms. 
The actual values (in SI units) and change from baseline in clinical laboratory parameters will be 
summarized by treatment group for Neutrophils (ANC), Aspartate aminotransferase (AST), 
Alanine aminotransferase (ALT), Glucose, Hemoglobin A1c, Cholesterol (total), Triglycerides, 
High-density lipoprotein cholesterol (HDL-C) and Low-density lipoprotein cholesterol (LDL-C)
up to 12 cycles. Figures of mean actual values over time will also be generated for these clinical 
laboratory parameters (in SI units).
7.11.2 Vital Signs
The actual values and change from baseline for vital sign parameters including temperature, 
heart rate, systolic and diastolic blood pressure, and weight, will be summarized over time for 
each treatment arm up to 6 cycles.
7.11.3 12-Lead ECGs
The actual values and change from baseline for ECG results (QT, QTcF, PR interval, QRS 
interval, Ventricular Rate) will be summarized over time for each treatment group up to 6 cycles.
In addition, the number and percent of patients with increases >30 ms and >60 ms from pre-dose 
in QTcF will also be summarized over time up to 6 cycles.
All QT values will be converted to QTcF using Fridericia’s correction:
(sec)
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[Note: RR (sec) = 60 / ventricular rate in beats/minute].
7.11.4 ECOG Performance Status
Shifts from baseline to the worst post-baseline ECOG score will be tabulated by treatment arm
up to 6 cycles.
7.12
Interim Analysis
As specified in the protocol
There will be 2 interim analyses with early stopping rules for futility in both the single-agent
MLN0128 and MLN0128 + MLN1117 arms using the Bayesian predictive probability design.
The endpoint for the interim analysis will be based on the number of patients who achieve 
complete or partial response of any duration, or stable disease ≥ 16 weeks as assessed by the 
investigator (clinical benefit at 16 weeks). The decision rule for the interim analyses is derived 
based on the following assumptions:

Ineffective CBR-16 rate (Ho): 30%.

Effective CBR-16 rate (Ha): 50%.

Alpha = 10%; power = 80%.

Prior Beta Distribution Parameters: α0 = 0.30, β0 = 0.70.

The probability of early termination under the null hypothesis is 77%.
Each interim analysis will be based on patients who have had the opportunity to complete a
minimum of 4 cycles or have discontinued study drug before the end of Cycle 4. The data cut-off 
is when the 20th patient achieves end of Cycle 4 in the treatment arms single-agent MLN0128 
and MLN0128 + MLN1117. For all patients, use data up to Cycle 4 for interim analysis. Based 
on the first 20 patients in each arm, 1 or both arms may be dropped if at most 6 patients 
experience clinical benefit at 16 weeks in each arm. After the first 30 patients in each arm have 
been evaluated following 4 cycles of treatment, 1 or both arms may be dropped if at most 10 
patients experience clinical benefit at 16 weeks in each arm.
For the interim analysis CBR at 16 weeks is defined as the number of patients who achieve CR 
or PR at the end of cycle 2 or end of cycle 4, or have SD at the end of Cycle 2 and at the end of 
Cycle 4 (based on unconfirmed response.).
Futility analysis
An additional futility analysis will be performed when 50% of PFS events have occurred for the 
paclitaxel and paclitaxel+MLN0128 treatment arms. The decision rule is based on a Bayesian 
framework: posterior probability (true HR > 0.78 | observed HR) is greater than 70%. The 
futility criteria will be met if the observed PFS HR for the comparison of paclitaxel vs 
paclitaxel+MLN0128 at the interim analysis for futility is greater than or equal to 0.898.
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7.13
Changes in the Statistical Analysis Plan 
1. QOL instruments, EORTC QLQ-C30 and EORTC QLQ EN24, will be analyzed over time 
and not restricted to just change from baseline to end of study visit as stated in the protocol.
2. The Per-protocol population was added to the analysis populations.
3. For PFS analysis, patients who started alternate subsequent therapy prior to disease 
progression will be censored at the date of last adequate assessment prior to the start of 
subsequent therapy. The protocol did not explicitly state this condition.
4. In addition to Kaplan-Meier method that will be used to analyze distribution of PFS, OS and 
TTP for each treatment arm and the p-values from a stratified log-rank test, the HRs and 
95% CIs from a stratified Cox regression model with treatment arm and stratification factors 
as covariates will also be presented for comparison of paclitaxel to paclitaxel+MLN0128, 
paclitaxel to MLN0128 and paclitaxel to MLN0128+MLN1117. The protocol did not 
explicitly state the model for estimating the HRs.
5. The secondary endpoints e.g. ORR, CBR, CBR-16 and DOR will be based on both 
confirmed and unconfirmed best overall response.
6. Added details for the sensitivity analyses based on IRC review of scans. The IRC will only 
be performed for Arms A (paclitaxel) and B (paclitaxel + MLN0128).
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8.0
REFERENCES
None
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9.0
APPENDIX
Appendix A: By-Subject Listings:
In addition to the analysis outputs outlined above in the main text, separate by-patient listings 
will also be generated to include the following information:

Disposition of subjects.

Demographic and other baseline characteristics (including stratification factors).

Important protocol deviations (including flag to indicate deviations that excluded patients 
from the per protocol population).

Concomitant medications.

Follow-up anti-cancer therapy.

TEAEs resulting in discontinuation of study drug.

SAEs.

Deaths and cause of death.

Sparse PK data.

RECIST response assessment and best overall response based on investigator assessment and 
IRC assessment [Arms A (paclitaxel) and B (paclitaxel + MLN0128) only].
Appendix B: Date Imputation Rules
Incomplete Dates in the Screening Period
1. If only the day-component is missing, the first day of the month will be used if the year 
and the month are the same as those for the first dose of study drug. Otherwise, the 
fifteenth will be used.
2. If only the year is present, and it is the same as the year of the first dose of study drug, the 
fifteenth of January will be used unless it is later than the first dose, in which case the 
date of the first of January will be used.
3. If only the year is present, and it is not the same as the year of the first dose of study 
drug, the fifteenth of June will be used.
Incomplete Adverse Event Onset Date
Assumption: For on-study Adverse Events.
If year is missing (or completely missing): set to the date of first dose.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
If year = year of first dose: set the date to the first dose date.
If year < year of first dose: set month and day to December 31st.
If year > year of first dose: set month and day to January 1st.
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If month and year are present and day is missing:
If year = year of first dose, and:
If month = month of first dose: set day to day of first dose.
If month < month of first dose: set day to last day of month.
If month > month of first dose: set day to 1st day of month.
If year < year of first dose: set day to last day of month.
If year > year of first dose: set day to 1st day of month.
            For all other cases: set to date of first dose.
Incomplete Concomitant Medication Start Date
If year is missing (or completely missing): do not impute.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
Set month and day to January 1st.
            If year and month are present and day is missing:
Set day to 1st day of month.
Incomplete Concomitant Medication End Date
If year is missing (or completely missing): do not impute.
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
Set month and day to December 31st.
If year and month are present and day is missing:
Set day to last day of the month.
Incomplete Subsequent Anti-Cancer Therapy Start Date
If year is missing (or completely missing): set to date of last dose of study treatment + 1
If (year is present and month and day are missing) or (year and day are present and month 
is missing):
If year > year of the last dose: Set month and day to January 1st.
If year = year of the last dose: Set month and day to date of last dose of study 
treatment +1
If year and month are present and day is missing:
Set day to 1st day of month if the resulting imputed date is greater than date of last 
dose.
Otherwise set the imputed date to date of last dose + 1
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