Conditions: Non-hematologic Malignancy
Keywords: Drug therapy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: no

Brief summary:
The purposes of this study are to evaluate the safety and tolerability of sapanisertib (MLN0128) milled active pharmaceutical ingredient (API) capsules administered both as a single agent and in combination with paclitaxel, to characterize the effect of a high-fat meal on the pharmacokinetics (PK) of sapanisertib milled API capsules, and to characterize the PK of sapanisertib milled API capsules when administered on an empty stomach approximately 24 hours after paclitaxel infusion.

Detailed description:
The drug being tested in this study is called sapanisertib (MLN0128). Sapanisertib is being tested to assess its safety and tolerability when administered alone or in combination with paclitaxel in people who have nonhematologic malignancies. Sapanisertib is also being tested to characterize its PK properties (how is processed by the body) when administered with a high-fat meal compared to on an empty stomach. This study will look at side effects and lab results in people who take sapanisertib with or without paclitaxel.

This open label study enrolled 61 patients. Participants receiving only sapanisertib will participate in a 6-day PK Run-In Period where sapanisertib 4 mg capsules are administered under fasted conditions on Days 1 and 4, and with a high-fat breakfast on Day 3. The main treatment period will begin within 14 days from Day 6 of the PK Run-In Period. In the main treatment period participants will receive sapanisertib 4 mg daily in a 28-day Cycle for up to 12 cycles. Participants in the treatment arm receiving sapanisertib and paclitaxel will not have a PK Run-In Period and will receive sapanisertib 6 mg daily on Days 2-4, 9-11, 16-18, and 23-25 in a 28-day Cycle for up to 12 cycles and paclitaxel 80 mg/m\^2 intravenously (IV) on Days 1, 8, and 15 in 28-day Cycle, for up to 12 cycles. The dose of sapanisertib may be modified based on safety and tolerability during each 28-day cycle in either treatment arm.

This multi-centre trial will be conducted in the United States. The overall time to participate in this study is up to 15 months. Participants in the sapanisertib only arm will make up to 32 visits to the clinic and participants in the sapanisertib and paclitaxel arm will make up to 26 visits to the clinic. All participants will make a final visit to the clinic 30 days after the last dose of study drug for a follow-up assessment.

Arms:
arm 1: Following Pharmacokinetic (PK) - Run in Period, sapanisertib 3 mg milled capsules, orally, once, daily in a 28-day Cycle, under fasted conditions, starting from Cycle 2 for up to 9 cycles. The dose of sapanisertib was modified based on safety and tolerability during each 28-day cycle. arm 2: Following PK Run-In Period, sapanisertib 4 mg milled capsules, orally, once, daily in a 28-day Cycle, under fasted conditions, for up to 13 cycles. arm 3: Sapanisertib 4 mg milled capsules, orally, once, for 3 consecutive days following each paclitaxel administration (Days 2-4, 9-11, 16-18, and 23-25) in a 28-day Cycle, under fasted conditions, for up to 12 cycles, and paclitaxel 80 mg/m\^2, intravenously (IV), on Days 1, 8, and 15 in 28-day Cycle, for up to 6 cycles. arm 4: Sapanisertib 6 mg milled capsules, orally, once, for 3 consecutive days following each paclitaxel administration (Days 2-4, 9-11, 16-18, and 23-25) in a 28-day Cycle, under fasted conditions, for up to 9 cycles, and paclitaxel 80 mg/m\^2, IV, on Days 1, 8, and 15 in 28-day Cycle, for up to 9 cycles. The dose of sapanisertib was modified based on safety and tolerability during each 28-day cycle. arm 5: Sapanisertib 20 mg, capsules milled API, QW in a 28-day Cycle, for up to 6 cycles. arm 6: Sapanisertib 30 mg, capsules, milled API, QW in a 28-day Cycle, for up to 10 cycles.

Interventions: intervention 1: Sapanisertib intervention 2: Paclitaxel
Intervention descriptions: intervention 1: Sapanisertib capsules intervention 2: Paclitaxel injection

Protocol document:
Prot_000.pdf: 


•
Title: A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
MLN0128 (an Oral mTORC 1/2 Inhibitor) as a Single Agent and in Combination With Paclitaxel 
in Adult Patients With Advanced Nonhematologic Malignancies
NCT Number: NCT02412722
Protocol Approve Date: 27 November 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


MLN0128
Clinical Study Protocol MLN0128-1004 Amendment 3
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CLINICAL STUDY PROTOCOL MLN0128-1004 AMENDMENT 3
MLN0128
A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
MLN0128 (an Oral mTORC 1/2 Inhibitor) as a Single Agent and in Combination With 
Paclitaxel in Adult Patients With Advanced Nonhematologic Malignancies
Protocol Number:
MLN0128-1004
Indication:
Advanced nonhematologic malignancies
Phase:
1
Sponsor:
Millennium Pharmaceuticals, Inc.
Therapeutic Area:
Oncology
Protocol History
Original
30 September 2014
Amendment 1
25 March 2015
Amendment 2
14 May 2015
Amendment 3
27 November 2017
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA  02139  USA
Telephone:  +1 (617) 679-7000
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
Signature
Date DD Month  YYYY
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior 
written authorization of Millennium Pharmaceuticals is expressly prohibited.
PPD


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Rationale for Amendment 3
This document describes the changes in reference to the protocol incorporating 
Amendment 3. The primary reason for this amendment is to update those sections affected 
by new nonclinical data for MLN0128 metabolism by specific cytochrome P450 (CYP) 
isoforms. The study’s exclusion criteria, list of prohibited concomitant medications, list of 
relevant CYP inhibitors and inducers, and dietary restrictions related to CYP inhibitors and 
inducers have been updated accordingly. The required frequency of radiographic disease 
assessments for patients who have received at least 1 year of continuous MLN0128 
treatment has also been reduced. Minor grammatical, editorial, and formatting changes are 
included for clarification purposes only.
For specific descriptions of text changes and where the changes are located, see 
Appendix 14.7.
Changes in Amendment 3
1. Remove the exclusion criterion relating to treatment with strong CYP inhibitors or
inducers.
2. Update the list of concomitant medications prohibited during the study.
3. Update the list of relevant CYP inhibitors and inducers.
4. Remove dietary restrictions related to CYP inhibitors and inducers.
5. Insert language to reduce the required frequency of radiographic disease assessments
for patients who have received at least 1 year of continuous MLN0128 treatment per
protocol.


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PROTOCOL SUMMARY
Study Title:  A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of MLN0128 (an Oral mTORC 1/2 Inhibitor) as a Single Agent and in 
Combination With Paclitaxel in Adult Patients With Advanced Nonhematologic Malignancies
Number of Patients:  Approximately 44 to 56 evaluable patients will be enrolled from 5 study 
centers in the United States.
Study Objectives
Primary

To evaluate the safety and tolerability of MLN0128 milled active pharmaceutical ingredient
(API) capsules administered both as a single agent and in combination with paclitaxel

To characterize the effect of a high-fat meal on the pharmacokinetics (PK) of MLN0128
milled API capsules

To characterize the PK of MLN0128 milled API capsules when administered on an empty
stomach approximately 24 hours after paclitaxel infusion
Secondary

To characterize the PK of MLN0128 milled API capsules versus unmilled API capsules,
when administered on an empty stomach

To evaluate the preliminary efficacy of MLN0128 milled API capsules when administered
as a single agent and in combination with paclitaxel
Overview of Study Design:  
This study is a multicenter, open-label, phase 1 trial of MLN0128 administered orally both as a 
single agent and in combination with intravenous (IV) infusions of paclitaxel in adult patients with 
advanced nonhematologic malignancies for whom standard, curative, or life-prolonging anticancer 
treatment does not exist or is no longer effective.  The study will consist of 3 arms:  a Single-Agent 
QD (daily dosing) Arm, a Combination Arm, and a Single-Agent QW (weekly dosing) Arm.  The 
3 arms will enroll in parallel and will administer study treatment in repeated 28-day cycles.  
The Single-Agent QD Arm will test the safety, tolerability, and PK of MLN0128 milled API 
capsules when administered on an empty stomach and will additionally characterize the PK profile 
when taken with a standardized high-fat breakfast.  In the same patients, the PK of MLN0128 
unmilled API capsules when taken on an empty stomach will also be assessed as a point of reference 
for comparison of milled API capsule PK.  The PK assessments will be performed during a PK 
Run-In period during which each patient will receive a total of three 4-mg doses of MLN0128 as 
described below:

PK Run-In Visit 1:  MLN0128 4-mg unmilled API capsule taken on an empty stomach.

PK Run-In Visit 2 (24 hours [1 hr] after PK Visit 1):  24-hour postdose PK sample
collected.

PK Run-In Visit 3 (≥48 hours after PK Visit 1):  MLN0128 4-mg milled API capsule taken
with a standardized high-fat breakfast.

PK Run-In Visit 4 (24 hours [1 hr] after PK Visit 3):  24-hour postdose PK sample
collected.


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
PK Run-In Visit 5 (≥48 hours after PK Visit 3):  MLN0128 4-mg milled API capsule taken 
on an empty stomach.

PK Run-In Visit 6 (24 hours [1 hr] after PK Visit 5):  24-hour postdose PK sample 
collected.  Note:  If scheduling permits, Visit 6 can be combined with Cycle 1 Day 1 of the 
Study Treatment period.  That is, the 24-hour postdose PK sample for the Visit 5 PK dose 
can be drawn before the first administration of the patient’s assigned Study Treatment dose 
if the timing allows.
Each patient in the Single-Agent QD Arm will complete the PK Run-In period within 14 days before 
Cycle 1 Day 1 of the Study Treatment period.  Study treatment for the Single-Agent QD Arm will 
consist of repeated 28-day cycles of oral MLN0128 milled API capsules taken on an empty stomach.  
The first 6 patients enrolled into the Single-Agent QD Arm Study Treatment period will receive 
MLN0128 at 4 mg once daily (QD).  An evaluation of safety and tolerability will be conducted after 
these first 6 patients have completed Cycle 1 to determine the dose to be administered during the 
Study Treatment period for the next patients enrolled into the Single-Agent QD Arm. Safety 
evaluations will continue before enrolling each subsequent cohort into the Single-Agent QD Arm.  A
total of 16 subjects will complete the protocol-specified PK evaluations in the Single-Agent QD 
Arm.
The Combination Arm will test the safety, tolerability, and PK of MLN0128 milled API capsules 
when administered on an empty stomach in combination with paclitaxel.  Paclitaxel (80 mg/m2) will 
be administered as an IV infusion on Days 1, 8 (± 1 day), and 15 (± 1 day) of each 28-day cycle 
according to the institution’s standard clinical practice.  MLN0128 will be administered QD × 3 days 
each week (QW) of each cycle, beginning 24 hours after completion of the Day 1 paclitaxel infusion; 
ie, MLN0128 will be administered on an empty stomach on Days 2 through 4, 9 through 11, 
16 through 18, and 23 through 25 of every 28-day cycle.  The starting MLN0128 dose for the 
Combination Arm will be 6 mg (QD × 3 days QW).  Plasma samples to characterize the PK of 
MLN0128 will be collected on Cycle 1 Day 2.  Consistent with the Single-Agent QD Arm, an 
interim safety and tolerability review will be conducted for the Combination Arm after the initial 
cohort of 6 patients has completed Cycle 1.  According to standard dose escalation rules on the basis 
of the safety and tolerability observed in the initial 6 evaluable patients, the dose of MLN0128 
(QD × 3 days QW) for the next cohort of 6 patients will be either reduced, maintained, or escalated.  
The Single-Agent QW Arm will evaluate the safety, tolerability, and PK of MLN0128 milled API 
when administered on an empty stomach in 2 sequential cohorts, each consisting of 6 to 12 patients.  
Initially, 6 patients in Cohort 1 will receive 20 mg of MLN0128 capsules based on milled API once 
every week (QW).  Serial plasma specimens will be collected for evaluation of MLN0128 PK.  A 
safety and tolerability assessment will be performed after the last patient in the cohort completes 
Cycle 1.  If ≥2 patients experience a dose-limiting toxicity (DLT) during Cycle 1, then the starting 
dose of MLN0128 milled API for the subsequent cohort (Cohort 2) will be reduced to 15 mg QW.  If 
≤1 patient in Cohort 1 experiences a DLT in Cycle 1, then the dose of milled MLN0128 in Cohort 2 
will be increased to 30 mg QW.  If the dose of MLN0128 milled API is deemed safe in any cohort 
based on 3+3 rules, then the cohort may be expanded to 12 patients to confirm the recommended 
phase 2 dose for single-agent MLN0128 milled API capsules when administered QW.  Plasma 
samples to characterize the PK of MLN0128 will be collected on Cycle 1 Day 1.  


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Study Population:  To be eligible for the study, a patient must be ≥18 years of age before the 
Screening visit; have advanced nonhematologic malignancies, with the exception, of primary brain 
tumor; and have failed or be ineligible for standard-of-care therapy.  Patients with a history of treated 
brain metastasis may be eligible provided, that they are off treatment, have no sign of disease 
progression or hemorrhage, and have no ongoing requirement for dexamethasone or anti-epileptic 
drugs.  All patients must have an Eastern Cooperative Oncology Group Performance Status of ≤1, 
adequate clinical laboratory values, and acceptable left ventricular ejection fraction.  
Duration of Study:  In the absence of unacceptable treatment-related toxicity or disease 
progression, patients may receive study treatment for up to 1 year at the discretion of the investigator 
and beyond 1 year with the agreement of the investigator and the sponsor if, in the opinion of the 
investigator, the patient is benefitting from treatment.


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STUDY FLOW DIAGRAM
Abbreviations:  PK = pharmacokinetic; QD = once daily; QW = once weekly.


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STUDY DRUG DOSING DIAGRAM
Abbreviations:  API = active pharmaceutical ingredient; hr(s)= hour(s); PK = pharmacokinetic; QD = once daily; QW = once weekly; TBD = to be determined. 


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SINGLE-AGENT QD AND SINGLE-AGENT QW ARMS SCHEDULES OF EVENTS
Table 1-1   
Single-Agent QD and Single-Agent QW Arms Schedule of Events
Screeninga
PK Run-In Period (≤14 Days of Cycle 1 
Day 1)
Single-Agent QD Arm Only
Study Treatment Period (28-Day Cycles)
EOS/ 
ET
Visitf
Visit
1
Visit
2b
Visit
3c
Visit
4b
Visit
5d
Visit
6b
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥ 7
Day
1
Day 
2e
Day 8 
(±2 Days)
Day 15 
(±2 Days)
Day
1
Day 8 
(±2 Days)
Day 15 
(±2 Days)
Day
1
Study Procedures
Informed consent
X
Eligibility criteria
X
Demographics
X
Medical history
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
X
Vital signsg
X
X
X
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
ECHO/MUGA
X
Single, 12-lead ECGh
X1
X2h
X2h
X2h
X2h
X1
Disease assessmenti
X
Q2C
Q2C
X
Concomitant medications 
and procedures reporting
X
Recorded from first dose of study drug through 30 days after the last dose of study drug
SAE reportingj
SAEsj recorded from signing of the informed consent form through 30 days after the last study drug dose
Adverse event reporting
Recorded from first dose of study drug through 30 days after the last dose of study drug


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Table 1-1   
Single-Agent QD and Single-Agent QW Arms Schedule of Events
Screeninga
PK Run-In Period (≤14 Days of Cycle 1 
Day 1)
Single-Agent QD Arm Only
Study Treatment Period (28-Day Cycles)
EOS/ 
ET
Visitf
Visit
1
Visit
2b
Visit
3c
Visit
4b
Visit
5d
Visit
6b
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥ 7
Day
1
Day 
2e
Day 8 
(±2 Days)
Day 15 
(±2 Days)
Day
1
Day 8 
(±2 Days)
Day 15 
(±2 Days)
Day
1
MLN0128 Dosing
Single-Agent QD Arm
X
X
X
QD continuously (cohort-specific dose TBD)
Single-Agent QW Arm
Days 1, 8, 15, 22, and 28 of each 28-day cycle (see Section 4.1)
Samples and Laboratory Assessments
Hematology
X1
X1
X1
X1
X1k
X1
X1
X1j
X1
X1
X1j
X1
Chemistry
X1
X1
X1
X1
X1k
X1
X1
X1j
X1
X1
X1j
X1
Urinalysis
X1l
X1
X1
X1k
X1
X1j
X1
X1j
X1
Pregnancy testm
X1
X1m
X1m
Coagulation (PT/INR, 
aPTT)
X1
X1
X1
X1
X1
X1
X1
X1
Fasting serum glucosen
X1
X1
X1
X1
X1
X1
X1
X1
In-home fasting glucose 
monitoringo
Measured daily (predose), See Section 7.4.16
Fasting lipid profile
X1p
X1
X1
X1
X1
HbA1c
X1
Xq
Xq
Q3Cq
Blood sample for PK
analysis for Single-Agent 
QD Arm (see Table 1-2)s
X8
X1
X8
X1
X8
X1
Blood sample for PK
analysis for Single-Agent 
QW Arm (see Table 1-3)s
X8t
X1t
CCI


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Table 1-1   
Single-Agent QD and Single-Agent QW Arms Schedule of Events
Screeninga
PK Run-In Period (≤14 Days of Cycle 1 
Day 1)
Single-Agent QD Arm Only
Study Treatment Period (28-Day Cycles)
EOS/ 
ET
Visitf
Visit
1
Visit
2b
Visit
3c
Visit
4b
Visit
5d
Visit
6b
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥ 7
Day
1
Day 
2e
Day 8 
(±2 Days)
Day 15 
(±2 Days)
Day
1
Day 8 
(±2 Days)
Day 15 
(±2 Days)
Day
1
Abbreviations:  aPTT = activated partial thromboplastin time; C = cycle; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOS = end-of-study; ET = early termination; HbA1c = glycosylated hemoglobin; INR = international 
normalized ratio; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition (scan); PK = pharmacokinetic; PT = prothrombin time; Q = every; 
SAE = serious adverse event; TBD = to be determined; X# = number of samples required (eg, 2 samples = X2).
Tests and procedures should be performed on schedule, but occasional changes are allowable (± 2 days) with permission from the medical monitor for holidays, 
vacations, and other administrative reasons.  
a Screening assessments are performed within 28 days before PK Visit 1.  Screening assessments performed not more than 3 days before the PK Visit 1 dose need 
not be repeated, unless otherwise specified.
b Visit should occur 24 hours after the prior PK Run-In Visit.
c PK Run-In Visit 3 should occur at least 48 hours after PK Run-In Visit 1.
d PK Run-In Visit 5 should occur at least 48 hours after PK Run-In Visit 3.
e The Day 2 visit occurs only on Cycle 1 for patients in the Single-Agent QW Arm to collect a blood sample for PK analysis.
f
Patients will attend an EOS/ET visit 30 to 40 days after receiving their last dose of study drug.
g Vital sign measurements include blood pressure (diastolic and systolic), heart rate, and temperature.
h When the timing of an ECG coincides with blood samples for PK, the ECG should be completed first.  On Cycle 1 Day 1 and Cycle 2 Day 1, an ECG should be 
completed predose in addition to 2 hours (± 30 min) postdose.
i
Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be obtained within 4 weeks before the first dose of MLN0128.  .  The same 
imaging modality (CT [with contrast], MRI, or bone scan) should be used on a patient throughout the study.  Bone scans may be performed on patients with bone 
metastases rather than CT or MRI.  Scans are permitted up to 7 days in advance of the scheduled visit.  At EOS, tumor assessments will be done only on patients 
who have not previously demonstrated disease progression in the study unless completed within the previous 4 weeks.  See Section 7.4.18. For long term 
patients, defined as study participation (≥1 year, a CT (with contrast)/MRI of chest, abdomen, and pelvis will be obtained at intervals of up to every 4 cycles 
(plus or minus 7 days) as clinically indicated. 
j
Including serious pretreatment events; see Section 9.1.1.
k May be assessed up to 24 hours before the study visit. 
l
For screening, creatinine clearance must be ≥50 mL/min based either on Cockroft-Gault estimate or based on a 12- or 24-hour urine collection.  
m In the Single-Agent QD Arm, a serum pregnancy test will be performed only for patients of childbearing potential during screening and again at PK Run-In Visit 


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Table 1-1   
Single-Agent QD and Single-Agent QW Arms Schedule of Events
Screeninga
PK Run-In Period (≤14 Days of Cycle 1 
Day 1)
Single-Agent QD Arm Only
Study Treatment Period (28-Day Cycles)
EOS/ 
ET
Visitf
Visit
1
Visit
2b
Visit
3c
Visit
4b
Visit
5d
Visit
6b
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥ 7
Day
1
Day 
2e
Day 8 
(±2 Days)
Day 15 
(±2 Days)
Day
1
Day 8 
(±2 Days)
Day 15 
(±2 Days)
Day
1
1 (baseline) if the screening test was performed > 3 days before PK Run-In Visit 1 (a urine test may be performed at PK Visit 1 if the serum results are not yet 
available).  In the Single-Agent QW Arm, a serum pregnancy test will be performed only for patients of childbearing potential during screening and again at 
Cycle 1 Day 1 (baseline) if the screening test was performed > 3 days before the first dose of any study drug (a urine test may be performed at Cycle 1 Day 1 if 
the serum results are not yet available).  The results must be negative within 3 days before PK Visit 1 in the Single-Agent QD Arm or within 3 days before Cycle 
1 Day 1 in the Single-Agent QW Arm, or as otherwise required by local regulations.  Additional pregnancy testing may be performed during the study at the 
discretion of the investigator, at the request of an independent ethics committee/institutional review board, or if required by local regulations.
n Fasting serum glucose will be measured in the clinic.  Patients are required to fast overnight (nothing except water and prescribed medications after midnight or 
for ≥8 hours before the assessment) for each measurement.  See Section 7.4.15.
o Patients will be given a glucometer on Cycle 1 Day 1 to monitor daily fasting glucose levels at home throughout Cycles 1 and 2, and will be instructed to notify 
the study clinician when the fasting glucose is abnormal (ie, ≥ 150 mg/dL).  In-home glucose monitoring is not required on days when fasting glucose is 
measured in the clinic.  See Section 7.4.16 for further instruction.
p To be completed within 14 days of PK Visit 1 dosing.
q During the Study Treatment period, HbA1c will be tested on Day 1 of Cycles 2 through 5, and on Day 1 of every third cycle thereafter (ie, Cycle 8, 11, 14, etc).
r
To be collected predose on PK Run-In Visit 1 in the Single-Agent QD arm and predose on Cycle 1 Day 1 in the Single-Agent QW Arm.
s Blood samples for PK analysis will be performed according to the schedule presented in Table 1-2 for patients in the Single-Agent QD Arm and in Table 1-3 for 
patients in the Single-Agent QW Arm.
t
The blood samples for PK analysis in the Single-Agent QW Arm will be performed on Cycle 1 only (see Table 1-3).


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Table 1-2   
Pharmacokinetic Sampling Time Points for the Single-Agent QD Arm
PK Run-In Period (≤14 Days Before Cycle 1 Day 1 of Study Treatment Period)
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
MLN0128 Dosing:
4 mg (unmilled API) 
taken on an empty 
stomacha
4 mg (milled API) 
taken after a high-fat 
breakfastb
4 mg (milled API) 
taken on an empty 
stomacha
PK Sampling Time Points
Predose (within 0.5 hours)
X1a
X1b
X1a
0.5 hours postdose (10 min)
X1
X1
X1
1 hour postdose (10 min)
X1
X1
X1
2 hours postdose (30 min)
X1
X1
X1
3 hours postdose (30 min)
X1
X1
X1
4 hours postdose (30 min)
X1
X1
X1
6 hours postdose (30 min)
X1
X1
X1
8 hours postdose (45 min)
X1
X1
X1
24 hours postdose (1 hr)
X1
X1
X1c
Abbreviations:  API = active pharmaceutical ingredient; min = minutes; PK = pharmacokinetic; X# = number of samples required (eg, 1 sample = X1).
a Patients will be instructed to fast overnight (nothing except water and prescribed medications after midnight or for a minimum of 8 hours).  Patients will 
then receive study drug with a full glass of water (250 mL).  
b Patients will report to the site fasted, having had nothing to eat or drink for at least 8 hours before the scheduled time of the high-fat breakfast.  Patients will 
then be given a standardized, high-fat breakfast that they are required to finish within 30 minutes (+5 min).  Patients will immediately receive study drug 
with a full glass of water (250 mL) within 5 minutes of the completion of the meal.
c If scheduling permits, Visit 6 can coincide with Cycle 1 Day 1 of the Study Treatment period.  That is, the 24-hour PK sample following administration of 
the Visit 5 PK Run-In dose can be drawn before the first administration of the patient’s assigned Study Treatment dose if the timing allows.


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Table 1-3   
Pharmacokinetic Sampling Time Points for the Single-Agent QW Arm
PK Sampling Time Point
Cycle 1 Day 1
Cycle 1 Day 2
Predose (within 0.5 hours)
X1a
0.5 hours postdose (10 min)
X1
1 hour postdose (10 min)
X1
2 hours postdose (30 min)
X1
3 hours postdose (30 min)
X1
4 hours postdose (30 min)
X1
6 hours postdose (30 min)
X1
8 hours postdose (45 min)
X1
24 hours postdose (1 hour)
X1
Abbreviations:  min = minutes; PK = pharmacokinetic; X# = number of samples required (eg, 1 sample = X1).
a Patients will hold their medication in the morning and take their MLN0128 dose after the predose PK sample has 
been collected.


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COMBINATION ARM SCHEDULES OF EVENTS
Table 1-4   
Combination Arm Schedule of Events
Screeninga
Study Treatment Period (28-Day Cycles)
EOS/ 
ET
Visitb
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥7
Day 1
Day 2
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Study Procedures
Informed consent
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Height
X
Weight
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
Vital signsc
X
X
X
X
X
X
X
X
X
ECOG performance status
X
X
X
X
X
X
X
ECHO/MUGA
X
Single, 12-lead ECGd
X1
X2d
X1
Disease assessmente
X
Q2Ce
Q2Ce
Xe
Concomitant medications & procedures 
reporting
Recorded from first dose of study drug through 30 days after the last dose of study drug
SAE reportingf
SAEsf recorded from signing of the informed consent form through 30 days after the last dose of study drug
Adverse event reporting
Recorded from first dose of study drug through 30 days after the last dose of study drug
Paclitaxel administration 
X
X
X
X
X
X
Xg
MLN0128 administration
Days 2-4, 9-11, 16-18, and 23-25 of each 28-day cycle 


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Table 1-4   
Combination Arm Schedule of Events
Screeninga
Study Treatment Period (28-Day Cycles)
EOS/ 
ET
Visitb
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥7
Day 1
Day 2
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Samples/Laboratory Assessments
Hematologyh
X1
X1i
X1
X1
X1i
X1
X1
X1i
X1
Chemistryh
X1
X1i
X1
X1
X1i
X1
X1
X1i
X1
Urinalysis
X1j
X1i
X1
X1i
X1
X1i
X1
Pregnancy testk
X1
X1k
Coagulation (PT/INR, aPTT)
X1
X1
X1
X1
X1
X1
X1
Fasting serum glucosel
X1
X1
X1
X1
X1
X1
X1
In-home daily fasting glucose 
monitoringm
Measured daily (predose), See Section 7.4.16
Fasting lipid profile
X1n
X1
X1
X1
X1
HbA1co
X1
Xo
Xo
Q3Co
Blood sample for PKanalysis (Cycle 1, 
only; see Table 1-5)q
X8
Abbreviations:  aPTT = activated partial thromboplastin time; C = cycle; CT = computed axial tomography; ECG = electrocardiogram; ECHO = echocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOS = end-of-study; ET = early termination; HbA1c = glycosylated hemoglobin; INR = international 
normalized ratio; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition (scan); PK = pharmacokinetic; PT = prothrombin time; Q = every; 
SAE = serious adverse event; 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) with permission from the medical monitor for holidays, 
vacations, and other administrative reasons.  
a Screening assessments are performed within 28 days before the Cycle 1 Day 1 dose.  Screening assessments performed ≤ 3 days before the first dose will qualify 
as baseline assessments and need not be repeated, unless otherwise specified.
b Patients will attend an EOS/ET visit 30 to 40 days after receiving their last dose of study drug.
CCI


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Table 1-4   
Combination Arm Schedule of Events
Screeninga
Study Treatment Period (28-Day Cycles)
EOS/ 
ET
Visitb
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥7
Day 1
Day 2
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
c Vital sign measurements include blood pressure (diastolic and systolic), heart rate, and temperature.
d When the timing of an ECG coincides with blood samples for PK, the ECG should be completed first.  On Cycle 1 Day 1 and Cycle 2 Day 1, an ECG should be 
completed predose in addition to 2 hours (± 30 min) postdose.
e Baseline CT (with contrast) or MRI scan of the chest, abdomen, and pelvis must be obtained within 4 weeks before the first dose of MLN0128 and at Cycle 3 
Day 1, after which CT (with contrast) or MRI may be performed every 2 cycles (ie, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 9 Day 1, etc), as clinically indicated, 
according to standard of care.  The same imaging modality (CT [with contrast] MRI, or bone scan) should be used on a patient throughout the study.  Bone 
scans may be performed on patients with bone metastases rather than CT or MRI.  Scans are permitted up to 7 days in advance of the scheduled visit.  At EOS, 
tumor assessments will be done only on patients who have not previously demonstrated disease progression in the study unless completed within the previous 4 
weeks.  See Section 7.4.18 for more details.
f
Including serious pretreatment events; see Section 9.1.1.
g Paclitaxel may be administered on Cycle 7 and beyond at the discretion of the investigator.
h Full hematology and chemistry panels are to be tested and reviewed by the investigator or appropriate designee before administering paclitaxel on Day 1 of each 
treatment cycle through Cycle 6. 
i
May be assessed up to 24 hours before the study visit. 
j
For screening, creatinine clearance must be ≥50 mL/min based either on Cockroft-Gault estimate or based on a 12- or 24-hour urine collection.  
k A serum pregnancy test will be performed only for patients of childbearing potential during screening and again at Cycle 1 Day 1 (baseline) if the screening test 
was performed > 3 days before the first dose of any study drug (a urine test may be performed at Cycle 1 Day 1 if the serum results are not yet available).  The 
results must be negative within 3 days before Cycle 1 Day 1, or as otherwise required by local regulations.  Additional pregnancy testing may be performed 
during the study at the discretion of the investigator, at the request of an independent ethics committee/institutional review board, or if required by local 
regulations.
l
Fasting serum glucose will be measured in the clinic before study drug dosing (and prior to administration of any prophylactics for paclitaxel).  Patients are 
required to fast overnight (nothing except water and prescribed medications after midnight or for a minimum of 8 hours before the assessment) for each of these 
measurements.  In-home glucose monitoring is not required on days when fasting glucose is measured in the clinic.  See Section 7.4.15.
m Patients in the Combination Arm will be given a glucometer on Cycle 1 Day 1 to monitor daily fasting glucose levels at home throughout Cycles 1 and 2, and 
will be instructed to notify the study clinician when the fasting glucose is abnormal (ie, ≥ 150 mg/dL).  See Section 7.4.16 for further instruction.
n To be completed within 14 days of Cycle 1 Day 1 dosing.
o During the Study Treatment period, HbA1c will be tested on Day 1 of Cycles 2 through 5 and on Day 1 of every third cycle thereafter (ie, Cycle 8, 11, 14, etc).
p To be collected predose on Cycle 1 only.


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Table 1-4   
Combination Arm Schedule of Events
Screeninga
Study Treatment Period (28-Day Cycles)
EOS/ 
ET
Visitb
Cycles 1 and 2
Cycles 3, 4, 5, and 6
Cycle ≥7
Day 1
Day 2
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
Day 8
(±2 Days)
Day 15
(±2 Days)
Day 1
q In Cycle 1 only, blood samples for PK analysis will be performed according to the schedule presented in Table 1-5.
Table 1-5   
Pharmacokinetic Sampling Time Points for the Combination Arm
PK Sampling Time Point
Cycle 1 Day 2
Predose (within 0.5 hours)
X1a
0.5 hours postdose (10 min)
X1
1 hour postdose (10 min)
X1
2 hours postdose (30 min)
X1
3 hours postdose (30 min)
X1
4 hours postdose (30 min)
X1
6 hours postdose (30 min)
X1
8 hours postdose (45 min)
X1
Abbreviations:  min = minutes; PK = pharmacokinetic; X# = number of samples required (eg, 1 sample =
X1).
a Patients will hold their medication in the morning and take their MLN0128 dose after the predose PK 
sample has been collected.


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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................20
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................22
1. BACKGROUND AND STUDY RATIONALE..............................................................24
1.1 Scientific Background ..............................................................................................24
1.1.1 Disease Under Treatment...................................................................................24
1.1.2 Study Drug ........................................................................................................24
1.2 Nonclinical Experience.............................................................................................24
1.3 Clinical Experience ..................................................................................................25
1.4 Study Rationale ........................................................................................................26
1.5 Potential Risks and Benefits .....................................................................................28
2. STUDY OBJECTIVES ..................................................................................................29
2.1 Primary Objectives ...................................................................................................29
2.2 Secondary Objective.................................................................................................29
3. STUDY ENDPOINTS....................................................................................................29
3.1 Primary Endpoints....................................................................................................29
3.2 Secondary Endpoints................................................................................................30
4. STUDY DESIGN...........................................................................................................30
4.1 Overview of Study Design........................................................................................30
4.2 Number of Patients...................................................................................................33
4.3 Duration of Study.....................................................................................................33
5. STUDY POPULATION.................................................................................................34
5.1 Inclusion Criteria......................................................................................................34
5.2 Exclusion Criteria.....................................................................................................36
6. STUDY DRUG..............................................................................................................38
6.1 Study Drug Administration.......................................................................................38
6.2 Definitions of Dose-Limiting Toxicity......................................................................39
6.3 Dose Escalation Plan for the Single-Agent QD Arm.................................................41
6.4 Dose Escalation Plan for MLN0128 in the Combination Arm...................................41
6.5 Dose Escalation Plan for the Single-Agent QW Arm ................................................42
6.6 Dose Modification Guidelines ..................................................................................43
6.7 Excluded Concomitant Medications, Foods, and Procedures.....................................52
6.7.1 All Treatment Arms...........................................................................................52
6.7.2 Combination Arm ..............................................................................................53
6.8 Permitted Concomitant Medications and Procedures.................................................53
6.8.1 All Treatment Arms...........................................................................................53
6.8.2 Combination Arm ..............................................................................................53
6.9 Precautions and Restrictions .....................................................................................54
6.9.1 All Treatment Arms...........................................................................................54
6.9.2 Combination Arm ..............................................................................................55
6.10 Management of Clinical Events:  All Treatment Arms............................................55
6.10.1 Management of Hyperglycemia .......................................................................55
6.10.2 Management of Hyperlipidemia.......................................................................57
6.10.3 Management of Oral Mucositis ........................................................................58
6.10.4 Management of Rash .......................................................................................59


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6.10.5 Management of Nausea and/or Vomiting .........................................................60
6.10.6 Management of Non-infectious Pneumonitis....................................................60
6.11 Management of Clinical Events:  Combination Arm...............................................61
6.12 Blinding and Unblinding ........................................................................................61
6.13 Description of Investigational Agents .....................................................................61
6.14 Preparation, Reconstitution, and Dispensation ........................................................62
6.15 Packaging and Labeling..........................................................................................62
6.16 Storage, Handling, and Accountability....................................................................63
7. STUDY CONDUCT ......................................................................................................64
7.1 Study Personnel and Organizations...........................................................................64
7.2 Arrangements for Recruitment of Patients ................................................................64
7.3 Treatment Group Assignments .................................................................................64
7.4 Study Procedures......................................................................................................64
7.4.1 Informed Consent ..............................................................................................64
7.4.2 Patient Demographics ........................................................................................64
7.4.3 Medical History.................................................................................................65
7.4.4 Physical Examination.........................................................................................65
7.4.5 Patient Height and Weight .................................................................................65
7.4.6 Vital Signs .........................................................................................................65
7.4.7 Pregnancy Test ..................................................................................................65
7.4.8 Eastern Cooperative Oncology Group Performance Status.................................65
7.4.9 Multiple Gated Acquisition Scan and/or Echocardiogram ..................................65
7.4.10 Concomitant Medications and Procedures........................................................66
7.4.11 Adverse Events................................................................................................66
7.4.12 Enrollment .......................................................................................................66
7.4.13 Electrocardiogram............................................................................................66
7.4.14 Clinical Laboratory Evaluations.......................................................................66
7.4.15 Fasting Serum Glucose ....................................................................................68
7.4.16 In-Home Daily Fasting Glucose Monitoring.....................................................68
7.4.17 DNA Measurements.........................................................................................68
7.4.18 Disease Assessment .........................................................................................69
7.4.19 Pharmacokinetic Measurements.......................................................................69
7.5 Completion of Treatment..........................................................................................69
7.6 Discontinuation of Treatment With Study Drug, and Patient Replacement................70
7.7 Study Compliance ....................................................................................................71
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................71
8.1 Statistical Methods ...................................................................................................71
8.1.1 Determination of Sample Size............................................................................71
8.1.2 Randomization and Stratification .......................................................................72
8.1.3 Populations for Analysis ....................................................................................72
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................72
8.1.5 Demographic and Baseline Characteristics.........................................................72
8.1.6 Efficacy Analysis...............................................................................................72
8.1.7 Pharmacokinetic Analysis ..................................................................................73
8.1.8 Safety Analysis ..................................................................................................73
8.1.9 Interim Analysis.................................................................................................74


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9. ADVERSE EVENTS .....................................................................................................75
9.1 Definitions................................................................................................................75
9.1.1 Pretreatment Event Definition............................................................................75
9.1.2 Adverse Event Definition...................................................................................75
9.1.3 Serious Adverse Event Definition ......................................................................75
9.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................76
9.3 Monitoring of Adverse Events and Period of Observation.........................................78
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........78
10. ADMINISTRATIVE REQUIREMENTS .....................................................................79
10.1 Good Clinical Practice............................................................................................79
10.2 Data Quality Assurance ..........................................................................................79
10.3 Electronic Case Report Form Completion...............................................................79
10.4 Study Monitoring ...................................................................................................80
10.5 Ethical Considerations............................................................................................80
10.6 Patient Information and Informed Consent..............................................................80
10.7 Patient Confidentiality............................................................................................80
10.8 Investigator Compliance.........................................................................................81
10.9 On-site Audits ........................................................................................................81
10.10 Investigator and Site Responsibility for Drug Accountability................................81
10.11 Product Complaints ..............................................................................................81
10.12 Closure of the Study .............................................................................................82
10.13 Record Retention..................................................................................................83
11. USE OF INFORMATION............................................................................................83
12. INVESTIGATOR AGREEMENT................................................................................84
13. REFERENCES.............................................................................................................85
14. APPENDICES .............................................................................................................87
14.1 Eastern Cooperative Oncology Group (ECOG) Performance Status Scale ..............87
14.2 Cockroft-Gault Equation.........................................................................................87
14.3 New York Heart Association Classification of Cardiac Disease ..............................87
14.4 List of Relevant Cytochrome P450 Inhibitors and Clinically Significant Enzyme 
Inducers............................................................................................................88
14.5 Amendment 1 Rationale and Purposes....................................................................89
14.6 Amendment 2 Rationale and Purposes....................................................................90
14.7 Amendment 3 Detailed Summary of Changes.........................................................93
LIST OF TABLES
Table 1-1   
Single-Agent QD and Single-Agent QW Arms Schedule of Events...............8
Table 1-2   
Pharmacokinetic Sampling Time Points for the Single-Agent QD Arm.......12
Table 1-3   
Pharmacokinetic Sampling Time Points for the Single-Agent QW Arm ......13
Table 1-4   
Combination Arm Schedule of Events.........................................................14
Table 1-5   
Pharmacokinetic Sampling Time Points for the Combination Arm..............17
Table 6-1   
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay.......45


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Table 6-2   
Dose Modifications for Single-Agent QW Arm...........................................51
Table 6-3   
Management of Hyperglycemia...................................................................56
Table 6-4   
Management of Hyperlipidemia ..................................................................58
Table 6-5   
Management of Oral Mucositis ...................................................................59
Table 6-6   
Management of Rash...................................................................................59
Table 6-7   
Management of Nausea and/or Vomiting ....................................................60
Table 6-8   
Management of Non-infectious Pneumonitis...............................................61


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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
API
active pharmaceutical ingredient
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC0-inf
area under the plasma concentration versus time curve from zero extrapolated to 
infinity
AUC0-last
area under the plasma concentration versus time curve from zero to the last measurable 
concentration
CI
confidence interval
Cmax
maximum (peak) concentration
CT
computed tomography
CYP
cytochrome P450
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
ER+
estrogen receptor positive
FBG
fasting blood glucose
GCP
Good Clinical Practice
HbA1c
glycosylated hemoglobin
HDPE
high-density polyethylene
HER2
human epidermal growth factor receptor-2 negative
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee


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Abbreviation
Term
IRB
institutional review board
IV
intravenous(ly)
LVEF
left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTOR
mammalian (or mechanistic) target of rapamycin
MUGA
multiple gated acquisition (scan)
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PI3K
phosphoinositide 3-kinase
PI3K
phosphoinositide 3-kinase alpha isoform
PK
pharmacokinetic(s)
PPI
proton pump inhibitor
PT/INR
prothrombin time/international normalized ratio
QD
quaque die; each day; once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QW
once weekly
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
S473
Serine 473
SAE
serious adverse event
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse events
Tmax
first time of occurrence of maximum (peak) concentration 
TORC1
mammalian (or mechanistic) target of rapamycin complex 1
TORC2
mammalian (or mechanistic) target of rapamycin complex 2
ULN
upper limit of the normal range
US
United States
USPI
United States Prescribing Information
WBC
white blood cell


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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Disease Under Treatment
The mammalian (or mechanistic) target of rapamycin (mTOR) is a central regulator of cell 
growth, metabolism, and angiogenesis that functions in 2 distinct multiprotein complexes:  
mTOR complex 1 (TORC1) and mTOR complex 2 (TORC2).  Like rapamycin, several 
newly approved rapalogs (temsirolimus and everolimus) are specific and allosteric inhibitors 
of TORC1 but only partially inhibit TORC1 substrates.  They do not directly inhibit 
TORC2, which has shown to be an emerging target in cancer research.  MLN0128 (formerly 
INK128) is a novel, selective, orally bioavailable mTOR inhibitor that targets both TORC1 
and TORC2, which may lead to increased antitumor activity.
1.1.2   
Study Drug
MLN0128 is being developed for the non-oncology indication of bronchiolitis obliterans 
syndrome, an inflammatory disease in the lung.  
In oncology, MLN0128 is being investigated as a treatment for advanced solid tumors and 
hematologic malignancies, either as monotherapy or in combination with chemotherapy, 
other molecularly targeted therapies, or antihormonal agents.  MLN0128 is also being 
developed in combination with MLN1117 (an oral phosphoinositide-3-kinase [PI3K] alpha 
isoform [PI3K] inhibitor) as a treatment for advanced nonhematologic malignancies.
1.2   
Nonclinical Experience
MLN0128 is an orally available, potent, and highly selective adenosine triphosphate 
competitive inhibitor of mTOR kinase that exhibits dual specificity against both the TORC1 
and TORC2 complexes.  
In vitro studies have demonstrated that MLN0128 selectively and potently inhibits mTOR 
kinase (1 nM).  Relative to mTOR inhibition, MLN0128 has > 100-fold less potency on 
class I (PI3K isoforms , , γ, and ), class II (PI3KC2and PI3K2C), and class III 
(VPS34) PI3K family members.  MLN0128 inhibits (> 80%) the biochemical activity of 
5 kinases (mTOR, DNA-PK, PDGFR, Flt3, and CK1 epsilon kinases) out of a panel of 
222 protein kinases.  Out of a panel of 402 distinct kinases, MLN0128 inhibits the ligand 
binding of only 10 receptor and intracellular protein kinases (ACVR1, BMPR1B, CSF1R, 


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CSNK1D, CSNK1E, DDR1, MEK1, MEK2, PDGFR, and RIPK2).  MLN0128 also 
displays potent cellular inhibition of both the TORC1 and TORC2 pathway with cellular 
pharmacodynamically active concentrations at 50% inhibition values of < 10 nM. 
MLN0128, administered orally in multiple human tumor xenograft mouse models, can 
inhibit angiogenesis and tumor growth by inhibiting mTOR signaling at plasma 
concentrations associated with in vitro inhibition of mTOR in a dose- and time-dependent 
manner.  These effects display a clear pharmacokinetic (PK)-to-pharmacodynamic 
relationship.(1)  MLN0128 inhibits both the phosphorylation of S6 and eukaryotic initiation 
factor 4-binding protein (4E-BP1), the downstream substrates of TORC1, and selectively 
inhibits serine/threonine-specific protein kinase (AKT) phosphorylation at Serine 473 
(S473), as evidenced by decreased pAKT, the downstream substrate of TORC2.(1, 2, 3)  Dual 
TORC1/2 inhibition mitigates the feedback activation of AKT, which is known to cause 
resistance to TORC1-only inhibitors such as rapamycin.(4)  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 mutant 
endometrial, breast, and renal cell carcinomas.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN0128
may be found in the Investigator’s Brochure (IB).
1.3   
Clinical Experience
The MLN0128 clinical development program is designed to investigate the safety, PK, 
pharmacodynamics, and preliminary efficacy of MLN0128 for the treatment of advanced 
solid tumors and hematologic malignancies, either as a single agent or in combination with 
chemotherapy and/or human epidermal growth factor receptor-2 negative (HER2-)-targeting 
agents.  Single-agent MLN0128 is in clinical development with phase 1 studies in patients 
with advanced nonhematological malignancies (INK128-001) and in patients with relapsed 
or refractory multiple myeloma or Waldenström’s macroglobulinemia (INK128-002; 
completed).  A third phase 1 study of MLN0128 is ongoing in combination with paclitaxel 
with or without trastuzumab in patients with advanced solid tumors (INK128-003).  Also, a 
phase 1b/2 study is ongoing to evaluate MLN0128 in combination with either exemestane or 
fulvestrant in postmenopausal women with estrogen receptor-positive (ER+)/HER
advanced or metastatic breast cancer who have disease progression after previous treatment 
with everolimus (Study C31001).  Additionally, the combination of MLN0128 plus 
MLN1117 (an oral PI3Kinhibitor) is being evaluated in a phase 1b study in adult patients 


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with advanced nonhematologic malignancies (Study C32001).  Further details on these 
studies are provided in the MLN0128 IB.
Clinical Pharmacokinetics of MLN0128
The PK parameters measured for MLN0128 in the phase 1 clinical studies have been 
generally consistent across a range of doses and schedules.  MLN0128 has shown linear PK 
and fast oral absorption with single-dose first time of occurrence of maximum (peak) 
concentration (Tmax) occurring between 1 and 4 hours after dosing.  The mean terminal 
disposition half-life (t1/2) of MLN0128 is approximately 8 hours, and no accumulation has 
been observed in plasma after repeat daily dosing.  The PK properties of MLN0128 are 
further detailed in the IB.
1.4   
Study Rationale
The sponsor has developed MLN0128 capsules based on milled active pharmaceutical 
ingredient (API).  This phase 1 study will determine the safety, tolerability, and PK of these 
capsules administered as a single agent and in combination with paclitaxel.  The PK of the 
MLN0128 milled API capsules will also be characterized when administered with a 
standardized high-fat breakfast. 
The safety and tolerability observed in this study will inform the selection of the 
recommended phase 2 doses (RP2Ds) for MLN0128 milled API capsules when administered 
on 3 dosing schedules (single-agent once-daily [QD], single-agent once-weekly [QW] and 
QD × 3 days QW in combination with paclitaxel), that will be further investigated in the 
clinical development of MLN0128.
The study will consist of 3 arms:  the Single-Agent QD Arm, the Combination Arm, and the
Single-Agent QW Arm.  During the Study Treatment period, patients in all 3 treatment arms 
will receive MLN0128 milled API capsules at prespecified doses, taken on an empty 
stomach.  
Patients enrolled in the Single-Agent QD Arm will also participate in a PK Run-In period 
before entering the Study Treatment period.  The PK Run-In period will determine the PK of 
MLN0128 milled API capsules when administered on an empty stomach and also after a 
standardized meal.  In these same patients, the PK of MLN0128 unmilled API capsules 
when taken on an empty stomach will also be determined.  The MLN0128 dose selected for 
the PK Run-In period (4 mg) is lower than the current maximum tolerated dose (MTD) of 
6 mg MLN0128 when administered on a QD schedule.  The 4 mg dose of MLN0128 is 


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considered a safe starting dose to evaluate the single-dose PK characteristics during the PK 
Run-In period, followed by evaluation of safety and tolerability of single-agent QD dosing 
during the Study Treatment period.  MLN0128 Study Treatment doses for subsequent 
cohorts may either be escalated or de-escalated, depending upon tolerability observed in the 
prior cohort.
The Combination Treatment Arm will investigate MLN0128 in combination with paclitaxel.  
The proposed dosing regimens for the Combination Treatment Arm are based on an 
understanding of the proposed mechanism of action of MLN0128 as an mTORC1/mTORC2 
inhibitor and a desire to avoid interference with paclitaxel.  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.(5)  Pretreatment of mTOR inhibitors will arrest cells in the 
G1 phase and antagonize the toxic effect of paclitaxel.(6)  Accordingly, MLN0128 will be 
given 24 hours after paclitaxel administration so as not to interfere with the mechanism of 
paclitaxel.  Nonclinical in vivo xenograft data also suggest that administration of MLN0128 
approximately 24 hours following paclitaxel infusion may provide more synergy in tumor 
cell kill.  In addition, both rapamycin and MLN0128 significantly enhanced paclitaxel-
induced apoptosis when given 12 to 24 hours after chemotherapy administration 
(INK128-003 data).(7)
The Single-Agent QW Arm will evaluate the safety, tolerability and PK of milled MLN0128 
API capsules using a QW dosing schedule.  On the basis of biopharmaceutical 
considerations of API solubility in relation to the dose of MLN0128, the change from 
unmilled to milled API may result in faster absorption, and possibly result in a higher 
maximum observed plasma concentration (Cmax) than that observed with unmilled API, 
which could potentially alter the safety profile of MLN0128. The safety and tolerability 
observed in this treatment arm will inform the selection of the RP2Ds for MLN0128 milled 
API capsules when administered QW and will be further investigated in the clinical 
development of MLN0128.
The current MTD of MLN0128 unmilled API capsules when administered 24 hours after 
completion of a paclitaxel infusion (80 mg/m2 intravenously [IV] on Days 1, 8, and 15) in a 
28-day cycle is 10 mg when administered QD × 3 days QW, and the RP2D regimen is 8 mg 
QD × 3 days QW.  The starting dose of MLN0128 6 mg milled API capsules administered 
QD × 3 days QW beginning 24 hours after completion of a paclitaxel infusion is considered 


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a safe starting dose.  Depending on tolerability, MLN0128 dose regimens for subsequent 
cohorts in the Combination Arm may either be escalated or de-escalated.
1.5   
Potential Risks and Benefits
The most common treatment-emergent adverse events (TEAEs) observed with single-agent 
MLN0128 unmilled API capsules are consistent with the pharmacodynamic mechanism of 
mTOR inhibition that is also seen with rapalogs (TORC1 inhibition) or other dual 
mTORC1/2 inhibitors.  Treatment-emergent adverse events observed across MLN0128 
single-agent studies with unmilled API capsules include diarrhea, fatigue, vomiting, rash, 
mucosal inflammation, asthenia, dysgeusia, thrombocytopenia, stomatitis, and increased 
blood creatinine.  In general, observed toxicities have been mostly Grade 1 or Grade 2 and 
have been manageable with supportive care and/or an MLN0128 dose interruption or 
reduction.
During this study, risk mitigation strategies include, but are not limited to, strict application 
of the study eligibility criteria, frequent monitoring of clinical and laboratory results, 
guidelines for management and prophylaxis of potential toxicities, guidelines for dose 
modification, and regular monitoring of adverse events (AEs) and serious adverse events 
(SAEs) by the sponsor. 
The benefits of MLN0128 are discussed in Section 1.1.2.  Further details are presented in 
the MLN0128 IB.
CCI


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2.   
STUDY OBJECTIVES
2.1   
Primary Objectives
The primary objectives are:

To evaluate the safety and tolerability of MLN0128 milled API capsules 
administered both as a single agent and in combination with paclitaxel 

To characterize the effect of a high-fat meal on the PK of MLN0128 milled API 
capsules 

To characterize the PK of MLN0128 milled API capsules when administered on an 
empty stomach approximately 24 hours after paclitaxel infusion
2.2   
Secondary Objective
The secondary objectives are:

To characterize the PK of MLN0128 milled API capsules versus unmilled API 
capsules, when administered on an empty stomach 

To evaluate the preliminary efficacy of MLN0128 milled API capsules when 
administered as a single agent and in combination with paclitaxel
3.   
STUDY ENDPOINTS
3.1   
Primary Endpoints
The primary endpoints are:

TEAEs, SAEs 

Ratio of geometric means and associated 90% confidence intervals (CIs) of the 
maximum (peak) concentration (Cmax), area under the plasma concentration versus 
time curve (AUC) from zero to the last measurable concentration (AUC0-last), and 
AUC from zero extrapolated to infinity (AUC0-inf) of a single dose of MLN0128 
milled API capsules administered following a high-fat breakfast versus when 
administered on an empty stomach 


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
PK parameters including, but not limited to, Cmax, Tmax, and AUC of a single dose of 
MLN0128 milled API capsules administered on an empty stomach approximately 
24 hours after paclitaxel infusion (Combination Arm)
3.2   
Secondary Endpoints
The secondary endpoints are:

PK parameters including, but not limited to, Cmax, Tmax, and AUC of a single dose of 
MLN0128 milled or unmilled API capsules administered on an empty stomach
(Single-Agent QD and Single-Agent QW Arm)

Rates of overall response, progression-free survival, clinical benefit responses, and 
detectable changes in tumor volume/size from baseline
4.   
STUDY DESIGN 
4.1   
Overview of Study Design
This study is a multicenter, open-label, phase 1 trial of MLN0128 administered orally both 
as a single agent and in combination with IV infusions of paclitaxel in adult patients with 
advanced nonhematologic malignancies for whom standard, curative, or life-prolonging 
anticancer treatment does not exist or is no longer effective.  The study will consist of 
3 arms:  a Single-Agent QD Arm, a Combination Arm, and a Single-Agent QW Arm.  The 
3 arms will enroll in parallel and will administer study treatment in repeated 28-day cycles.  
Study eligibility will be determined during the Screening period, which may last for up to 
28 days before the first dose of study drug is administered. Patients who meet all eligibility 
criteria and provide written informed consent will be enrolled. 
The Single-Agent QD Arm will test the safety, tolerability, and PK of MLN0128 milled 
API capsules when administered on an empty stomach and will additionally characterize the 
PK profile when taken with a standardized high-fat breakfast.  In the same patients, the PK 
of MLN0128 unmilled API capsules when taken on an empty stomach will also be assessed
as a point of reference for comparison of milled API capsule PK.  The PK assessments will 
be performed during a PK Run-In period during which each patient will receive a total of 
three 4-mg doses of MLN0128 as described below and in Table 1-2.


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
PK Run-In Visit 1:  MLN0128 4-mg unmilled API capsule taken on an empty 
stomach. 

PK Run-In Visit 2 (24 hours [1 hr] after PK Visit 1):  24-hour postdose PK sample 
collected.

PK Run-In Visit 3 (≥48 hours after PK Visit 1):  MLN0128 4-mg milled API 
capsule taken with a standardized high-fat breakfast.  

PK Run-In Visit 4 (24 hours [1 hr] after PK Visit 3):  24-hour postdose PK sample 
collected.

PK Run-In Visit 5 (≥48 hours after PK Visit 3):  MLN0128 4-mg milled API 
capsule taken on an empty stomach.

PK Run-In Visit 6 (24 hours [1 hr] after PK Visit 5):  24-hour postdose PK sample 
collected.  Note:  If scheduling permits, Visit 6 can be combined with Cycle 1 Day 1 
of the Study Treatment period.  That is, the 24-hour postdose PK sample for the Visit 
5 PK dose can be drawn before the first administration of the patient’s assigned 
Study Treatment dose, if the timing allows.
Each patient in the Single-Agent QD Arm will complete the PK Run-In period within 
14 days before Cycle 1 Day 1 of the Study Treatment period.  Study treatment for the 
Single-Agent QD Arm will consist of repeated 28-day cycles of oral MLN0128 milled API 
capsules taken on an empty stomach.  The first 6 patients enrolled into the Single-Agent QD 
Arm Study Treatment period will receive MLN0128 at 4 mg QD.  An evaluation of safety 
and tolerability will be conducted after these first 6 patients have completed Cycle 1 to 
determine the dose to be administered (see Section 6.3) during the Study Treatment period 
for the next patients enrolled into the Single-Agent QD Arm. Safety evaluations will 
continue before enrolling each subsequent cohort into the Single-Agent QD Arm.  A total of 
16 subjects will complete the protocol-specified PK evaluations in the Single-Agent QD 
Arm.
The Combination Arm will test the safety, tolerability, and PK of MLN0128 milled API 
capsules when administered on an empty stomach in combination with paclitaxel.  Paclitaxel 
(80 mg/m2) will be administered as an IV infusion on Days 1, 8 (1 day), and 15 (1 day) 
of each 28-day cycle according to the institution’s standard clinical practice.  MLN0128 will 
be administered QD × 3 days QW of each cycle, beginning 24 hours after completion of the 


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Day 1 paclitaxel infusion; ie, MLN0128 will be administered on Days 2 through 4, 9 
through 11, 16 through 18, and 23 through 25 of every 28-day cycle.  The starting 
MLN0128 dose for the Combination Arm will be 6 mg (QD × 3 days QW).  Plasma samples 
to characterize the PK of MLN0128 will be collected on Cycle 1 Day 2. 
Consistent with the Single-Agent QD Arm, an interim safety and tolerability review will be 
conducted for the Combination Arm after the initial cohort of 6 patients has completed 
Cycle 1.  According to standard dose escalation rules on the basis of the safety and 
tolerability observed in the initial 6 evaluable patients, the dose of MLN0128 (QD × 3 days 
QW) for the next cohort of 6 patients will be either reduced, maintained or escalated (see 
Section 6.4).  
The Single-Agent QW Arm will evaluate the safety, tolerability, and PK of MLN0128 
milled API when administered on an empty stomach in 2 sequential cohorts, each consisting 
of 6 to 12 patients.  Initially, 6 patients in Cohort 1 will receive 20 mg of MLN0128 
capsules based on milled API once every week (QW).  Serial plasma specimens will be 
collected for evaluation of MLN0128 PK.  A safety and tolerability assessment will be 
performed after the last patient in the cohort completes Cycle 1.  If ≥2 patients experience a 
dose-limiting toxicity (DLT) during Cycle 1, then the starting dose of MLN0128 milled API 
for the subsequent cohort (Cohort 2) will be reduced to 15 mg QW.  If ≤1 patient in Cohort 
1 experiences a DLT in Cycle 1, then the dose of milled MLN0128 in Cohort 2 will be 
increased to 30 mg QW.  If the dose of MLN0128 milled API is deemed safe in any cohort 
based on 3+3 rules, then the cohort may be expanded to 12 patients to confirm the RP2D for 
single-agent MLN0128 milled API capsules when administered QW.  The escalation 
algorithm is displayed in Figure 4-1.


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Figure 4-1   
MLN0128 Dose Escalation for Single-Agent QW Arm
Blood will be collected from all patients for PK analysis of MLN0128. Blood samples for all 
PK analyses will be collected at the time points specified in Table 1-3
Throughout the study, patient safety will be monitored through assessment of AEs clinical 
laboratory values, vital signs, and electrocardiograms (ECGs).
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.(8)  
Dose-limiting toxicities (DLTs) are defined in Section 6.2.
4.2   
Number of Patients
Approximately 44 to 56 evaluable patients will be enrolled at approximately 5 study centers 
in the United States (US).  Enrollment is defined as the time of the initiation of the first dose 
of study drug (ie, MLN0128 or paclitaxel, whichever is administered first).
Patients in the Single-Agent QD Arm who are withdrawn from treatment before completing 
per-protocol PK assessments in the PK Run-In period will be replaced.  
4.3   
Duration of Study
In the absence of unacceptable treatment-related toxicity or disease progression, patients 
may receive study treatment for up to 1 year at the discretion of the investigator and beyond 
1 year with the agreement of the investigator and the sponsor if, in the opinion of the 
investigator, the patient is benefitting from treatment.


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It is anticipated that this study will last for approximately 12 months.
5.   
STUDY POPULATION
5.1   
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Age ≥ 18 years, including males and females.
2. Advanced nonhematologic malignancies, with the exception of primary brain tumor, 
and have failed or are not eligible for standard of care therapy. History of brain 
metastasis may be allowed if all the following criteria are met: brain metastases 
have been treated, there is no evidence of progression or hemorrhage after treatment, 
dexamethasone discontinued for ≥4 weeks before first study drug administration, 
and there is no ongoing requirement for dexamethasone or anti-epileptic drugs.
3. Received not more than 4 prior lines of systemic cytotoxic chemotherapy for 
advanced or metastatic disease.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.
5. Adequate organ function, including the following:

Bone marrow reserve consistent with absolute neutrophil count (ANC) 
≥1.5 109/L; platelet count ≥ 100 109/L; and hemoglobin ≥ 9 g/dL without 
transfusion in the last 2 weeks

Hepatic:  total bilirubin ≤ 1.5 the upper limit of the normal range (ULN), 
transaminases (aspartate aminotransferase [AST]/serum glutamic oxaloacetic 
transaminase and alanine aminotransferase [ALT]/serum glutamic pyruvic 
transaminase) ≤2.5 ULN (≤ 5 ULN if liver metastases are present)

Renal:  normal serum creatinine or calculated creatinine clearance ≥50 mL/min 
based either on Cockroft-Gault estimate (see Section 14.2) or based on urine 
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
Metabolic:  fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides 
≤300 mg/dL
6. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of 
institutional standard of normal as measured by echocardiogram (ECHO) or multiple 
gated acquisition scan (MUGA) within 4 weeks before first study drug 
administration (ie, if the institutional normal is 50%, subject’s LVEF may be as low 
as 45% to be eligible for the study).
7. 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 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
form through 90 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  (Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.)
Male patients, even if surgically sterilized (ie, status post-vasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 120 days 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, post-ovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception.)
8. Ability to swallow oral medications.
9. Voluntary written consent obtained 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 use enrolled in the 
study:
1. Diagnosis of primary brain tumor.
2. Untreated brain metastasis or history of leptomeningeal disease or spinal cord 
compression.
3. Failed to recover from the reversible effects of prior anticancer therapies, with the 
exception of alopecia, and after-effects associated with prior tyrosine kinase inhibitor 
therapy, such as hair depigmentation, hypothyroidism, and/or splinter hemorrhage.
4. Received prior cancer therapy or other investigational therapy within 2 weeks before 
the first administration of study drug.  For prior therapies with a half-life longer than 
3 days, the interval must be at least 28 days before the first administration of study 
drug, and the patient must have documented disease progression.
5. Initiation of hematopoietic growth factors within 1 week before the first 
administration of any study drug; patients already receiving hematopoietic growth 
factors on a chronic basis for ≥ 4 weeks are eligible.
6. Chronic systemic corticosteroid (except inhalers) use within 1 week before the first 
administration of study drug.  Premedication with dexamethasone before paclitaxel 
administration in this study is allowed.  Use of low-dose glucocorticoids for 
replacement therapy is also allowed.
7. Manifestations of malabsorption due to prior gastrointestinal surgery, gastrointestinal
disease, or for some other reason that may alter the absorption of MLN0128.  In 
addition, patients with enteric stomata are also excluded.
8. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) 
> 7%; subjects with a history of transient glucose intolerance due to corticosteroid 
administration are allowed if all other eligibility criteria are met.
9. Other clinically significant comorbidities, such as uncontrolled pulmonary disease, 
active central nervous system disease, active infection, or any other condition that 
could compromise the patient’s participation in the study.


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10. Known human immunodeficiency virus infection.
11. Pregnant (positive serum or urine pregnancy test) or breastfeeding.
12. 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 14.3)

Pulmonary embolism
13. Significant active cardiovascular or pulmonary disease before administration of the 
first dose of study drug, including:

Uncontrolled hypertension (ie, systolic blood pressure > 180 mm Hg; diastolic 
blood pressure > 95 mm Hg)

Pulmonary hypertension  

Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis 
or pulse oximetry on room air

Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention; or history of valve 
replacement

Medically significant (symptomatic) bradycardia 


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
History of arrhythmia requiring an implantable cardiac defibrillator

Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated 
demonstration of QTc interval > 480 ms, or history of congenital long QT 
syndrome, or torsades de pointes)
14. Diagnosed or treated for another malignancy within 2 years before the first dose 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.
15. Single-Agent QD Arm patients participating in the PK Run-In (only): patients 
who use proton pump inhibitors (PPIs) less than 5 days before the first MLN0128 
PK Run-In dose OR use H2 receptor antagonists within 24 hours of the first PK 
Run-In dose.  (Note that these restrictions apply to the PK Run-In period but do not 
apply to the Study Treatment period for any Arm).  See Section 6.7 for more 
information.
6.   
STUDY DRUG
6.1   
Study Drug Administration
Millennium-sponsored drug product will be provided to the study sites.  All protocol-
specific criteria for administration of study drug 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).  In all treatment arms, study 
drugs will be administered during the Study Treatment period in 28-day cycles. Each 
patient will participate in only 1 cohort and 1 dosing schedule.
Eligible patients will report to the study site to receive their assigned study treatment on 
days specified in the corresponding Schedules of Events.  Each patient in the Single-Agent 
QD Arm will complete the PK Run-In period (see Table 1-2) within 14 days before Cycle 1 
Day 1 of the Study Treatment period.  During the Study Treatment period for the 
Single-Agent QD Arm, study drug administration will consist of repeated 28-day cycles of 
daily oral MLN0128 milled API capsules taken on an empty stomach.  


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Study drug administration during the Study Treatment period for all treatment arms will 
follow the schedules shown in the Study Drug Dosing Diagram.  MLN0128 will be 
administered at approximately the same time on each dosing day.  On dosing days when the 
patient does not have a clinic visit, patients will take their assigned MLN0128 dose at home.  
Except as specified in Table 1-2, MLN0128 will be taken on an empty stomach.  Patients 
should be instructed to refrain from eating and drinking (except water and prescribed 
medications) for 2 hours before and 1 hour after each dose.  It is recommended that each 
dose of MLN0128 be taken with 8 ounces (240 mL) of water.  
During the Study Treatment period for all treatment arms, patients will be instructed to 
record in their dosing diary (see the Pharmacy Manual) each MLN0128 dose they take.  If 
severe emesis or mucositis prevents the patient from taking an MLN0128 dose, that dose 
will be skipped.  If emesis occurs after study medication ingestion, 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 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.  A forgotten or 
missed dose of MLN0128 should be taken if it is possible to do so within 6 hours of the 
scheduled dosing time for the Single-Agent QD Arm and Combination Arm and within 
12 hours of the scheduled dosing time for the Single-Agent QW Arm; otherwise, that dose 
should be skipped, and the next dose should be taken as scheduled.  Any skipped dose 
should be considered a missed dose.  For doses missed during the PK Run-In phase, 
evaluability and replacement of patients will be assessed and carried out accordingly.
All missed MLN0128 doses or doses administered within approximately 1 hour before a 
vomiting episode should be recorded in the electronic case report form (eCRF).
Additional information for the Combination Arm:  Commercially available paclitaxel 
will be procured or distributed according to the Pharmacy Manual.  Paclitaxel (80 mg/m2
IV) will be administered on Days 1, 8 (1 day), and 15 (1 day) of each Study Treatment 
cycle.  The investigator will refer to the current paclitaxel product label for the most recent 
instructions on drug handling, administration, risks, and potential side effects.(9, 10)
6.2   
Definitions of Dose-Limiting Toxicity 
Dose-limiting toxicities are defined according to the AE profile observed in Cycle 1 and the 
PK Run-In period as described below.  All AEs should be considered possibly related to 
MLN0128 unless such relationship can be definitively excluded.


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Toxicity will be evaluated according to NCI CTCAE (Version 4.03, effective 14 June 
2010).(8)  These criteria are provided in the Study Manual.  Dose-limiting toxicity will be 
defined as any of the following events that are considered by the investigator to be at least 
possibly related to therapy with MLN0128:

Grade 3 or higher nonhematologic toxicity, despite adequate treatment, except for 
the following:
o
Grade 3 hyperglycemia lasting ≤ 14 days (all patients should receive optimal 
antiglycemic treatment, including insulin)
o
Grade 3 rash lasting ≤ 3 days (all patients should receive topical steroid 
treatment, oral antihistamines, and oral steroids, if necessary)

Grade 3 thrombocytopenia with hemorrhage

Grade 4 neutropenia lasting > 7 days in the absence of growth factor support

Grade 4 neutropenia of any duration accompanied by fever ≥ 38.5°C and/or systemic 
infection

Any other ≥ Grade 4 hematologic toxicity

Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 
due to study drug-related toxicity

Any clinically significant occurrence that the investigator and sponsor agree would 
place patients at an undue safety risk
Patients who experience an AE that meets the definition of a DLT during or after completing 
Cycle 1 should have their study drug treatment interrupted.  If the event resolves to Grade 1 
or baseline values within 2 weeks of interrupting planned therapy, and in the opinion of the 
investigator and the sponsor’s project clinician the benefits of continuing treatment outweigh 
the risks posed by the toxicity, patients may continue study treatment with MLN0128 up to a 
33% dose reduction (ie, dose reduced to 4 mg QD × 3 days) with approval of the sponsor’s 
project clinician.  If study drug dosing is delayed for more than 14 consecutive days for 
MLN0128-related toxicity, despite supportive treatment per standard clinical practice, or 
more than 2 dose reductions of MLN0128 are required, the patient will be discontinued from 
the study.


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Although DLTs may occur at any point during treatment, only DLTs occurring during 
Cycle 1 of treatment will necessarily influence decisions regarding the starting dose for the 
second cohort in the Single-Agent QW Arm and for the expansion of the second cohort in 
the Single-Agent QW Arm.  Patients will be monitored through all cycles of therapy for 
treatment-related toxicities.
6.3   
Dose Escalation Plan for the Single-Agent QD Arm
All patients in the Single-Agent QD Arm will first complete the PK Run-In period before 
entering the Study Treatment period.  During the Study Treatment period, all patients will 
receive MLN0128 milled API capsules.
An interim safety and tolerability review will be conducted for each Single-Agent QD Arm 
cohort following completion of Cycle 1 of the Study Treatment period to determine the 
Study Treatment dose for the next Single-Agent QD Arm cohort.  Dose escalation rules for 
the Single-Agent QD Arm are outlined below.
The first cohort of 6 patients will receive 4 mg QD.

If ≤ 1 DLTs occur in these 6 patients at 4 mg QD, the next 6 patients will receive
5 mg QD.  
o
If ≤ 1 DLTs occur, the next 6 patients will receive 5 mg QD.
o
If ≥ 2 DLTs occur, the next 6 patients will receive 4 mg QD.  

If ≥ 2 DLTs occur in the initial 6 patients receiving 4 mg QD, the next 6 patients will 
receive 3 mg QD.
o
If 1 DLTs occur, the next 6 patients will receive 3 mg QD.
o
If ≥ 2 DLTs occur, enrollment in the Single Agent Arm will be closed.
6.4   
Dose Escalation Plan for MLN0128 in the Combination Arm
All patients in the MLN0128 Combination Arm will receive MLN0128 milled API capsules 
on a dosing schedule beginning approximately 24 hours after completion of the Day 1 
infusion of paclitaxel (80 mg/m2 IV).


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The first 6 patients enrolled into the Combination Arm will receive MLN0128 6 mg 
QD × 3 days QW beginning approximately 24 hours after completion of the Day 1 infusion
of paclitaxel.  An interim safety and tolerability review will be conducted after the initial 
cohort of 6 evaluable patients has completed Cycle 1. On the basis of the safety and 
tolerability observed in a minimum of 3 of the 6 evaluable patients, the MLN0128 dose 
administered to the next Combination Arm cohort will either be 4 mg QD × 3 days QW, 
6 mg QD × 3 days QW, or 8 mg QD × 3 days QW, initiated approximately 24 hours after 
completion of the Day 1 infusion of paclitaxel. 
If ≥ 2 DLTs occur in the 6 mg QD × 3 days QW cohort, the MLN0128 dose will be reduced 
to 4 mg QD × 3 days QW in the 6 patients in the next Combination Arm cohort:  

If ≤ 1 DLTs occur in the 6 patients at 4 mg QD × 3 days QW, the cohort will be 
expanded by enrolling 6 additional patients at 4 mg QD × 3 days QW.  If ≤ 1 DLTs 
occur in the additional 6 patients at 4 mg QD × 3 days QW, this is the MTD.

If ≥ 2 DLTs occur in the 6 patients at 4 mg QD × 3 days QW, the study will be 
stopped.  
If 1 DLTs occur in the 6 mg QD × 3 days QW cohort, the MLN0128 dose will be 
escalated to 8 mg QD × 3 days QW in the 6 patients in the next Combination Arm cohort:  

If ≤ 1 DLTs occur in the 6 patients at 8 mg QD × 3 days QW, the cohort will be 
expanded by enrolling 6 additional patients at 8 mg QD × 3 days QW.  If ≤1 DLTs 
occur in the additional 6 patients at 8 mg QD × 3 days QW, this is the MTD.  

If ≥ 2 DLTs occur in the 6 patients at 8 mg QD × 3 days QW, the dose will be 
reduced, and 6 additional patients will be enrolled at 6 mg QD × 3 days QW.  If 
≤1 DLTs occur in the additional 6 patients at 6 mg QD × 3 days QW, this is the 
MTD.   
The decision to escalate or de-escalate the dose of MLN0128 milled API in the second 
cohort of the Combination Arm cohort will be based on safety, and will be informed by 
review of available PK data.
6.5   
Dose Escalation Plan for the Single-Agent QW Arm
The starting dose of MLN0128 in the second cohort (Cohort 2) in the Single-Agent QW 
Arm will be based on the occurrence of DLTs in the first cohort as follows: 


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
If ≥2 patients in the first cohort (Cohort 1) of 6 patients receiving 20 mg MLN0128 
QW experience DLTs during Cycle 1, then the starting dose for the subsequent 
cohort will be reduced to 15 mg MLN0128 QW. 

If 0 or 1 patient in the first cohort of 6 patients receiving 20 mg MLN0128 QW 
experiences a DLT, then the starting dose for the subsequent cohort (Cohort 2) of 
6 patients will be increased to 30 mg MLN0128 QW. 
The decision to escalate or de-escalate the dose of MLN0128 milled API in the second 
cohort (Cohort 2) in the Single-Agent QW Cohort will be based on safety, and will be 
informed by review of available PK data. 
6.6   
Dose Modification Guidelines
The investigators should try to the best of their ability to assess whether an AE is possibly 
related to study drug, and if so, attribute it to MLN0128 only, paclitaxel only, or MLN0128 
and paclitaxel, and treat the patient accordingly. This section and Table 6-1 provide 
suggested guidelines for the management of various study drug-related toxicities that may 
occur in this study.  
In general, dose modification rules when managing hematologic or nonhematologic 
toxicities are intended for use in a similar manner for patients enrolled in either arm.  
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 > 2 dose reductions of either MLN0128 or paclitaxel (4 total), 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 and written approval 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:


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Paclitaxel:  Paclitaxel dosing should be withheld for ≥ Grade 2 paclitaxel-related toxicities 
and resumed at the same dose or at a 20-mg/m2 dose reduction depending on the timing of 
recovery and number of episodes that occurred (see Table 6-1).  If paclitaxel dosing is 
delayed because of paclitaxel-related toxicities for > 21 consecutive days despite supportive 
treatment per standard clinical practice or > 2 dose reductions of paclitaxel (≤40 mg/m2) are 
required, paclitaxel therapy should be stopped.
MLN0128:  In general, MLN0128 dosing should be withheld for ≥Grade 3 
MLN0128-related nonhematologic toxicities.  Table 6-1 provides suggested guidelines for 
the investigators to use along with their best judgment for an 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 > 2 MLN0128 dose reductions are required, 
stop MLN0128 (and paclitaxel therapy, if applicable), discontinue the subject from the 
study, and complete the end-of-study visit within 30 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 Combination Treatment Arm, as a general approach to manage taxane-related 
hematologic toxicities, paclitaxel should be reduced first (or delayed) before initiation of 
myeloid growth factors or 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.


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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 6-1, is strongly 
encouraged if appropriate as an intervention step at the repeat occurrence of neutropenia 
requiring dose modification.  Short-acting myeloid growth factors are preferred, and they 
should be discontinued for an appropriate number of days before restarting protocol 
treatment.
Table 6-1   
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
Adverse Event
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
Absolute Neutrophil Count (ANC)
Grade 2 
(< 1500-
1000/mm3)
No change.  Continue MLN0128 at same 
dose and schedule.
No change.  Continue paclitaxel at same 
dose and schedule.
For ANC 1500/mm3, consider the use of 
prophylactic myeloid growth factors (ie, 
GCSF):

Start 1 or 2 days after paclitaxel 
infusion and use for 2 to 6 days 
according to patient’s need, at 
physician discretion, and to avoid dose 
reduction.

Growth factor should not be given on 
the same day as paclitaxel infusion.

GCSF is preferred over pegfilgrastim 
because of the weekly dosing of 
paclitaxel in this study.
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 by 25% for all 
subsequent cycles.

> 2 weeks of interrupting planned 
therapy:  stop paclitaxel and 
discontinue patient from study.
Consider use of prophylactic myeloid 
growth factor support per guidelines above.


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Table 6-1   
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
Adverse Event
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
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 for all 
subsequent cycles. 

> 2 weeks:  stop MLN0128 and 
discontinue patient 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 
by 25% for all subsequent cycles.

2 weeks of interrupting planned 
therapy:  stop paclitaxel and 
discontinue patient 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-
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% for all subsequent cycles.

> 2 weeks of interrupting planned 
therapy:  stop paclitaxel and 
discontinue patient from study.
Grade 3 
(25-
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 
to the next lower dose for all 
subsequent cycles. 

> 2 weeks:  stop MLN0128 and 
discontinue patient from study.
Platelet transfusions in the absence of 
bleeding should not be administered.
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% for all subsequent cycles. 

> 2 weeks of interrupting planned 
therapy:  stop paclitaxel and 
discontinue patient from study.
Platelet transfusions in the absence of 
bleeding should not be administered.


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Table 6-1   
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
Adverse Event
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
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 to 
the next lower dose for all subsequent 
cycles.

Third episode:  reduce MLN0128 to 
the next lower dose from the first 
reduced dose for all subsequent 
cycles.

Fourth episode:  stop MLN0128 and 
discontinue patient from study. 
Platelet transfusions should be 
administered prophylactically if platelets 
are 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:  reduce paclitaxel by 
25% from starting 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 patient from study.
Platelet transfusions should be administered 
prophylactically if platelets are 
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 
to the next lower dose for all 
subsequent cycles.

> 2 weeks:  stop MLN0128 and 
discontinue patient 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 patient’s medical history eCRF page.  
Hold paclitaxel until LFTs improve to 
Grade 1 or baseline values within 
2 weeks of interrupting planned therapy.
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% for all subsequent cycles.

> 2 weeks of interrupting planned 
therapy:  stop paclitaxel and 
discontinue patient from study.


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Table 6-1   
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
Adverse Event
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 to 
the next lower dose for all subsequent 
cycles.

Third episode:  reduce MLN0128 to 
the next lower dose from the reduced 
dose for all subsequent cycles.

Fourth episode:  stop MLN0128 and 
discontinue patient 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:  reduce paclitaxel 
dose by 25% (60 mg/m2) from starting 
dose for all subsequent cycles.

Third episode:  reduce paclitaxel dose 
by 50% (45 mg/m2) from starting dose 
for all subsequent cycles.

Fourth episode:  stop paclitaxel and 
discontinue patient 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 7

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 7

Urinalysis

12-hour urine collection

Spot urine for electrolytes, protein, 
and creatinine


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Table 6-1   
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
Adverse Event
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
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 7

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 in 
2 weeks of interrupting planned therapy.
Collect the following tests to help identify 
cause of renal dysfunction:

Chemistry 7

Urinalysis

12-hour urine collection 

Spot urine for electrolytes, protein, 
and creatinine
Consider IV hydration.
Resume paclitaxel at the same dose and 
schedule.
≥ 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 7
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 7

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% for all subsequent cycles. 

> 2 weeks of interrupting planned 
therapy:  stop paclitaxel and 
discontinue patient from study.


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Table 6-1   
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
Adverse Event
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
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% 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 by 25% dose 
reduction 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 
interruption).
Hyperglycemia
Grade 2
(ULN-
250 mg/dL)
Continue MLN0128 at same dose and 
schedule.  Refer to Section 6.10.1 for 
guidelines on hyperglycemia management.
Continue paclitaxel at same dose and 
schedule.  Refer to Section 6.10.1 for 
guidelines on hyperglycemia management.
Grade 3
(> 250 mg/dL)
Hold MLN0128 until hyperglycemia 
improves to Grade 2.  Refer to 
Section 6.10.1 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 6.10.1 for 
guidelines on hyperglycemia management.


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Table 6-1   
Guidelines for MLN0128 and Paclitaxel Dose Modification and Delay
Adverse Event
MLN0128 Dose Reduction and/or Delay
Paclitaxel Dose Reduction and/or Delay
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 6.10.4 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.
Abbreviations:  ANC = absolute neutrophil count; eCRF = case report form; GCSF = granulocyte-colony 
stimulating factor; IV = intravenous(ly); LFT = liver function test; ULN = upper limit of the normal 
range.
For the Single-Agent QW Arm, MLN0128 administration should be withheld for treatment-
related adverse events that are Grade 3 or higher, despite supportive treatment per standard 
clinical practice. If the event resolves to Grade 1 or to baseline values within 3 weeks of 
interrupting treatment, then the patient may resume study treatment at a dose reduced by 
1 level (see Table 6-2). If a patient does not tolerate 15 mg, then the investigator and the 
project clinician should discuss whether the patient would benefit from a further dose 
reduction.
Table 6-2   
Dose Modifications for Single-Agent QW Arm
Dose Level
Dose Regimen 
MLN0128 Capsules: Number and Strength
0
30 mg QW
Six 5-mg capsules 
1
20 mg QW
Four 5-mg capsules 
2
15 mg QW
Three 5-mg capsule 
3
10 mg QW
Two 5-mg capsules 
Abbreviations:  QW = once weekly.


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6.7   
Excluded Concomitant Medications, Foods, and Procedures
6.7.1   
All Treatment Arms
All prescription and over-the-counter medications, including influenza vaccines, taken by a 
patient as of the first study drug administration through 30 days after the last dose will be 
recorded on the designated eCRF.
The following medications, therapies, and foods are prohibited during the study, except as 
indicated below:

Other investigational agents or mTOR inhibitors.

Other anticancer therapies, including chemotherapy, immunotherapy, 
radioimmunotherapy, targeted agents, radiation, or surgery (patients can have 
palliative radiation or surgery during the study for pre-existing lesions).

Systemic corticosteroids (either IV or oral steroids, excluding inhalers), unless 
necessary for treatment of an MLN0128-related AE (eg, rash).  Premedication with 
dexamethasone before paclitaxel administration in this study is allowed.  Use of 
low-dose glucocorticoids for replacement therapy is also allowed.

Anti-epileptic drugs for patients with a history of treated brain metastasis.

Anti-emetic drugs associated with a significant risk for QT prolongation, including 
ondansetron.

Strong cytochrome CYP1A2 inhibitors and CYP inducers should be administered 
with caution and at the discretion of the investigator (refer to Section 14.4 for a list 
of these agents).  Alternative treatments, if available, should be considered.

No dietary restrictions will be imposed on study patients.

Administration of any proton pump inhibitor (PPI) is not permitted during the PK 
Run-In period of the Single-Agent QD and Single-Agent QW Arms.  Patients in the 
Single-Agent QD and Single-Agent QW Arms who receive PPI therapy before 
enrollment must stop using the PPI for 5 days before their first PK Run-In dose until 
completion of PK Visit 6.  Examples of PPIs include omeprazole, esomeprazole, 
pantoprazole, lansoprazole, and rabeprazole.  Note that this restriction does not apply 
to the Study Treatment period for any treatment arm.


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The use of an H2 receptor antagonist is not permitted during the PK Run-In period of the 
Single-Agent QD Arm, beginning 24 hours before administration of the first PK Run-In 
dose through completion of PK Visit 6.  Examples of H2 receptor antagonists include 
ranitidine, famotidine, and nizatidine.  Note that this restriction does not apply to the Study 
Treatment period for any treatment arm.  During the Study Treatment period, H2 receptor 
antagonists may be allowed, if needed, provided that the histamine H2 receptor antagonist is 
not taken within 12 hours before and within 6 hours after study drug administration.  
However, cimetidine, a moderate CYP1A2 inhibitor, is not recommended as a first-choice 
H2 receptor antagonist (refer to Section 14.4).
Treatment with neutralizing antacids (eg, Maalox Max, calcium carbonate) is not permitted 
within 4 hours before and within 6 hours after receiving a dose of MLN0128.
6.7.2   
Combination Arm
Benzodiazepines are to be avoided in patients receiving paclitaxel.  Please refer to the most 
recent paclitaxel US Prescribing Information (USPI) for information on medications that are 
prohibited in patients receiving paclitaxel.
6.8   
Permitted Concomitant Medications and Procedures 
6.8.1   
All Treatment Arms
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications is encouraged, 
and these may be administered before the first dose of study drug, as needed throughout the 
study before each dosing, and as clinically indicated per standard practice. 
Concomitant treatment with bisphosphonates is permitted for treatment of osteoporosis or 
management of existing bone metastasis if initiated at least 4 weeks before administration of 
the first dose of study drug.  Bisphosphonates should be given after Cycle 1 to minimize 
confounding factors that may contribute to potential drug-related toxicities.
Other medications considered necessary for the safety and wellbeing of the patient may be 
administered at the discretion of the investigator.  Any concomitant medications added or 
discontinued during the study should be recorded on the eCRF.
6.8.2   
Combination Arm
Premedication with corticosteroids, diphenhydramine, or H2 receptor antagonists is 
permitted before each treatment with paclitaxel.


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6.9   
Precautions and Restrictions 
6.9.1   
All Treatment Arms
No dietary restrictions will be imposed on study patients.  Patients will be instructed to fast 
overnight for daily glucose monitoring (refer to Section 7.4.16).
Patients who show evidence of hyperglycemia during the study should be encouraged to 
follow a low carbohydrate diet.
It is not known what effects MLN0128 has on human pregnancy or development of the 
embryo or fetus; therefore, patients participating in this study should avoid becoming 
pregnant.  Nonsterilized patients in the reproductive age group should use effective methods 
of contraception through defined periods during and after study treatment as specified 
below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 90 days 
after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of 
contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 120 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 


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postovulation methods for the female partner] and withdrawal are not acceptable 
methods of contraception.) 
6.9.2   
Combination Arm
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.  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 for additional information on precautions and 
restrictions associated with paclitaxel administration.
6.10   
Management of Clinical Events:  All Treatment Arms 
6.10.1   
Management of Hyperglycemia
In addition to obtaining fasting serum glucose levels at the clinic visits as outlined in the 
Schedules of Events, all patients will be provided with a glucometer and trained in its use to 
monitor their daily predose fasting blood glucose (FBG) levels at home (see Section 7.4.16).  
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 fasting glucose testing may be reduced 
to twice weekly if the investigator approves.  Patients will continue to notify the investigator 
of FBG levels ≥150 mg/dL, and if blood glucose levels are not well controlled, or if they 
require either oral hypoglycemic agents or insulin to control blood glucose levels, then the 


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frequency of in-home testing of FBG levels will be reinstated to daily.  Guidelines for 
management of hyperglycemia are presented in Table 6-3.
Table 6-3   
Management of Hyperglycemia
Grade
Description
Treatment
MLN0128 Dose Modification
1
FBG > ULN-
160 mg/dL
Continue close monitoring of 
blood glucose.  Initiate oral 
hypoglycemic agent.
None
2
FBG > 160-
250 mg/dL
Initiate oral hypoglycemic agent 
and/or insulin if not well 
controlled on oral agent.
None
3
FBG > 250 mg/dL
Initiate oral hypoglycemic agent 
and/or insulin.
Hold drug until Grade 2.
Resume MLN0128 based on timing of 
recovery:

1 week:  resume at same dose 
and schedule.

> 1 but 2 weeks:  reduce to the
next lower dose. 

> 2 weeks:  stop MLN0128 and 
discontinue patient from the study.
Prevention/Prophylaxis

Follow fasting serum glucose levels during clinic visits.

Monitor home glucometer test results.

Check HbA1c levels every 3 months during therapy.

Recommend lifestyle modifications, as appropriate (balanced diet, limited alcohol consumption, 
increased physical activity).

Most episodes of Grade 1 and 2 hyperglycemia respond quickly to oral metformin.  Early initiation of 
therapy is recommended to prevent higher grade hyperglycemia.

FBG levels 150 mg/dL by glucometer should be followed by closer monitoring of serum glucose and 
possible intervention.
Abbreviations:  FBG = fasting blood glucose; HbA1c = glycosylated hemoglobin; ULN = upper limit of the 
normal range.
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).  To aggressively 
manage the hyperglycemia per standard clinical practice, the following guidelines are 
provided to aid the investigator in initiating antiglycemic therapies. 
In the clinical experience with MLN0128, most episodes of hyperglycemia observed have 
been Grade 1 or Grade 2 and have responded quickly to oral metformin.  Hyperglycemia has 
not been dose limiting since instituting a standard regimen for early treatment of 
hyperglycemia.  All patients developing hyperglycemia on the study should have their 


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glucose closely monitored by study staff.  The investigator may choose either to continue 
close monitoring of patients who 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 because of the higher risk of 
inducing hypoglycemia in patients.  The dose of oral hypoglycemic agents should be 
adjusted in patients with renal insufficiency.
6.10.2   
Management of Hyperlipidemia
Guidance on study drug dose modification for patients with hyperlipidemia is provided in 
Table 6-4.


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Table 6-4   
Management of Hyperlipidemia
Grade
Description
Treatment
MLN0128 Dose Modification
1
Cholesterol:
> ULN-300 mg/dL
Triglycerides:
> 150-300 mg/dL
None
None
2
Cholesterol:
> 300-400 mg/dL
Triglycerides:
> 300-500 mg/dL
Treat hyperlipidemia according to 
standard guidelines.  Triglycerides ≥ 
500 mg/dL should be treated urgently 
because of the risk of pancreatitis.
Maintain dose if tolerable.  If 
toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤ Grade 1.  Reinitiate 
at same dose.
3
Cholesterol:
> 400-500 mg/dL
Triglycerides:
> 500-1000 mg/dL
Same as for Grade 2
Hold dose until recovery to 
≤Grade 1, then restart with the 
next lower dose. 
4
Cholesterol:
> 500 mg/dL
Triglycerides:
> 1000 mg/dL
Same as for Grade 2
Discontinue treatment.
Prevention/Prophylaxis

Lifestyle modifications, as appropriate (balanced diet, limited consumption of alcoholic beverages, 
increased physical activity).
Abbreviations:  ULN = upper limit of the normal range.
6.10.3   
Management of Oral Mucositis
Guidance for the management of oral mucositis is provided in Table 6-5.


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Table 6-5   
Management of Oral Mucositis
Grade
Description
Treatment
MLN0128 Dose Modification
1
Asymptomatic or 
mild symptoms 
Nonalcoholic mouthwash or 0.9% saltwater 
rinse; consider topical corticosteroids at 
earliest signs of mucositis.
None
2
Moderate pain not 
interfering with 
oral intake; 
modified diet 
indicated 
Topical analgesic mouth treatments; topical 
corticosteroids; initiate antiviral or 
antifungal therapy, if indicated.
Maintain dose if tolerable.  If 
toxicity becomes intolerable, 
interrupt MLN0128 dosing 
until recovery to ≤ Grade 1.  
Reinitiate at same dose.
3
Severe pain 
interfering with 
oral intake
Same as for Grade 2; consider intralesional 
corticosteroids.
Hold dose until recovery to 
≤Grade 1, then restart with 
the next lower dose. 
4
Life-threatening 
consequences 
Same as for Grade 2; consider intralesional 
corticosteroids.
Discontinue treatment.
Prevention/Prophylaxis

Consider initiation of a nonalcoholic mouthwash or 0.9% saltwater rinses 4 to 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.
6.10.4   
Management of Rash
Guidance for management of rash is provided in Table 6-6.
Table 6-6   
Management of Rash
Grade
Description
Treatment
MLN0128 Dose Modification
2
Macules/papules 
covering ≤30% body 
surface area with or 
without symptoms
Consider treatment with 
topical steroid 
cream/ointment and/or oral 
antihistamines.
None
3
Macules/papules 
covering 30% body 
surface area with or 
without symptoms 
Consider treatment with 
topical steroid 
cream/ointment, oral 
antihistamines, and/or 
pulsed steroids.
Hold until Grade 2; resume 
MLN0128 based on timing of recovery:

≤ 2 weeks:  reduce MLN0128 to 
the next lower dose. 

> 2 weeks:  discontinue MLN0128 
treatment. 


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6.10.5   
Management of Nausea and/or Vomiting
Guidance for the management of nausea and/or vomiting is provided in Table 6-7.
Table 6-7   
Management of Nausea and/or Vomiting
Grade
Description
Treatment
MLN0128 Dose Modification
2
Loss of appetite with or without 
decreased oral intake; 1to 
5 episodes of vomiting within 
24 hours
Maximize anti-emetic 
therapy; consider IV fluid 
hydration.
None
3
Inadequate oral intake; 
≥6 episodes of vomiting within 
24 hours
Maximize anti-emetic 
therapy; initiate tube 
feeding, IVF, or TPN.
Hold until Grade 1; resume 
MLN0128 without dose 
modification.
Prevention/Prophylaxis
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications is encouraged, and these may be 
administered before each dose of MLN0128 as needed throughout the study.
Abbreviations:  IV = intravenous(ly); IVF = intravenous fluids; TPN = total parenteral nutrition.
6.10.6   
Management of Non-infectious Pneumonitis
Guidance for the management of pneumonitis is provided in Table 6-8.


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Table 6-8   
Management of Non-infectious Pneumonitis
Grade
Description 
Treatment
MLN0128 Dose Modification
1
Asymptomatic:  Radiographic 
findings only
Rule out infection and 
closely monitor
None
2
Symptomatic:
Not interfering with activities 
of daily living
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1.
Interrupt MLN0128 treatment:

When symptoms ≤Grade 1, 
re-initiate MLN0128 
treatment with a 25% dose 
reduction.a

If no recovery within 
4 weeks, then discontinue 
MLN0128 treatment.
3
Symptomatic:
Interfering with activities of 
daily living;
Requires administration of 
oxygen
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1.
Interrupt MLN0128 treatment 
until symptoms resolve to ≤ 
Grade 1.

Consider re-initiating 
MLN0128 treatment with a 
25% dose reduction.a

If toxicity recurs at Grade 3, 
discontinue MLN0128 
treatment.
4
Life-threatening:
Ventilatory support indicated
Rule out infection and 
consider treatment with 
corticosteroids.
Discontinue MLN0128 
treatment.
Abbreviation:  QD = once daily; QD 5D = once daily for 5 days each week.
a If dose modification is required for patients receiving 4 mg QD, then the frequency of dosing should be 
decreased to QD 5D, rather than decreasing the daily dose administered.
6.11   
Management of Clinical Events:  Combination Arm 
Please refer to the most recent paclitaxel USPI for more information on the management of 
clinical events in patients receiving paclitaxel.  
6.12   
Blinding and Unblinding
This is an open-label study; no blinding methods will be used.  
6.13   
Description of Investigational Agents
Upon receipt of drug supply, contents must be verified promptly and the proper contacts 
notified of any discrepancies or damages as described in the Study/Pharmacy Manual.
MLN0128 will be supplied as capsules for oral administration.  MLN0128 is available in 
3 dose strengths1 mg, 3 mg, and 5 mgeach containing 1 mg, 3 mg, and 5 mg of 


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MLN0128, respectively, in addition to the following inactive ingredients:  microcrystalline 
cellulose (solid filler/diluents), magnesium stearate (lubricant), and hard gelatin capsule.
All 3 dose strengths are formulated into size 2 capsules, and each dose strength is 
differentiated by color, as listed below:

1-mg MLN0128 capsules:  white opaque color

3-mg MLN0128 capsules:  Swedish orange opaque color

5-mg MLN0128 capsules:  gray opaque color 
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 for more information regarding paclitaxel.
6.14   
Preparation, Reconstitution, and Dispensation
MLN0128 study drug will be provided in 60-cc high-density polyethylene (HDPE) bottles 
with polypropylene, child-resistant caps and induction seals.  MLN0128 will be dispensed 
with dosing instructions for home use, including the requirement that capsules are stored in 
their original containers and that capsules be swallowed whole and not opened, chewed, or 
manipulated in any way.  Materials provided by the sponsor should be dispensed to patients 
with clear administration instructions from the investigator.  
Both study drugs in this study are anticancer drugs; as with other potentially toxic 
compounds, caution should be exercised when handling these agents.
6.15   
Packaging and Labeling
MLN0128 study drug will be provided by Millennium.  MLN0128 capsules are packaged in 
60-cc HDPE bottles with polypropylene, child-resistant caps and induction seals.  For all 
3 dose strengths, each bottle contains 30 capsules and will have a label containing pertinent 
study information, country-specific requirements, and a caution statement.
Supplies of the MLN0128 milled API capsules will be accompanied by a new label to 
differentiate them from the existing supplies of the MLN0128 unmilled API capsules. 


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Paclitaxel may be supplied either by the site or from commercial sources.  When provided 
by Millennium, paclitaxel will be appropriately labeled in compliance with local and 
regional regulations.
6.16   
Storage, Handling, and Accountability
Paclitaxel should be stored according to instructions provided in the manufacturer’s package 
insert.(9, 10)
Upon receipt at the investigative site, MLN0128 study drug 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 study drug should be used before the 
retest expiry date.  Storage area temperature conditions must be monitored and recorded 
daily.  A daily temperature log will also be kept at the study site.
A drug dispensing log, including records of drug received from the sponsor and MLN0128 
drug dispensed to the patients, will be provided and kept at the study site.  
Because MLN0128 is an investigational agent, it should be handled with due care.  In case 
of contact with broken capsules, raising dust should be avoided during the clean-up 
operation.  The product may be harmful if inhaled, ingested, or absorbed through the skin.  
Gloves and protective clothing should be worn during the clean-up operation.  The area 
should be ventilated and the spill site washed after material pick-up is complete.  The spilled 
material should be disposed of as hazardous medical waste in compliance with federal, state, 
and local regulations.  In case of contact with the powder (eg, from a broken capsule), skin 
should be washed immediately with soap and copious amounts of water for at least 
15 minutes.  In case of contact with the eyes, copious amounts of water should be used to 
flush the eyes for at least 15 minutes.  Medical personnel should be notified.
Patients will be given clear dosing instructions from the investigator for home storage and 
administration of MLN0128 capsules, including the requirement that the capsules must be 
stored in their original containers and that the capsules are to be swallowed whole and not 
chewed or manipulated in any way.  Patients will also receive diary cards to record dosing 
compliance with their MLN0128 treatment assignment, with instructions for their 
completion.  Patients will be instructed to return any unused MLN0128 study drug in the 
original packaging along with their completed diary cards at the appropriate visits.


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Please refer to the Study Manual and the Pharmacy 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 
Treatment group assignments in this open-label study will be at the discretion of the 
investigator and based on cohort availability.
7.4   
Study Procedures
Refer to the Schedules 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.


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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 7.4.10. 
7.4.4   
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedules 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 Schedules of Events.
7.4.6   
Vital Signs 
Vital signs will be assessed at the times specified in the Schedules of Events.
7.4.7   
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening
and within 3 days before the first dose of study drug (ie, Visit 1 of the PK Run-In period for 
patients in the Single-Agent QD Arm, and Cycle 1 Day 1 for patients in the Combination 
Arm and Single-Agent QW Arm).  The results from these tests must be available and 
negative before the first dose of study drug is administered.  If the serum pregnancy results 
will not be available before the first dose of study drug, a urine pregnancy test may be 
performed.
7.4.8   
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status (refer to Section 14.1) will be assessed at the times specified 
in the Schedules of Events.
7.4.9   
Multiple Gated Acquisition Scan and/or Echocardiogram
A MUGA scan or ECHO will be administered at the time points specified in the Schedules 
of Events.


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7.4.10   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF according to the Schedules of events.  See Section 6.7 and Section 6.8
for medications and therapies that are prohibited or allowed during the study. 
7.4.11   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedules of Events.  Refer to Section 9 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.  
7.4.12   
Enrollment
A subject is considered to be enrolled in the study when the first dose of any study drug (ie, 
MLN0128 or paclitaxel) is administered.  Procedures for completing the enrollment 
information are described in the Study Manual.
7.4.13   
Electrocardiogram
A single, 12-lead ECG will be administered at the time points specified in the Schedules of 
Events.  Additional ECGs may be obtained as clinically indicated.
7.4.14   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally.  Handling and shipment of clinical 
laboratory samples will be outlined in the Study Manual and/or Laboratory Manual.  
Clinical laboratory evaluations will be performed as outlined below.
Clinical Chemistry, Hematology, 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 Schedules 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.
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 Schedules of Events.  
The hematology panel includes the following:


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
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 Schedules 
of Events.  The coagulation panel includes the following:

Activated partial thromboplastin time (aPTT)

Prothrombin time/international normalized ratio (PT/INR)
Clinical Chemistry 
A blood sample for the clinical chemistry panel will be obtained at the times specified in the 
Schedules of Events.  The clinical chemistry panel includes the following:

Blood urea nitrogen (BUN)

Creatinine

Bilirubin (total)

Urate

Lactate dehydrogenase 
(LDH)

Gamma glutamyl 
transferase (GGT)

Phosphate

Albumin

Alkaline 
phosphatase 
(ALP)

AST

ALT

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon dioxide (CO2)

Magnesium

Amylase

HbA1c (only at the 
times specified in the 
Schedules of Events) 
Urinalysis
Urine samples for urinalysis will be obtained at the times points specified in the Schedules 
of Events.  Urinalysis will include macroscopic assessment of the amount of protein, 
glucose, WBCs, and blood if they are present (levels should be recorded if available) and 
microscopic analysis if abnormality is noted.  The urinalysis panel includes the following:

Turbidity and color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult blood

Nitrite

Urobilinogen

Glucose

Leukocytes


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Fasting Lipid Profile
Prospective monitoring for hyperlipidemia will be managed through fasting lipid testing at 
the time points specified in the Schedules of Events.  Patients are required to fast overnight 
(nothing except water and prescribed medications after midnight or for a minimum of 
8 hours) for each of these measurements.  The fasting lipid profile includes the following:

Total cholesterol

Triglycerides

High-density 
lipoprotein cholesterol 
(HDL-C)

Low-density 
lipoprotein cholesterol 
(LDL-C)
7.4.15   
Fasting Serum Glucose
Fasting serum glucose will be measured at the time points specified in the Schedules of 
Events before administration of MLN0128, and at other times at the discretion of the 
investigator.  Patients are required to fast overnight (nothing except water and prescribed 
medications after midnight or for a minimum of 8 hours) for each of these measurements.  
7.4.16   
In-Home Daily Fasting Glucose Monitoring
Patients will be instructed to complete daily glucose monitoring at home after fasting 
overnight (nothing except water and prescribed medications after midnight or for a 
minimum of 8 hours) for each of these measurements.  Patients will be instructed to bring 
the glucometer with them to each study visit so that the data collected can be reviewed and 
recorded into source documents.  On the basis of investigator judgment, and after 
2 consecutive months of well-controlled blood glucose levels, the frequency of in-home 
fasting glucose testing may be reduced to twice weekly.  During this period of reduced 
monitoring, patients will continue to notify the investigator of FBG levels that exceed 
150 mg/dL.  If blood glucose levels are not well controlled at any time during the study (see 
Section 6.10.1), or if the patient requires either oral hypoglycemic agents or insulin to 
control blood glucose levels, in-home testing of FBG levels will be resumed daily with the 
provided glucometer.  On study visit days where fasting glucose is assessed in the clinic, the 
in-home daily fasting glucose monitoring does not need to be completed.  
7.4.17   
DNA Measurements 
CCI


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7.4.18   
Disease Assessment
Patients will undergo a computed tomography (CT) scan (with contrast) as appropriate to 
monitor and assess disease progression.  Investigators will assess patients’ disease status 
using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (Version 1.1),
where measureable disease is defined as ≥1 extraosseous lesion that can be accurately 
measured in at least 1 dimension.(11)  Specific disease sites that cannot be adequately imaged 
by CT may be documented by magnetic resonance imaging (MRI).  Anatomical 
measurements will be collected at baseline and at each subsequent evaluation for each target 
lesion using an imaging modality consistent with that used at screening.  The same method 
(CT with contrast, MRI, or bone scan) must be consistently used on a patient throughout the 
study. Bone scans may be performed on patients with bone metastases rather than CT or 
MRI.  
Objective assessments will be performed at each time point as described in the Schedules of 
Events.  When possible, the same qualified physician will interpret results to reduce 
variability.  
Radiographic images will be maintained at the site, and test results and physicians’ findings 
will be filed in patient source documents.  The sponsor may request electronic images for 
those patients who demonstrate a response. 
7.4.19   
Pharmacokinetic Measurements
Serial blood samples for PK analysis of MLN0128 will be collected at the time points 
specified in the Pharmacokinetic Sample Breakdown tables.  The dates and exact times of 
administration of MLN0128 before collection of the blood sample for PK analysis and the 
dates and exact times of the postdose PK sample collection will be recorded on the eCRF.
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 7.6.
The maximum duration of treatment for patients will be 12 months unless, after discussion 
between the investigator and sponsor, it is determined that a patient would derive benefit 
from continued treatment beyond 12 months.
Patients will be considered to have completed the study if they withdraw from the study for 
any of the reasons outlined in Section 7.6.


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7.6   
Discontinuation of Treatment With Study Drug, and Patient Replacement
Treatment with study drug may also be discontinued for any of the following reasons: 

Adverse event

Protocol violation

Progressive disease 

Study terminated by sponsor

Withdrawal by subject

Lost to follow-up

Other
Once study drug has been discontinued, all study procedures outlined for the End of 
Treatment visit will be completed as specified in the Schedules 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 before completing the full treatment course; these will remain in the study for 
posttreatment assessments as outlined in the Schedules of Events until disease progression 
occurs.
Patients in the Single-Agent QD Arm who are withdrawn from treatment before completing 
per-protocol PK assessments in the PK Run-In period will be replaced.  In addition, patients 
in the Single-Agent QD Arm who miss a dose (see Section 6.1) or experience emesis within 
8 hours of dosing before completing per-protocol PK assessments in the PK Run-In period 
will be replaced (but not removed from treatment) to achieve a sample size of 16 subjects 
completing the protocol-specified PK evaluations (see Section 8.1.1).  Patients in all 
treatment arms who are withdrawn from treatment during Cycle 1 for reasons other than 
DLT will be replaced.


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7.7   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
Patients will receive a sufficient quantity of MLN0128 for each treatment cycle and a diary 
in which to record their dosing.  The study center staff will check the patient’s diary versus 
the patient’s supply of remaining MLN0128 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
Statistical analyses will be primarily descriptive and graphical in nature.  No formal 
statistical hypothesis testing will be performed.  A formal statistical analysis plan will be 
developed and finalized before database lock.
8.1.1   
Determination of Sample Size
Each subject will participate in only 1 dose cohort.   
The within-subject coefficient of variation for AUC0-last was estimated to be 39% on the 
basis of preliminary PK data from Cycle 1 Day 1 and Cycle 2 Day 1 from Study
INK128-001. Assuming a geometric mean AUC ratio of 1, with a sample size of 16, the 
2-sided 90% CI for the geometric mean AUC ratio is expected to be (0.796, 1.257). 
On the basis of these calculations, a sample size of 16 subjects completing the 
protocol-specified PK evaluations in the Single-Agent QD Arm has been selected to enable 
adequate precision in the estimation of the geometric mean ratios.
In the Combination Arm, 6 patients will be enrolled in the first cohort (6 mg QD × 3 days 
QW), and another 6 patients will be enrolled in the second cohort (either 4 mg QD × 3 days 
QW or 8 mg QD × 3 days QW). Any cohort may be expanded up to 12 patients for 
confirmation of RP2Ds for MLN0128 milled API capsules when administered QD × 3 days 


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QW in combination with paclitaxel.  The number of patients is based on clinical 
considerations. 
For the Single-Agent QW Arm, 6 patients will be enrolled in the first cohort (20 mg QW), 
and another 6 patients will be enrolled in the second cohort (either 15 or 30 mg QW). Any 
cohort may be expanded up to 12 patients for confirmation of RP2Ds for MLN0128 milled 
API capsules when administered QW.  The number of patients is based on clinical 
considerations. 
8.1.2   
Randomization and Stratification  
This study will not require randomization or stratification.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:

Safety population:  patients who receive at least 1 dose of study drug will be 
included in all safety analyses and efficacy analyses.

PK population:  patients with sufficient dosing and PK data to reliably estimate PK 
parameters will be included in the PK analyses.
8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be presented 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, including gender, age, race, 
weight, height, and other parameters as appropriate.  No inferential statistics will be carried 
out.
8.1.6   
Efficacy Analysis
Data listings will present the tumor measurements from CT or MRI (including changes from 
baseline), disease response category (ie, complete response, partial response, and stable 


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disease), overall response, duration of response, and duration of stable disease or other 
appropriate measures of efficacy.
8.1.7   
Pharmacokinetic Analysis
Single-dose PK parameters will be calculated for MLN0128 by noncompartmental analysis 
as permitted by the data.  These parameters will include, but will not be limited to, Cmax, 
Tmax, AUC0-last, AUC0-inf, t1/2, and apparent oral clearance.  These parameters will be 
summarized by treatment arm (Single-Agent QD, Combination, or Single-Agent QW), 
MLN0218 API (milled vs unmilled) and dosing condition (dosing on an empty stomach vs 
following a standardized meal) as appropriate.  The following statistical analyses will be 
performed on the data collected during the PK Run-In period of the Single-Agent QD Arm:  

An analysis of variance will be performed with log-transformed Cmax and AUC0-last
as the dependent variables, treatment as the fixed effect, and patient as the random 
effect.  

Least-square mean ratios between the treatment states (MLN0128 dosed with 
high-fat breakfast [Test]) versus MLN0128 dosed on an empty stomach [Reference]) 
or (MLN0128 milled API capsules [Test] versus MLN0128 unmilled API capsules 
[Reference]) will be calculated along with 90% confidence intervals (CIs).  
8.1.8   
Safety Analysis
All safety analyses will be performed using the Safety population.  
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.
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.  
Adverse events will be tabulated according to the Medical Dictionary for Regulatory 
Activities (MedDRA) and will include the following categories: 

TEAEs

Drug-related TEAEs


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
Grade 3 or higher TEAEs

Grade 3 or higher drug-related TEAEs

The most commonly reported TEAEs 

SAEs
The most commonly reported TEAEs will be tabulated by MedDRA Preferred Term.
A listing of deaths within 30 days of the 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 based on changes in NCI CTCAE grade from baseline to the worst postbaseline 
value for laboratory parameters will be generated. 
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 summarized according to World Health Organization drug 
dictionary preferred term.
Additional safety analyses may be performed to more clearly enumerate rates of toxicities 
and to further define the safety profile of MLN0128 in combination with paclitaxel or 
single-agent MLN0128.
Electrocardiogram Analysis
A summary of ECG abnormalities will be presented at each scheduled time point.  
Descriptive statistics for ECG intervals (QT, electrocardiograph with Fridericia correction 
[QTcF], PR, QRS, and ventricular rate) and changes from baseline will be presented at each 
scheduled time point.
8.1.9   
Interim Analysis
No formal interim analysis is planned for this study.


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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.
9.1.2   
Adverse Event Definition
Adverse event (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   
Serious Adverse Event Definition
Serious AE (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).


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
Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, 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.(8)  Clarification should be made 
between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 or 4), 
because the terms serious and severe are NOT synonymous.  The general term severe is 
often used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a Grade 3 headache).  This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above, and is usually associated with events that pose a threat to a patient’s life or ability to 
function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
9.2   
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF (see Section 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.


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Regardless of causality, SAEs and serious pretreatment events (as defined in Section 9.1) 
must be reported (see Section 9.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below).  This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event.  The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site.  A sample of the SAE Form may be found in the Study Manual.  
Follow-up information on the SAE or serious pretreatment event may be requested by 
Millennium.  SAE report information must be consistent with the data provided on the 
eCRF.
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.(8)  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?
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9.3   
Monitoring of Adverse Events and Period of Observation
Adverse events, both nonserious and serious, will be monitored throughout the study as 
follows:  

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 informed consent 
form (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.
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 9.2).  Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.


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10.   
ADMINISTRATIVE REQUIREMENTS
10.1   
Good Clinical Practice
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 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 study patient.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible.  The audit trail entry will show the user’s 
identification information and the date and time of the correction.


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Millennium, or a designee, will retain the eCRF data and corresponding audit trails.  A copy 
of the final archival eCRF in the form of a compact disk or other electronic media will be 
placed in the investigator’s study file.
10.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation.  During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements. The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.  
10.5   
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the patients.  The study will 
be conducted only at sites where IRB/IEC approval has been obtained.  The protocol, IB, 
ICF, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC by the investigator or the sponsor, as allowed by local 
regulations.
10.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
10.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, 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.


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10.8   
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies).  Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium.  Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients.  Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 
circumstances permit, to discuss the planned course of action.  Any departures from the 
protocol must be documented.
10.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
10.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the 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 
 (see 
below) and report the event.  Whenever possible, the associated product should be 
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maintained in accordance with the label instructions pending further guidance from a 
Millennium Quality representative.
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed and sent to 
(refer to Section 9.2).
10.12   Closure of the Study
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause.  
Written notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, 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.  If 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.
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10.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.  
11.   
USE OF INFORMATION
All information regarding MLN0128 supplied by Millennium to the investigator is 
privileged and confidential information.  The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from 
Millennium.  It is understood that there is an obligation to provide Millennium with 
complete data obtained during the study.  The information obtained from the clinical study 
will be used toward the development of MLN0128 and may be disclosed to regulatory 
authority(ies), other investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.


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12.   
INVESTIGATOR AGREEMENT
I have read Protocol MLN0128-1004 Amendment 3:  A Phase 1, Open-label Study to 
Evaluate the Safety, Tolerability, and Pharmacokinetics of MLN0128 (an Oral mTORC 1/2 
Inhibitor) as a Single Agent and in Combination With Paclitaxel in Adult Patients With 
Advanced Nonhematologic Malignancies.
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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13.   
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3.
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).
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De P, Sun Y, Wu H, Rommel C, Yi L, Dey N, et al. Pre-clinical potency of INK128, 
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6.
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. Clinical Cancer Research 2004;10(20):7031-42.
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Shafer A, Zhou C, Gehrig PA, Boggess JF, Bae-Jump VL. Rapamycin potentiates 
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proliferation and induction of apoptosis. Int J Cancer 2010;126(5):1144-54.
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U.S. Department of Health and Human Services, National Institutes of Health 
National Cancer Institute. Common Terminology Criteria for Adverse Events 
(CTCAE). Version 4.03. 14 June 2010.
9.
PACLITAXEL - paclitaxel injection, solution [package insert]. Princeton, NJ: 
Sandoz; 2011.
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Abraxane 5 mg/mL powder for suspension for infusion [Summary of Product 
Characteristics]. Uxbridge, United Kingdom: Celgene Europe Ltd; 2013. Report No.: 
EU/1/07/428/001.
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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.
12.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology 1982;5(6):649-55.


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13.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
14.
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) Performance Status Scale
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.(12)
14.2   
Cockroft-Gault Equation
Creatinine Clearance  =
0.85 (140 - age [years]) weight [kg]
    72 (serum creatinine [mg/dL])
OR
0.85 (140 - age [years]) weight [kg]
   0.81 (serum creatinine [µmol/L])
Source:  Cockcroft DW, Gault MH. 1976.(13)
14.3   
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.  1994.(14)


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14.4   
List of Relevant Cytochrome P450 Inhibitors and Clinically Significant 
Enzyme Inducers
Moderate CYP1A2 Inhibitors
cimetidine
methoxsalen 
Strong CYP1A2 Inhibitors
fluvoxamine
Ciprofloxacin
Clinically Significant Enzyme Inducers
carbamazepine
Rifabutin
St. John’s wort
phenobarbital
Rifampin
phenytoin
rifapentine 
Source: fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm.
Note that these lists are not exhaustive.


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14.5   
Amendment 1 Rationale and Purposes
Rationale for Amendment 1
Clinical Study Protocol MLN0128-1004 is being amended to provide clarifications and 
corrections to procedures in the Schedules of Events.  Additionally, this amendment clarifies 
that patients taking low-dose glucocorticoids for replacement therapy may be enrolled in the 
study.  A clarification is also being added to indicate that patients in the Single-Agent Arm 
may be replaced if they are withdrawn from treatment before completing per-protocol 
pharmacokinetic (PK) assessments in the PK Run-In period.  Lastly, a guide for managing 
patients with noninfectious pneumonitis has been added.
Purposes for Amendment 1
The purposes of this amendment are to:

Delete the requirement to perform multiple gated acquisition scan (MUGA) or 
echocardiogram on Cycle 1, Day 1 and Cycle 2, Day 1.

Add the requirement to perform fasting lipid profiles on Cycle 1, Day 1 and Cycle 2, 
Day 1.

Clarify that hematology, chemistry, and urinalysis may be performed up to 24 hours 
before study visit on Day 1 of Cycle 3 and beyond.

Clarify that a predose blood sample for PK analysis is required on Visit 5 during the 
PK Run-In period for patients in the Single-Agent Arm.

Clarify that blood samples for
 

Clarify the patients in the Combination Arm may be administered paclitaxel beyond 
Cycle 6, Day 15 at the discretion of the investigator.

Consolidate and clarify the exclusion criteria for patients with cardiovascular and 
pulmonary disease

Clarify that patients taking low-dose glucocorticoids for replacement therapy may be 
enrolled into the study.

Clarify that if emesis occurs after study medication administration, the dose will be 
counted as missed and will not be re-administered.

Clarify that patients who experience an adverse event (AE) that meets the definition 
of a dose-limiting toxicity (DLT) may continue study treatment with MLN0128 up to 
a 33% dose reduction after the event resolves to Grade 1 or baseline values within 
2 weeks of interrupting planned therapy.

Clarify that 16 patients will complete the protocol-specified PK evaluations in the 
Single-Agent Arm.

Clarify that patients in the Single-Agent Arm who are withdrawn from treatment 
before completing per-protocol PK assessments in the PK Run-In period will be 
replaced.
CCI


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
Provide guidance for the management of patients with noninfectious pneumonitis.

Update the vendor and contact information for reporting product complaints.

Correct typographical errors, punctuation, grammar, and formatting.
14.6   
Amendment 2 Rationale and Purposes
Rationale for Amendment 2
Clinical Study Protocol MLN0128-1004 was amended to evaluate the safety, tolerability, 
and pharmacokinetics (PK) of MLN0128 capsules based on milled active pharmaceutical 
ingredient (API) when administered once weekly (QW).  In addition, clarifications on 
procedures outlined in the protocol were provided.
Purposes for Amendment 2
The purposes of this amendment were to:
Study Procedures

Add a third arm to assess the safety, tolerability, and PK of milled MLN0128 API 
capsules administered QW.

Add 1 study center and 12 to 24 patients to be enrolled into the study.

Add the Single-Agent QW Arm to the Single-Agent QD (daily dosing) Arm Schedule 
of Events. 

Add blood sampling for PK analysis in the Single-Agent QW Arm.

Clarify that 12-lead electrocardiograms (ECGs) should be performed both predose 
and 2 hours postdose during the Study Treatment period for patients in both the 
Single-Agent QD Arm and the Combination Arm.

Clarify that bone scans may be performed to assess bony lesions in patients rather 
than computed tomography (CT) or magnetic resonance imaging (MRI).

Clarify that patients in the Single-Agent QD Arm are required to fast overnight on the 
evenings before Visit 1 and Visit 5 of the PK Run-In Period.

Clarify that the high-fat breakfast must be completed within 30 minutes (+5 min) 
followed by administration of MLN0128 within 5 minutes after completion of the 
high-fat breakfast on Visit 3 of the PK Run-In Period for patients in the Single-Agent 
QD Arm.

Provide the fasting requirements for fasting lipid testing.

Clarify that the blood sample to 
 
.

Remove the requirement to measure patient weight on Day 8 in all cycles of all 
treatment arms.
CCI


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Analysis

Add a secondary endpoint: the PK parameters of a single dose of MLN0128 milled 
API capsules administered on an empty stomach in the Single-Agent QW Arm.

Provide sample-size assumptions for the Single-Agent QW and Combination Arms.

Clarify that single-dose PK parameters will be summarized by treatment arm as 
appropriate.
Eligibility

Clarify that patients may not take strong CYP3A4, CYP2C9, or CYP2C19 inhibitors 
or clinically significant inducers of CYPs 3A4, 2C9, or 2C19 within 7 days of the 
first dose of MLN0128.

Clarify that patients who have enteric stomata should be excluded from the study.

Clarify that patients in the Single-Agent QD Arm participating in the PK Run-In 
period may not take proton pump inhibitors (PPIs) less than 5 days before the first 
MLN0128 PK Run-In dose or H2 receptor antagonists within 24 hours of the first PK 
Run-In dose.

Clarify that if male patients do not practice true abstinence, they must agree to 
practice effective barrier contraception during the entire Study Treatment period and 
through 120 days after the last dose of study drug.
Study Drug

Update dose-limiting toxicity (DLT) definitions for patients in the Single-Agent QW 
Arm.

Provide the dose escalation plan for the Single-Agent QW Arm.

Provide dose modification criteria for the Single-Agent QW Arm.

Clarify that patients who are withdrawn from treatment in Cycle 1 for reasons other 
than DLT will be replaced.

Clarify that strong CYP3A4, CYP2C9, and CYP2C19 inhibitors and clinically 
significant enzyme inducers should only be administered with extreme caution at the 
discretion of the investigator.

Clarify that patients in the Single-Agent QW Arm may take a forgotten or missed 
dose of MLN0128 within 12 hours of the scheduled dosing time.

Clarify that the decision to escalate or de-escalate the dose of MLN0128 in the 
Combination Arm will be based on safety and review of PK data.

Clarify that anti-emetic drugs associated with a significant risk for QT prolongation 
are prohibited during the study.

Clarify that during the Study Treatment period, H2 receptor antagonists may be 
allowed, if needed, provided that the histamine H2 receptor antagonist is not taken 
within 12 hours before and within 6 hours after study drug administration.

Provide clarification on guidance of the management of Grade ≥ 3 rash.

Clarify that DLTs are defined according to the adverse event (AE) profile observed in 
Cycle 1 and the PK Run-In period.


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Background Information

Provide rationale for inclusion of the Single-Agent QW Arm.


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14.7   
Amendment 3 Detailed Summary of Changes
The primary sections of the protocol affected by the changes in Amendment 3 are 
indicated. The corresponding text has been revised throughout the protocol.
Change 1: Remove the exclusion criterion relating to treatment with strong CYP 
inhibitors or inducers.
The primary change occurs in Section 5.2 Exclusion Criteria #15:
Deleted text:
15. Use of strong CYP3A4, CYP2C9, or CYP2C19 inhibitors or 
clinically significant inducers of CYPs 3A4, 2C9, or 2C19 within 7 days 
of the first dose of MLN0128 (See Section 14.4 for a list of these drugs).
Rationale for Change:
This change, which removes enrollment restrictions for patients taking CYP3A4, 
CYP2C9, or CYP2C19 inhibitors and/or inducers in this study, was made to allow more 
flexibility in patient enrollment based on updated data on MLN0128 metabolism by 
specific CYP isoforms. 
Change 2: Update the list of concomitant medications prohibited during the study.
The primary change occurs in Section 6.7 Excluded Concomitant Medications, Foods, 
and Procedures:
Initial 
wording:

Strong CYP3A4, CYP2C9, and CYP2C19 inhibitors and clinically 
significant enzyme inducers may not be used during the PK Run-In 
Period or at any time during Cycle 1 (see the nonexhaustive list 
provided in Section 14.4).  After Cycle 1, treatment with any of these 
medications may only be administered on a case-by-case basis after 
approval by the study clinician.  In addition, patients should not 
consume food or beverages containing the fruit or juices listed in 
Section 14.4 within 1 week before the first dose of MLN0128 and 
throughout the study.
[…]

[…]Examples of H2 receptor antagonists include ranitidine, famotidine, 
cimetidine and nizatidine.


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Amended 
or new 
wording:

Strong CYP3A4, CYP2C9, and CYP2C19 CYP1A2 inhibitors and 
clinically significant enzyme CYP inducers may not be used during the 
PK Run-In Period or at any time during Cycle 1 (see the nonexhaustive 
list provided in Section 14.4).  After Cycle 1, treatment with any of 
these medications may only be administered on a case-by-case basis 
after approval by the study clinician.  should be administered with 
caution and at the discretion of the investigator (refer to 
Section 14.4 for a list of these agents).  Alternative treatments, if 
available, should be considered.
[….]

[…]Examples of H2 receptor antagonists include ranitidine, 
famotidine, cimetidine, and nizatidine.  However, cimetidine, a 
moderate CYP1A2 inhibitor, is not recommended as a first-
choice H2 receptor antagonist (refer to Section 14.4).
Rationale for Change:
This change was made to update the recommendations on concomitant medication use 
during the study based on MLN0128 metabolism by specific CYP isoforms.
Change 3 Update the list of relevant CYP inhibitors and inducers.
The primary change occurs in Section 14.4 List of Relevant Cytochrome P450 Inhibitors 
and Clinically Significant Enzyme Inducers:
Description 
of the 
change:
The list of relevant CYP inhibitors and inducers was updated to remove 
sections listing strong CYP2C19 inhibitors and strong CYP3A4 inhibitors; 
to add a section listing strong and moderate CYP1A2 inhibitors; and 
update the section listing clinically significant enzyme inducers.
Rationale for Change: 
This change was made for consistency with updated data on MLN0128 metabolism by 
specific CYP isoforms.
Change 4 Remove dietary restrictions related to CYP inhibitors and inducers.
The primary change occurs in Section 6.7 Excluded Concomitant Medications, Foods, 
and Procedures: 
Deleted 
text:
[…]In addition, patients should not consume food or beverages containing 
the fruit or juices listed in Section 14.4 within 1 week before the first dose 
of MLN0128 and throughout the study.


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Rationale for Change: 
The change was made for consistency with new data that removes the necessity for 
restrictions concerning CYP2C9 and 2C19.
The following sections also contain this change:

Section 6.9 Precautions and Restrictions

Section 14.4 List of Relevant Cytochrome P450 Inhibitors and Clinically 
Significant Enzyme Inducers. 
Change 5: Insert language to reduce the required frequency of radiographic disease 
assessments for patients who have received at least 1 year of continuous MLN0128 
treatment per protocol.
The primary change occurs in footnote “i” the Single-Agent QD and Single-Agent QW 
Arms Schedule of Events:
Added text:
For long term patients, defined as study participation (greater than 
or equal to) 1 year, a CT (with contrast)/MRI of chest, abdomen, and 
pelvis will be obtained at intervals of up to every 4 cycles (plus or 
minus 7 days) as clinically indicated. 
Rationale for Change:
This change was made to reduce the burden and minimize radiation exposure for long-
term patients.


 
  
 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm ‘UTC’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
090101d68076f2a4
A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of MLN0128 (an Oral
mTORC 1/2 Inhibitor) as a Single Agent and in Combination With Paclitaxel in Adult Patients With Advanced
Nonhematologic Malignancies
Clinical Approval
13-Dec-2017 20:47 UTC
PPD

SAP_001.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1, Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of 
MLN0128 (an Oral mTORC 1/2 Inhibitor) as a Single Agent and in Combination With 
Paclitaxel in Adult Patients With Advanced Nonhematologic Malignancies 
NCT Number: NCT02412722
SAP Approve Date: 12Aug2015 
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.


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Statistical Analysis Plan, Study MLN0128-1004
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TABLE OF CONTENTS
1. INTRODUCTION............................................................................................................4
1.1 Study Design..............................................................................................................4
1.2 Study Objectives ........................................................................................................6
1.2.1 Primary Objectives ..............................................................................................6
1.2.2 Secondary Objectives...........................................................................................6
2. POPULATIONS FOR ANALYSIS..................................................................................7
2.1 Safety Population .......................................................................................................7
2.2 Pharmacokinetics Population......................................................................................7
2.3 DLT Evaluable Population .........................................................................................7
3. HYPOTHESES AND DECISION RULES.......................................................................7
4. INTERIM ANALYSIS.....................................................................................................7
5. STATISTICAL METHODOLOGY .................................................................................7
5.1 Sample Size Justification............................................................................................8
5.2 Randomization and Stratification................................................................................9
5.3 Unblinding .................................................................................................................9
5.4 Data Handling ............................................................................................................9
5.4.1 Methods for Handling Missing Data.....................................................................9
5.4.2 Definition of Baseline Values ..............................................................................9
5.4.3 Windowing of Visits............................................................................................9
5.4.4 Justification of Pooling ........................................................................................9
5.4.5 Withdrawals, Dropouts, Lost to Follow-up...........................................................9
5.5 Patient Disposition ...................................................................................................10
5.6 Demographics and Baseline Disease Characteristics.................................................10
5.6.1 Demographics....................................................................................................10
5.6.2 Medical History.................................................................................................10
5.7 Treatments and Medications .....................................................................................11
5.7.1 Concomitant Medications ..................................................................................11
5.7.2 Study Treatments...............................................................................................11
5.8 Efficacy Analyses.....................................................................................................12
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis .................................13
5.9.1 Pharmacokinetic Analyses .................................................................................13
5.9.2 Pharmacodynamic Analyses...............................................................................15
5.9.3 Biomarker Analysis ...........................................................................................15
5.10 Safety Analyses ......................................................................................................15
5.10.1 Adverse Events................................................................................................15
5.10.2 Laboratory Data...............................................................................................18
5.10.3 Vital Signs and Weight ....................................................................................19
5.10.4 Electrocardiograms ..........................................................................................19
5.10.5 ECOG Performance Status...............................................................................19
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................19
7. PROGRAMMING CONSIDERATIONS .......................................................................20
7.1 Statistical Software...................................................................................................20
7.2 Rules and Definitions ...............................................................................................20


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List of Abbreviations and Definitions of Terms
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
API
active pharmaceutical ingredient
BMI
body mass index
AUC
area under the plasma concentration versus time curve
BUN
blood urea nitrogen
CI
confidence interval
Cmax
maximum plasma concentration
CRF
case report form
CSR
clinical study report
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF 
electronic case report form
HbA1c
glycosylated hemoglobin
IV
intravenous(ly)
MedDRA
Medical Dictionary for Regulatory Activities
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PK
pharmacokinetic(s)
QD
quaque die; each day; once daily
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QW
once weekly
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SLD
Sum of the longest diameter
TEAE
treatment emergent adverse event
Tmax
first time of occurrence of maximum (peak) concentration
SD
standard deviation
WBC
white blood cell
WHO
World Health Organization


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1.   
INTRODUCTION
In general, the purpose of the statistical analysis plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies.  Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that will 
addresses the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1   
Study Design
This study is a multicenter, open-label, phase 1 trial of MLN0128 administered orally both 
as a single agent and in combination with IV infusions of paclitaxel in adult patients with 
advanced nonhematologic malignancies for whom standard, curative, or life-prolonging 
anticancer treatment does not exist or is no longer effective.  The study will consist of 
3 arms: a Single-Agent QD Arm, a Combination Arm, and a Single-Agent QW Arm.  The 
3 arms will enroll in parallel and will administer study treatment in repeated 28-day cycles.  
Study eligibility will be determined during the Screening period, which may last for up to 
28 days before the first dose of study drug is administered.  Patients who meet all eligibility 
criteria and provide written informed consent will be enrolled.  
The Single-Agent QD Arm will test the safety, tolerability, and PK of MLN0128 milled 
API capsules when administered on an empty stomach and will additionally characterize the 
PK profile when taken with a standardized high-fat breakfast.  In the same patients, the PK 
of MLN0128 unmilled API capsules when taken on an empty stomach will also be assessed
as a point of reference for comparison of milled API capsule PK.  The PK assessments will 
be performed during a PK Run-In period during which each patient will receive a total of 
three 4-mg doses of MLN0128 as described below: 

PK Run-In Visit 1:  MLN0128 4-mg unmilled API capsule taken on an empty 
stomach. 

PK Run-In Visit 2 (24 hours [1 hr] after PK Visit 1):  24-hour postdose PK sample 
collected.

PK Run-In Visit 3 (≥48 hours after PK Visit 1):  MLN0128 4-mg milled API 
capsule taken with a standardized high-fat breakfast.  


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
PK Run-In Visit 4 (24 hours [1 hr] after PK Visit 3):  24-hour postdose PK sample 
collected.

PK Run-In Visit 5 (≥48 hours after PK Visit 3):  MLN0128 4-mg milled API 
capsule taken on an empty stomach.

PK Run-In Visit 6 (24 hours [1 hr] after PK Visit 5):  24-hour postdose PK sample 
collected.  Note:  If scheduling permits, Visit 6 can be combined with Cycle 1 Day 1 
of the Study Treatment period.  
Each patient in the Single-Agent QD Arm will complete the PK Run-In period within 
14 days before Cycle 1 Day 1 of the Study Treatment period.  Study treatment for the 
Single-Agent QD Arm will consist of repeated 28-day cycles of oral MLN0128 milled API 
capsules taken on an empty stomach.  The first 6 patients enrolled into the Single-Agent QD 
Arm Study Treatment period will receive MLN0128 at 4 mg QD.  An evaluation of safety 
and tolerability will be conducted after these first 6 patients have completed Cycle 1 to 
determine the dose to be administered during the Study Treatment period for the next 
patients enrolled into the Single-Agent QD Arm. Safety evaluations will continue before
enrolling each subsequent cohort into the Single-Agent QD Arm.  A total of 16 patients will 
complete the protocol-specified PK evaluations in the Single-Agent QD Arm.
The Combination Arm will test the safety, tolerability, and PK of MLN0128 milled API 
capsules when administered on an empty stomach in combination with paclitaxel. Paclitaxel 
(80 mg/m2) will be administered as an IV infusion on Days 1, 8 (1 day), and 15 (1 day)
of each 28-day cycle according to the institution’s standard clinical practice.  MLN0128 will 
be administered QD × 3 days QW of each cycle, beginning 24 hours after completion of the 
Day 1 paclitaxel infusion; ie, MLN0128 will be administered on Days 2 through 4, 9
through 11, 16 through 18, and 23 through 25 of every 28-day cycle.  The starting 
MLN0128 dose for the Combination Arm will be 6 mg (QD × 3 days QW).  Plasma samples 
to characterize the PK of MLN0128 will be collected on Cycle 1 Day 2. 
Consistent with the Single-Agent QD Arm, an interim safety and tolerability review will be 
conducted for the Combination Arm after the initial cohort of 6 patients has completed 
Cycle 1.  According to standard dose escalation rules, on the basis of the safety and 
tolerability observed in the initial 6 evaluable patients, the dose of MLN0128 (QD × 3 days 
QW) for the next cohort of 6 patients will be either reduced, maintained, or escalated.
The Single-Agent QW Arm will evaluate the safety, tolerability, and PK of MLN0128 
milled API when administered on an empty stomach in 2 sequential cohorts, each consisting 


MLN0128
Statistical Analysis Plan, Study MLN0128-1004
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of 6 to 12 patients. Initially, 6 patients in Cohort 1 will receive 20 mg of MLN0128 
capsules based on milled API once every week (QW). Serial plasma specimens will be 
collected for evaluation of MLN0128 PK. A safety and tolerability assessment will be 
performed after the last patient in the cohort completes Cycle 1. If ≥2 patients experience a 
dose-limiting toxicity (DLT) during Cycle 1, then the starting dose of MLN0128 milled API 
for the subsequent cohort (Cohort 2) will be reduced to 15 mg QW.  If ≤1 patient in Cohort 
1 experiences a DLT in Cycle 1, then the dose of milled MLN0128 in Cohort 2 will be 
increased to 30 mg QW. If the dose of MLN0128 milled API is deemed safe in any cohort 
based on 3+3 rules, then the cohort may be expanded to 12 patients to confirm the RP2D for 
single-agent MLN0128 milled API capsules when administered QW.  
Blood will be collected from all patients for PK analysis of MLN0128. Throughout the 
study, patient safety will be monitored through assessment of AEs clinical laboratory values, 
vital signs, and electrocardiograms (ECGs).  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.
1.2   
Study Objectives
1.2.1  Primary Objectives

To evaluate the safety and tolerability of MLN0128 milled API capsules 
administered both as a single agent and in combination with paclitaxel 

To characterize the effect of a high-fat meal on the PK of MLN0128 milled API 
capsules 

To characterize the PK of MLN0128 milled API capsules when administered on an 
empty stomach approximately 24 hours after paclitaxel infusion
1.2.2  Secondary Objectives

To characterize the PK of MLN0128 milled API capsules versus unmilled API 
capsules, when administered on an empty stomach

To evaluate the preliminary efficacy of MLN0128 milled API capsules when 
administered as a single agent and in combination with paclitaxel


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2.   
POPULATIONS FOR ANALYSIS
2.1       Safety Population
The safety population includes all patients who receive at least 1 dose of study drug, and 
will be used for all safety and efficacy analyses.   
2.2   
Pharmacokinetics Population 
The pharmacokinetics population includes patients with protocol specified dosing and 
conditions and PK data to reliably estimate PK parameters and will be used for all PK 
analyses.   
2.3     DLT Evaluable Population
The DLT evaluable population is defined as patients who received 75% or more of planned 
doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of planned doses 
because of study drug related AE (considered as a DLT).  Patients who receive at least 75% 
(21 of 28 for QD dosing schedule; 3 of 4 for QW dosing schedule; 9 of 12 for QDx3d QW 
dosing schedule) of the planned doses in Cycle 1 will be considered to have sufficient safety 
data/follow-up to support dose escalation.  Patients who receive less than 75% of the 
planned doses in the first cycle of treatment for reasons unrelated to study drug toxicity will 
be considered to have inadequate data to support dose escalation.
3.   
HYPOTHESES AND DECISION RULES
Not applicable.
4.   
INTERIM ANALYSIS
Not applicable.
5.   
STATISTICAL METHODOLOGY
In general, summary tabulations will be presented that display the number of observations, 
mean, standard deviation (SD), median, minimum, and maximum for continuous variables, 
and the number and percent (of nonmissing) per category for categorical data, unless 
specified otherwise.  


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Data will be summarized by dose level [ordered] for each arm:  
Single-Agent QD Arm
MLN0128
4 mg QD
MLN0128
TBD mg QD
Total
Single-Agent QD Arm: Adverse event tables
PK Run-In
MLN0128 4 mg x 3 doses
MLN0128
4 mg QD
MLN0128
TBD mg QD
Total
Combination Arm:
MLN0128 6 mg QDx3
+ Paclitaxel 80  mg/m2
MLN0128 TBD mg QDx3
+ Paclitaxel 80  mg/m2
Total
Single-Agent QW Arm:
MLN0128
30 mg QW
MLN0128
TBD mg QW
Total
5.1   
Sample Size Justification
The within-patient coefficient of variation for AUC0-last was estimated to be 39% on the 
basis of preliminary PK data from Cycle 1 Day 1 and Cycle 2 Day 1 from Study INK128-
001. Assuming a geometric mean AUC ratio of 1, with a sample size of 16, the 2-sided 90% 
CI for the geometric mean AUC ratio is expected to be (0.796, 1.257). On the basis of these 
calculations, a sample size of 16 patients completing the protocol specified PK evaluations 
in the Single-Agent Arm has been selected to enable adequate precision in the estimation of 
the geometric mean ratios.
In the Combination Arm, 6 patients will be enrolled in the first cohort (6 mg QD × 3 days 
QW), and another 6 patients will be enrolled in the second cohort (either 4 mg QD × 3 days 
QW or 8 mg QD × 3 days QW). Any cohort may be expanded up to 12 patients for 
confirmation of RP2Ds for MLN0128 milled API capsules when administered QD × 3 days 
QW in combination with paclitaxel.  The number of patients is based on clinical 
considerations. 
For the Single-Agent QW Arm, 6 patients will be enrolled in the first cohort (20 mg QW), 
and another 6 patients will be enrolled in the second cohort (either 15 or 30 mg QW). Any 
cohort may be expanded up to 12 patients for confirmation of RP2Ds for MLN0128 milled 
API capsules when administered QW.  The number of patients is based on clinical 
considerations. 


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5.2   
Randomization and Stratification
Not applicable.
5.3   
Unblinding
Not applicable.
5.4   
Data Handling
5.4.1   
Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations.  Data 
that are potentially spurious or erroneous will be examined under the auspices of standard 
data management operating procedures.
5.4.2   
Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of study drug administration.  
5.4.3   
Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected.  These 
visit designators are predefined values that appear as part of the visit tab in the eCRF.  
5.4.4   
Justification of Pooling
All data from all sites will be pooled.  Study center or treatment-by-center interaction will 
not be included in any statistical analysis.
5.4.5   
Withdrawals, Dropouts, Lost to Follow-up
Patients in the Single-Agent QD Arm who are withdrawn from treatment before completing 
per-protocol PK assessments in the PK Run-In period will be replaced.  In addition, patients 
in the Single-Agent QD Arm who miss a dose or experience emesis within 8 hours of dosing
before completing per-protocol PK assessments in the PK Run-In period will be replaced 
(but not removed from treatment) to achieve a sample size of 16 patients completing the 
protocol-specified PK evaluations .  Patients in all treatment arms who are withdrawn from 
treatment during Cycle 1 for reasons other than DLT will be replaced.


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5.5   
Patient Disposition
The number of patients screened, in the safety population, in the PK population, in the DLT 
evaluable population, and the reason study drug was discontinued will be summarized.  All 
percentages will be based on the number of patients in the safety population.
A listing with date of first dose, date of last dose, number of cycles, reason for 
discontinuation of study treatment, and study populations will be generated.
5.6   
Demographics and Baseline Disease Characteristics
Listings with demographic, disease characteristics, prior therapy, radiation, and surgery will 
be generated.
5.6.1   
Demographics
The following demographic characteristics will be summarized: age at date of informed 
consent, sex, ethnicity, race, baseline weight, and height. 
5.6.2   
Medical History
5.6.2.1   Disease-Specific History
The following will be summarized:

Baseline ECOG performance status

Primary diagnosis 

Years since first positive biopsy

Stage of disease at initial diagnosis
The number and percentage of patients with prior surgery, prior radiation, and prior systemic 
anticancer therapies will be summarized.  The following will be summarized for those 
patients with prior systemic therapies:

Systemic regimen received (WHO generic name)

Number of prior systemic treatment regimens

Setting of most recent systemic treatment

Best response to most recent systemic treatment

Reason most recent systemic treatment discontinued


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5.7   
Treatments and Medications
5.7.1   
Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary. The number and percentage of patients taking concomitant medications will be 
tabulated by WHO generic name.
5.7.2   
Study Treatments
In the Single-Agent QD arm each patient will receive a total of three 4-mg doses of 
MLN0128 during the PK Run-In period at least 48 hours apart.  Following the PK Run-In 
period, single-arm QD patients will receive repeated 28-day cycles of oral MLN0128 milled 
API capsules taken on an empty stomach.  The first 6 patients enrolled into the Single-Agent
Arm will receive MLN0128 at 4 mg QD.  Further cohorts will receive either 3 mg QD or 5 
mg QD. 
In the Combination Arm, paclitaxel (80 mg/m2) will be administered as an IV infusion on
Days 1, 8 (1 day), and 15 (1 day) of each 28-day cycle. MLN0128 will be administered 
QD × 3 days QW of each cycle, beginning 24 hours after completion of the Day 1 paclitaxel
infusion; ie, MLN0128 will be administered on Days 2 through 4, 9 through 11, 16 through
18, and 23 through 25 of every 28-day cycle.  The starting MLN0128 dose for the
Combination Arm will be 6 mg QD × 3 days QW. Further cohorts will receive either 4 mg
QD × 3 days QW or 8 mg QD × 3 days QW.
In the Single-Agent QW arm patients will receive repeated 28-day cycles of oral MLN0128 
milled API capsules taken on an empty stomach.  The first 6 patients enrolled into the
Single-Agent Arm QW arm receive MLN0128 at 20 mg QW.  Further cohorts will receive 
either 15 mg QW or 30 mg QW. 
5.7.2.1   Extent of Exposure
The overall treatment duration in weeks (date of last dose – date of first dose + 1/ 7), total 
number of cycles administered (distribution and summary statistics), cumulative dose, dose 
per administration (cumulative dose divided by the total number of doses taken) and the 
percentage of planned original dose will be summarized.  For patients in the single-agent 
QD arm participating in the PK run-in period the treatment duration will be based on the 
first dose of MLN0128 during the PK run-in period.


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The percentage of planned original dose is calculated as the cumulative dose taken (mg for 
MLN0128 and mg/m2 for paclitaxel) divided by the total planned dose (mg for MLN0128 
and mg/m2 for paclitaxel).  The total planned dose is: 
Assigned dose level at study start * doses per cycle * maximum number of cycles.               
In the single-Agent QD arm there are 28 planned MLN0128 doses per cycle and 3 MLN0128
doses planned during the PK run-in period, in the Combination with Paclitaxel arm there are 
12 planned MLN0128 planned doses per cycle, and in the Single-Agent QW arm there are 4 
planned MLN0128 doses per cycle.  In the Combination with Paclitaxel arm there are 12
planned paclitaxel doses per cycle.
The number and percentage of patients will be summarized for the following actions on 
study drug:

MLN0128 Dose Reduced at Least Once

MLN0128 Dose Interrupted due to Adverse Event at Least Once

MLN0128 Dose Interrupted due to Dosing Error at Least Once

MLN0128 Dose Interrupted due to Other Reasons at Least Once
For the single-agent QD arm any actions on study drug that occur during the PK run-in 
period will be included in the above summaries.  For the Combination with paclitaxel arm
similar summaries will be provided for paclitaxel. 
A listing with study drug administration results for MLN0128 and paclitaxel as collected on 
the eCRF, including timing of action on study drug will be generated.
5.8   
Efficacy Analyses
The best overall response, objective response rate (CR+ PR), and clinical benefit rate (CR + 
PR + SD, and CR + PR + SD of at least 6 months) will be summarized.
The duration of stable disease will be calculated for those patients with a best response of 
stable disease.  The duration of SD is the number of days from cycle 1 day 1 until 
progressive disease or until the last response assessment if there is no progressive disease.
The duration of objective response will be calculated for those patients with a best response 
of CR or PR, and is defined as the number of days from the start date of CR, or PR 
(whichever response is achieved first) until progressive disease or until the last response 
assessment if there is no progressive disease.
Data listings will present the tumor measurements from CT or MRI, change/percent change
from baseline in sum of the longest diameter (SLD), change/percent change from nadir in 


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SLD, non-target disease assessment, new lesion assessment and disease response assessment 
by the investigator based on RECIST criteria at each response assessment. In addition, the 
best overall response, duration of SD, and duration of objective response will be presented 
in a data listing.
5.9   
Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis
5.9.1   
Pharmacokinetic Analyses
The pharmacokinetics population will be used for the description of the concentration-time 
profiles and for the estimation of the PK parameters.
Pharmacokinetic Concentrations
Descriptive statistics (number of patients, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of variation, geometric mean, median, minimum, and maximum) will 
be used to summarize the plasma concentrations.  BQL values at the beginning of the profile 
will be set to zero. BQL values that occur after the first quantifiable point will be considered 
missing.
Linear and semi-logarithmic plots of the mean plasma concentration versus scheduled 
sampling time will be provided for the following:
1. Single- agent QD arm for treatment state (combination of dosing condition and 
MLN0128 API capsules) during the PK-run in period:
•
MLN0128 unmilled API capsules taken on an empty stomach
•
MLN0128 milled API capsules following a high-fat meal
•
MLN0128 milled API capsules taken on an empty stomach
2. Single-agent QW arm by dose level
3. Combination with Paclitaxel arm by dose level
Linear and semi-logarithmic plots of individual plasma concentration versus actual sampling 
time will be provided as described above. All individual patient plasma concentration data 
will be in a data listing.
Pharmacokinetic Parameters
PK parameters will be estimated using non-compartmental methods with WinNonlin®
Professional Version 6.1 or higher (Pharsight Corp., Mountain View, CA).  The plasma PK 
parameters will be estimated from the concentration-time profiles for all PK population 
patients. In estimating the PK parameters, BQL values at the beginning of the profile will be 


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set to zero. BQL values that occur after the first quantifiable point will be considered 
missing. Values that are embedded between BQLs, or quantifiable values occurring after 
two or more BQLs, will be set to missing at the discretion of the pharmacokineticist. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times.
Descriptive statistics (number of patients, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of deviation, geometric mean, median, minimum value, and maximum 
value) will be used to summarize the calculated PK parameters. For Tmax, only median, 
minimum value, and maximum value will be presented.  All individual patient PK parameter  
data will be in a data listing.
Descriptive statistics will be presented for the plasma PK parameters listed below for each 
treatment state (combination of dosing condition and MLN0128 API capsules) during the 
PK-run in period (MLN0128 unmilled API capsules taken on an empty stomach, MLN0128 
milled API capsules following a high-fat meal, and MLN0128 milled API capsules taken on 
an empty stomach) and by dose level for the Single-Agent QW and Combination with 
Paclitaxel arm.
Data permitting, the following single-dose PK parameters will be calculated for MLN0128 
by noncompartmental analysis:

Area under the plasma concentration-time curve from time 0 to time of last
measurable concentration (AUC0-last )

Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf)

Area under the plasma concentration-time curve from time 0 to 24 hr (AUC24hr)

Area under the plasma concentration-time curve from time 0 to 8 hr (AUC8hr)
[combination with paclitaxel arm only] 

Observed maximum plasma concentration (Cmax)

Time to observed maximum plasma concentration (Tmax)

Terminal disposition phase rate constant (lambdaz)

Terminal phase phase half-life (t1/2)

Apparent oral clearance (CL/F)

Apparent terminal phase volume of distribution (Vz/F)
For the single-agent QD arm an analysis of variance will be performed for the log-
transformed Cmax and AUC0-last as the dependent variables, treatment state as the fixed effect, 
and patient as the random effect.  Least-square mean ratios between the treatment states 


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MLN0128 dosed with high-fat breakfast [Test]) versus MLN0128 dosed on an empty 
stomach [Reference]) and MLN0128 milled API capsules [Test] versus MLN0128 unmilled 
API capsules [Reference] will be calculated along with 90% confidence intervals (CIs).
5.9.2   
Pharmacodynamic Analyses
5.9.3   
Biomarker Analysis
Not applicable.
5.10   Safety Analyses
Safety evaluations will be based on the incidence, severity, type of AEs, clinically
significant changes, or abnormalities in the patient’s physical examination, vision 
examination, vital signs, ECG, and clinical laboratory results.  These analyses will be 
performed using the safety population.
5.10.1   Adverse Events
5.10.1.1   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 adverse events are defined as adverse events that start on or after the 
first dose of study drug and less than or equal to 30 days after the last dose of study drug.  
The reported adverse event term will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version in use at the time of database lock (v17.0 or higher).
CCI


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Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If the start date has month and year but day is missing, the event will be considered 
treatment-emergent if both the month and year of the start date of the event are on or 
after the month and year of the date of the first dose of MLN0128 and on or before 
the month and year of the date of the last dose of MLN0128 plus 30 days.

If the start date has year, but day and month are missing, the event will be considered 
treatment -emergent if the year of the start date of the event is on or after the year of 
the date of the first dose of MLN0128 and on or before the year of the date of the last 
dose of MLN0128 plus 30 days.

If the start date of an event is completely missing, then the event is assumed to be 
treatment-emergent.
Treatment emergent adverse events will be summarized based on the number and percentage 
of patients experiencing events by MedDRA system organ class and preferred term.  Tabular 
summaries by system organ class and preferred term will be provided for the following:

All TEAEs

TEAEs related to Study Drug

Grade 3 or greater TEAEs

Grade 3 or greater TEAEs related to Study Drug

Most common (at least 10% in each arm)  (by preferred term)

Most common (at least 10% in each arm ) TEAEs by maximum grade and preferred 
term
In the Combination with Paclitaxel arm related to study drug refers to either MLN0128 or 
paclitaxel.  For the MLN1028 Single-Agent QD arm, AEs starting that start during the PK-
run in period will be summarized separately.  Patients reporting the same event more than 
once will have that event counted only once within each body system, and once within each 
preferred term.
A listing of patients with a DLT in Cycle 1, and all treatment-emergent adverse events will 
be provided.  


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Adverse events of interest will be tabulated for the following:
Adverse event of 
interest
MedDRA Preferred Term
Hyperglycemia
Glucose tolerance impaired, Hyperglycaemia, Impaired fasting 
glucose
Rash
Fixed eruption,  Mucocutaneous rash,  Rash, Rash generalized,
Rash macular, Rash maculo-papular,  Rash maculovesicular, 
Rash morbilliform,  Rash rubelliform,  Rash scarlatiniform, 
Rash vesicular,  Dermatitis exfoliative,  Drug eruption,  Drug 
hypersensitivity,  Drug rash with eosinophilia and systemic 
symptoms, Reaction to drug excipients, Toxic skin eruption, 
Administration related reaction,  Erythema,  Generalised 
erythema,  Rash erythematous,  Rash popular,  Rash 
papulosquamous
Renal Insufficiency
(MedDRA 
Standardized Medical 
Query)
Acute phosphate nephropathy , Acute prerenal failure (Narrow), 
Anuria (Narrow), Azotaemia (Narrow), Continuous 
haemodiafiltration (Narrow), Dialysis (Narrow), Haemodialysis 
(Narrow), Neonatal anuria (Narrow), Nephropathy toxic 
(Narrow), Oliguria (Narrow), Peritoneal dialysis (Narrow), 
Prerenal failure (Narrow), Renal failure (Narrow), Renal failure 
acute (Narrow), Renal failure neonatal (Narrow), Renal 
impairment (Narrow), Renal impairment neonatal (Narrow), 
Albuminuria (Broad), Blood creatinine abnormal (Broad), 
Blood creatinine increased (Broad), Blood urea abnormal 
(Broad), Blood urea increased (Broad), Blood urea 
nitrogen/creatinine ratio, Creatinine renal clearance abnormal, 
Creatinine renal clearance decreased, Creatinine urine abnormal 
(Broad), Creatinine urine decreased (Broad), Crystal 
nephropathy (Broad),  Glomerular filtration rate abnormal,  
Glomerular filtration rate decreased, Hypercreatininaemia 
(Broad), Nephritic syndrome (Broad),  Nephritis (Broad), 
Oedema due to renal disease (Broad), Protein urine present 
(Broad), Proteinuria (Broad), Renal function test abnormal 
(Broad), Renal transplant (Broad), Renal tubular disorder 
(Broad), Renal tubular necrosis (Broad), Tubulointerstitial 
nephritis (Broad), Urea renal clearance decreased (Broad), 
Urine output decreased (Broad)
Mucosal Inflammation
Burning sensation mucosal,  Mucosal erosion,  Mucosal 
excoriation,  Mucosal exfoliation,  Mucosal hyperaemia,  
Mucosal inflammation, Mucosal necrosis, Mucosal ulceration, 
Aphthous stomatitis, Mouth ulceration, Oral mucosa erosion, 
Stomatitis, Stomatitis haemorrhagic, Stomatitis necrotizing, 
Oral discomfort, Oral mucosal blistering, Oral mucosal 
erythema, Oral mucosal exfoliation, Oropharyngeal blistering, 
Oropharyngeal discomfort, Oropharyngeal pain


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Adverse event of 
interest
MedDRA Preferred Term
Asthenic Conditions
Asthenia, Fatigue, Lethargy, Listless, Malaise, Sluggishness, 
Muscle Weakness
5.10.1.2   Serious Adverse Events
The number and percentage of patients experiencing treatment-emergent serious AEs (SAE) 
and treatment-emergent study drug related SAE will be summarized by MedDRA primary 
system organ class, and preferred term.
In addition, a by-patient listing of the SAEs will be presented. 
5.10.1.3   Deaths
A by-patient listing of deaths within 30 days of last dose of study drug based on adverse 
events with an outcome of fatal will be presented.
5.10.1.4   Adverse Events Resulting in Discontinuation of Study Drug
The following listings will be generated:

TEAEs resulting in discontinuation of study drug [action taken= drug withdrawn]

TEAEs resulting in reduction or interruption of study drug [action taken=dose 
interrupted or action taken=dose reduced]
In the Combination with Paclitaxel arm study drug refers to either MLN0128 or paclitaxel.  
5.10.2   Laboratory Data
For the purposes of summarization, all laboratory values will be converted to standardized 
units.  Whenever available, laboratory values will be assigned toxicity grades using the NCI 
CTCAE version 4.0.  The NCI CTCAE version 4.0.3 toxicity criteria for creatinine will be 
modified to exclude the comparison to baseline.  The number and proportion of patients with 
shifts in NCI CTCAE toxicity grades relative to the baseline toxicity grade will be 
summarized.  For those laboratory tests not assigned NCI-CTCAE toxicity grades the 
number and proportion of patients with shifts in laboratory values to outside the laboratory 
normal range relative to the baseline value will be summarized. 


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5.10.3   Vital Signs and Weight
Vital sign results (diastolic and systolic blood pressure) and body weight will be 
summarized as follows:

Baseline value

Minimum post-baseline value

Maximum post-baseline value
Changes to the minimum and maximum post-baseline values will be calculated relative to 
the baseline value.
5.10.4   Electrocardiograms
For the subset of patients enrolled under amendment #2 with pre-dose and 2 hour post-dose 
ECGs performed on Day 1 of each cycle the minimum and maximum 2 hour post dose 
values will be summarized for each ECG parameter (ventricular rate, PR, QRS, QT, and 
QTc (Fridericia) .  The pre-dose value and the change from the pre-dose to the minimum and 
maximum 2 hour value will also be summarized. For the maximum change from pre-dose
in QT/QTc interval the number and percent of patients with increases >30 ms and >60 ms 
will also be summarized.
All QT values will be converted to QTcF using Fridericia’s correction:
(sec)
[Note: convert RR recorded on ECG CRF from msec to sec, if the RR is not available use: 
60 seconds divided by the ventricular rate in beats/minute].
5.10.5     
ECOG Performance Status
ECOG performance status scores will be summarized in the same manner as described for 
vital signs in section 5.10.3 (maximum post-baseline only).
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol MLN0128-1004 
Amendment 2 dated 14May2105 and the accompanying data collection Case Report Form  
version 1.0 dated  06Mar2015.


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7.   
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.2 (or higher) will be used for all analyses.  
7.2   
Rules and Definitions
Populations are defined in Section 2.
Treatment-emergent AEs are defined in Section 5.10.1.1.