Conditions: Advanced Solid Tumors
Keywords: Drug therapy
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 44
Healthy volunteers: no

Brief summary:
The purpose of this study is to characterize the effect of a single dose of 40 mg sapanisertib (MLN0128) on the electrocardiographic QT/QTc interval in participants with advanced solid tumors.

Detailed description:
The drug being tested in this study is called sapanisertib (MLN0128). Sapanisertib is being tested to determine the effect of a single 40 mg dose on the electrocardiographic measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart (QT)/rate corrected QT (QTc) interval in patients with advanced solid tumors. This study will look at electrocardiogram (ECG) results before and after a single dose of sapanisertib.

The study will enroll approximately 30 patients. All participants will receive a single 40 mg dose of sapanisertib capsules on Day 1. Participants may continue to receive sapanisertib for up to 1 year at a dose of up to 30 mg once weekly if a clinical benefit is being derived.

This multi-centre trial will be conducted in the United States. The overall time to participate in this study is up to 14 months. Participants will make 6 visits to the clinic and end of study visit 30 to 40 days after last dose of study drug for a follow-up assessment. Participants that continue treatment with sapanisertib will continue to make additional visits to the clinic once or twice every 4 weeks and the end of study visit 30 to 40 days after last dose of study drug for a follow-up assessment.

Arms:
arm 1: Sapanisertib starting dose of 40 mg, capsules, orally, once, on Day 1, Cycle 1 (28 days cycle) followed by sapanisertib 30 mg, capsules, orally, once weekly (QW) starting on Cycle 1, Day 8 based on safety and tolerability and as per investigator's discretion up to disease progression, unacceptable sapanisertib-related toxicity, withdrawal of consent, or for up to 12 months (whichever occurred first).

Interventions: intervention 1: Sapanisertib
Intervention descriptions: intervention 1: Sapanisertib capsules.

Protocol document:
Prot_000.pdf: 



Title:  Phase 1 Study to Evaluate the Effect of MLN0128 on the QTc Interval in Patients With 
Advanced Solid Tumors
NCT Number: NCT02197572
Protocol Approve Date: 28 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.


M L N 0 1 2 8
Cli nic al St u d y Pr ot oc ol C 3 1 0 0 2 Pr ot oc ol A m e n d me nt 2
1
C LI NI C A L S T U D Y P R O T O C O L C 3 1 0 0 2 P R O T O C O L A M E N D M E N T 2
M L N 0 1 2 8
A P h ase 1 St u dy t o Ev al u ate t he Effect of M L N 0 1 2 8 o n t he Q Tc I nterv al i n P atie nts Wit h 
A dv a nce d S oli d T u m ors
Pr ot oc ol N u m ber:
C 3 1 0 0 2
I n dic ati o n:
A d va nce d s oli d t u m ors
P h ase:
1
S p o ns or:
Mille n ni u m P har m ace uticals, I nc.
E u dr a C T N u m ber:
N ot a p plica ble
T her a pe utic Are a:
O nc o l og y
Pr ot oc ol Hist or y
Ori gi nal
2 9 Oct o ber 2 0 1 3
Pr ot oc ol  A me n d me nt 1
2 6 J u ne 2 0 1 4
Pr ot oc ol  A me n d me nt 2
2 8 N o ve m ber 2 0 1 7
Mille n ni u m P har mace uticals, I nc.
4 0 La n ds d o w ne Street
Ca m bri d ge, M A  U S A  0 2 1 3 9
T el e p h o ne:  + 1 ( 6 1 7) 6 7 9 - 7 0 0 0
N ote: Mille n ni u m P har mace uticals, I nc, a w h oll y o w ne d s u bsi diar y of Ta ke da P har mace utical 
C o m pa n y Li mite d, ma y be referre d t o i n t his pr ot oc ol as: " mille n ni u m”, " S p o ns or" or " Ta ke da. ”
A p pr o ve d b y:
N ote:  If t his d oc u me nt was a p pr o ve d electr o nicall y, t he electr o nic a p pr o val si g nat ures ma y 
be f ou n d at t he e n d of t he d oc u me nt.
Si g nat ure
D ate D D M o nt h Y Y Y Y
P P D
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e


MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
2
Protocol Amendment 2 Summary of Changes
Rationale for Amendment 2
This document describes the changes in reference to the protocol incorporating 
Amendment 2. The primary purpose of this amendment is to update those sections affected 
by new nonclinical data for MLN0128 metabolism by specific cytochrome P450 (CYP) 
isoforms. The study’s exclusion criteria, list of prohibited concomitant medications, 
description of potential drug-drug interactions, list of relevant CYP inhibitors, and dietary 
restrictions related to CYP inhibitors and inducers have been updated accordingly. 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 examples of changes in text and where the changes are located, see 
Section 14.6.
The purposes of this amendment are to:
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 description of potential drug-drug interactions.
4. Update the list of relevant CYP inhibitors and inducers.
5. Remove the dietary restrictions related to CYP inhibitors and inducers.
6. 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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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
3
PROTOCOL SUMMARY
Study Title:  A Phase 1 Study to Evaluate the Effect of MLN0128 on the QTc Interval in Patients 
With Advanced Solid Tumors
Number of Patients:  Approximately 30 patients will be enrolled in this study.
Study Objectives
Primary
To characterize the effect of a single dose of 40 mg MLN0128 on the electrocardiographic
QT/QTc interval in patients with advanced solid tumors
Secondary
To evaluate the safety, tolerability, and pharmacokinetics of MLN0128 in patients with
advanced solid tumors
Overview of Study Design:  This is an open label, single-arm, multicenter study to evaluate the 
effect of a single dose of 40 mg MLN0128 on the QT/QTc interval in patients with advanced solid 
tumors.  The study will enable collection of time-matched pharmacokinetic (PK) and 
electrocardiogram (ECG) data before and after MLN0128 administration at the time points specified 
in the Schedule of Events.  A central ECG reader will be used and continuous 12-lead digital ECGs 
will be obtained using a Holter H12+ ECG recorder.  All planned 12-lead ECG collections will be 
obtained in triplicate.
On the morning of Screening; Day -1 baseline measurements of serial triplicate ECGs (0-10 hours) 
will be obtained.  Three Holter ECGs will be extracted at the time points that match the Cycle 1, Day 
1 PK/ECG sampling times.  The clock time of ECG assessments on Screening; Day -1 should 
coincide with the clock time of PK/ECG assessments for Cycle 1, Day 1.  After collection of the 
planned 10-hour ECG sample on Cycle 1, Day 1, the Holter recorders will not be removed and 
patients will be furloughed from the study site.  
On Screening; Day -1 and Cycle 1, Day 1, patients will be given the option to report to the site fasted 
or after having a light morning meal as long as the meal has been completed at least 2 hours before 
the scheduled baseline triplicate ECG on each day.  If patients report to the site fasted, they should 
do so with adequate time (approximately 3 hours before the scheduled baseline triplicate ECG) in 
order to eat a light, standard breakfast provided by the site that will need to be completed at least 
2 hours before the scheduled baseline triplicate ECG on each day. Patients will be instructed not to 
eat for the next 6 hours (ie, 2 hours before the 0-hour, predose time point and until completion of the 
collection of the 4-hour postdose PK/ECG assessments).  Light meals will be administered at the 
same time on Screening; Day -1 and Cycle 1, Day 1.  
In addition, all patients will be issued a glucometer and trained to use it to monitor their daily 
predose fasting blood glucose (FBG) levels at home for the days on which glucose is not measured at 
the clinic.  Patients will be instructed to notify the study staff immediately with any abnormal 
readings (ie, ≥ 150 mg/dL) for further instructions on the management of hyperglycemia.  In-home 
glucose monitoring is not required on days when fasting glucose is measured in the clinic.
To mitigate nausea and vomiting known to occur at a 40 mg dose of MLN0128, patients will be 
administered an antiemetic agent (0.25 mg palonosetron) on Cycle 1, Day 1.  
After collection of the 10-hour postdose PK/ECG assessment on Cycle 1, Day 1, patients will be 
furloughed from the study site.  The Holter recorders will not be removed during this furlough 
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
4
period.
On Cycle 1, Day 2 and Cycle 1, Day 3, patients may eat and drink up to approximately 2 hours 
before arriving at the study site for PK/ECG evaluations.
On Cycle 1, Day 2, patients will report to the clinical facility at least 1 hour before the 24-hour 
postdose PK/ECG (triplicate) assessments.  After the PK/ECG assessments are completed, the Holter 
recorders will be removed and patients will be furloughed from the study site.  
On Cycle 1, Day 3, patients will report to the clinical facility at least 1 hour before the 48-hour 
postdose assessments, which will represent the final study endpoint-specific planned PK/ECG 
assessments.  
After completing the PK/ECG assessments on Cycle 1, Day 3, patients may continue to receive 
MLN0128 if, in the opinion of the investigator, the patient is deriving clinical benefit, until they 
experience disease progression.  Patients continuing treatment with MLN0128 at the discretion of the 
investigator will receive a dose of MLN0128 up to 30 mg every week (QW).  Dose escalation will 
not be permitted, and a maximum of 2 dose reductions (for patients experiencing study drug-related 
toxicity) will be permitted.  Patients will return to the study site for follow-up visits at the time points 
in the Schedule of Events.  Treatment may continue until disease progression, unacceptable 
MLN0128-related toxicity, withdrawal of consent, or for up to 12 months (whichever occurs first).  
All patients enrolled in the study will attend the End of Study/Early Termination visit 30 (to 40) days 
after receiving their last dose of study drug.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (AEs), Version 4.03, effective date 14 June 2010.  AEs will be assessed, and 
laboratory values, vital signs, and ECGs will be obtained to evaluate the safety and tolerability of 
MLN0128.
Radiological evaluations (computed tomography [CT] scan or magnetic resonance imaging [MRI] as 
clinically indicated) will be obtained at baseline and Cycle 3, Day 28, after which point CT (with 
contrast) or MRI may be performed every 3 cycles at the investigator’s discretion as clinically 
indicated, according to standard of care.
Study Population:  Men or women 18 years or older with a radiographically or clinically evaluable 
solid tumor for which standard-of-care therapy has failed may be enrolled in this study; however, 
measurable disease as defined by modified Response Evaluation Criteria in Solid Tumors criteria is 
not required.  Patients with a history of brain metastasis may be eligible provided all of the following 
criteria are met:  treated brain metastases; no evidence of disease progression or hemorrhage after 
treatment; off-treatment with dexamethasone for 28 days before administration of the first dose of 
MLN0128; and no ongoing requirement for dexamethasone or anti-epileptic drugs.  Eligible patients 
must have an Eastern Cooperative Oncology Group performance status of 0 or 1 and the following 
clinical laboratory values within 28 days before the first dose of MLN0128:  total bilirubin 1.5 
the upper limit of normal (ULN); alanine aminotransferase and aspartate aminotransferase 2.5 
the ULN; creatinine clearance ≥ 50 mL/min; absolute neutrophil count ≥ 1.5109/L; platelet count 
≥100109/L; hemoglobin 10 g/dL; fasting glucose ≤ 120 mg/dL and fasting triglycerides 
≤300 mg/dL.  Left ventricular ejection fraction must be within 5 absolute percentage points of
institutional standard of normal within 28 days before the first dose of MLN0128.
Patients with a history of leptomeningeal disease or spinal cord compression or tumors with 
involvement of the mediastinum are not eligible.  Patients with a diagnosis of diabetes mellitus may 
not be enrolled in the study.  Patients with a history of any of the following within 6 months before 
study entry are also not eligible:  ischemic myocardial event; ischemic cerebrovascular event; 
requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia 
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
5
(including atrial flutter/fibrillation, ventricular fibrillation, or ventricular tachycardia); a pacemaker 
for control of rhythm; New York Heart Association Class III or IV heart failure; or pulmonary 
embolism.  Additionally, patients are not eligible if they have significant active cardiovascular or 
pulmonary disease at study entry, including:  uncontrolled high blood pressure (ie, systolic blood 
pressure > 180 mmHg, diastolic blood pressure > 95 mmHg); resting pulse rate of < 50 beats per 
minute or > 100 beats per minute at screening or predose; pulmonary hypertension; uncontrolled 
asthma or O2 saturation < 90%; significant valvular disease; severe regurgitation or stenosis, or 
history of valve replacement; medically significant (symptomatic) bradycardia; history of arrhythmia 
requiring an implantable cardiac defibrillator; requirement for QT-prolonging drugs with a risk of 
causing torsades de pointes (TdP).  Patients with a baseline prolongation of QTc (rate-corrected QT 
interval [msec] of electrocardiograph with Fridericia correction [QTcF] > 430 msec for men and 
QTcF > 450 ms for women), TdP, Brugada syndrome, or a history of thoracic surgery or congenital 
long QT syndrome (LQTS; or family history of LQTS) are not eligible for enrollment in this study.
Duration of Study:  It is anticipated that this study will last for approximately 12 months.
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
6
STUDY OVERVIEW DIAGRAM
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M L N 0 1 2 8
Cli nic al St u d y Pr o t oc ol C 3 1 0 0 2 Pr ot oc ol A m e n d me nt 2
7
S C H E D U L E O F E V E N T S
Scree ni n g a
Tre at me nt C ycles
E O S/ 
E arl y 
ter m-
i n ati o nb
C ycle 1
C ycle 2  
C ycle 3
C ycle 
4
C ycle 5 a n d 
be y o n d
D a y -2 8 t o 
D a y - 1
D a y 
1
D a y 2 ( 2 4 hr 
p ost d ose)
D a y 3 ( 4 8 hr 
p ost d ose)
D a y 1 5 
( ± 2 
d a ys)
D a y 
1
D a y 1 5 
( ± 2 
d a ys)
D a y 
1
D a y 
2 8 
(- 7 
d a ys)
D a y 1
D a y 
1
D a y 
2 8 
(- 7 
d a ys)
I nf or me d c o nse nt
X
I ncl usi o n/e xcl usi o n 
criteria
X
De m o gra p hics
X
Me dical hist or y
X
P h y sical 
e xa mi nati o n
X  
X
X
X  
X
X  
X
X
X  
X
X
Hei g ht
X
Wei g ht
X  
X  
X
X  
X  
X  
X  
X
X  
X
X
Vital si g ns c
X  
X
X
X  
X
X  
X
X
X
X
X
E C O G 
perf or ma nce stat us
X  
X
X
X
X  
X
M U G A/ E C H O
X
Si n gle, 1 2 -lea d 
E C G
X  
X d
X
Serial, tri plicate 
E C Gs f or 
c o nti n u o us 1 2 -lea d 
E C G H olter 
m o nit ori n g e
X
X  
X
X
Disease 
assess me nt f
X
X
Q 3 C f
P P D
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e


MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
8
Screeninga
Treatment Cycles
EOS/ 
Early 
term-
inationb
Cycle 1
Cycle 2
Cycle 3
Cycle 
4
Cycle 5 and 
beyond
Day -28 to 
Day-1
Day 
1
Day 2 (24hr 
postdose)
Day 3 (48hr 
postdose)
Day 15 
(±2 
days)
Day 
1
Day 15 
(±2 
days)
Day 
1
Day 
28 
(-7 
days)
Day 1
Day 
1
Day 
28 
(-7 
days)
Monitoring of 
concomitant 
medications and 
procedures
Recorded from first dose of study drug 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.
Serious adverse eventsg will be reported from signing of the informed consent form through 30 days after the last dose of study drug.
MLN0128 
administration
QW dosing (see Section 6.1)h
Antiemetic 
administrationi
X
Samples/Laboratory Assessments
Pregnancy testj
X1
X1
Hematology/
chemistryk
X1
X1
X1
X1
X1
X1
X1
X1
X1
Urinalysis
X1l
X1
X1
X1
X1
X1
X1
X1
X1
Fasting glucosem
X1
X
X1
X1
X1
X1
X1
In-home daily 
fasting glucose 
monitoringn
X
Fasting lipid 
profile
X1o
X1
X1
X1
X1
HbA1c
X1
X1
Q3C
Blood samples for 
PKp
X12
X1
X1
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
9
Screeninga
Treatment Cycles
EOS/ 
Early 
term-
inationb
Cycle 1
Cycle 2
Cycle 3
Cycle 
4
Cycle 5 and 
beyond
Day -28 to 
Day-1
Day 
1
Day 2 (24hr 
postdose)
Day 3 (48hr 
postdose)
Day 15 
(±2 
days)
Day 
1
Day 15 
(±2 
days)
Day 
1
Day 
28 
(-7 
days)
Day 1
Day 
1
Day 
28 
(-7 
days)
Abbreviations:  -hCG = beta-human chorionic gonadotropin; CBC = complete blood count; CT = computed tomography; CXDX = Cycle X, Day X; 
ECHO = echocardiogram; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; EOS = End of Study; HbA1c = glycosylated 
hemoglobin; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition (scan); PK = pharmacokinetic; Q3C = every 3 cycles; QW = every 
week; WBC = white blood cell; X# = number of samples required (eg, two samples = X2).
Tests and procedures should be performed on schedule, but occasional changes are allowable (± 2 days) with permission of the project clinician for holidays, 
vacations, and other administrative reasons.  If extenuating circumstances prevent a patient from beginning treatment or completing a scheduled 
procedure or assessment within this time, the patient may continue the study only with the written permission of the project clinician.
a Screening assessments are performed within 28 days before the C1D1 MLN0128 dose.  Screening assessments performed no more than 3 days before 
Screening; Day -1 will qualify as baseline assessments and need not be repeated, unless otherwise specified.  Screening; Day -1 is defined as the day before 
first dose of study drug; screening assessments must be completed by Screening; Day -1.
b Patients will attend an EOS/Early Termination visit 30 to 40 days after receiving their last dose of MLN0128.
c Vital sign measurements include blood pressure (diastolic and systolic), heart rate, and temperature.
d The C1D1 single, 12-lead ECG can be collected 2-4 hours after dosing.
e When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection 
of the blood sample.  
f
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 C3D28, 
after which point CT (with contrast) or MRI may be performed Q3C (ie, C6D28, C9D28, C12D28, etc) as clinically indicated, according to standard of care.  
The same imaging modality (CT [with contrast] or MRI) should be used throughout the study. Scans are permitted up to 7 days in advance of the study visit.
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. 
g Including serious pretreatment events; see Section 9.1.1 for definition.
h A single dose of 40 mg MLN0128 will be administered on C1D1; patients continuing treatment with MLN0128 after C1D3 at the discretion of the 
investigator will receive a maximum dose of 30 mg MLN0128 administered on a QW schedule.
i
Patients will be administered an antiemetic agent (0.25 mg palonosetron) as an intravenous infusion over 30 seconds, at least 30 minutes before study drug 
administration.
j
A serum -hCG pregnancy test will be performed only for patients of childbearing potential during screening and again at C1D1 if the screening test was 
performed more than 4 days before the first dose of any study drug.  The results must be negative within 4 days before the first dose of MLN0128 is 
administered (ie, within the 4 days before C1D1), or as otherwise required by local regulations.  Additional pregnancy testing may be performed during the 
study at the discretion of the investigator, upon request of an independent ethics committee/institutional review board, or if required by local regulations.
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
10
Screeninga
Treatment Cycles
EOS/ 
Early 
term-
inationb
Cycle 1
Cycle 2
Cycle 3
Cycle 
4
Cycle 5 and 
beyond
Day -28 to 
Day-1
Day 
1
Day 2 (24hr 
postdose)
Day 3 (48hr 
postdose)
Day 15 
(±2 
days)
Day 
1
Day 15 
(±2 
days)
Day 
1
Day 
28 
(-7 
days)
Day 1
Day 
1
Day 
28 
(-7 
days)
k The hematology and chemistry blood samples for C1D1 may be collected within 4 days before dosing to ensure patient eligibility on study Day 1.  If 
screening clinical laboratory testing was performed within 4 days before the C1D1 dose, it need not be repeated on C1D1.  For all other visits, assessments 
may be performed ≤ 24 hours before the study visit.  Hematology includes CBC with differential consisting of the following:  hemoglobin, hematocrit, 
leukocytes (WBC), differential WBC count, neutrophils, and platelets.  Machine counts are acceptable.  The chemistry panel consists of the following:  
sodium, potassium, carbon dioxide, chloride, blood urea nitrogen, creatinine, bilirubin, alkaline phosphatase, aspartate aminotransferase, alanine 
aminotransferase, lactate dehydrogenase, gamma glutamyl transferase, albumin, glucose, urate, calcium, phosphate, and magnesium.
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 Fasting glucose will be measured in the clinic.  Patients are required to fast overnight (nothing except water and/or medications after midnight or for a 
minimum of 8 hours before the assessment) for each of these measurements, beginning Cycle 1, Day 4; see 7.4.16 for fasting requirements.
n Patients will be given a glucometer on C1D1 to monitor daily fasting glucose levels at home and will be instructed to notify the study clinician when the 
fasting glucose is abnormal (ie, ≥ 150 mg/dL).  In-home glucose monitoring is not required on days when fasting glucose is measured in the clinic.  See 
Section 7.4.18 for further instruction.
o To be completed within 14 days of C1D1 dosing.  See Section 7.4.15 for further instruction.
p Blood samples for PK analysis will be obtained according to the schedule presented in the Pharmacokinetic Sample Breakdown.
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
11
PHARMACOKINETIC SAMPLE BREAKDOWN
Screening
Cycle 1
Day -1
Day 1b
Day 2
Day 3
Triplicate ECGa
PK
Triplicate ECGa
PK
Triplicate ECGa
PK
Triplicate ECGa
PK
Predose (On C1D1: ≤15 min before dosing)
X
X
X
0.25 hour postdose (5 min)
X
X
X
0.5 hour postdose (5 min)
X
X
X
1 hour postdose (15 min)
X
X
X
1.5 hours postdose (15 min)
X
X
X
2 hours postdose (15 min)
X
X
X
2.5 hours postdose (15 min)
X
X
X
3 hours postdose (30 min)
X
X
X
4 hours postdose (45 min)
X
X
X
6 hours postdose (45 min)
X
X
X
8 hours postdose (1 hour)
X
X
X
10 hours postdose (1 hour)
X
X
X
24 hours postdose (1 hour)
X
X
48 hours postdose (1 hour)
X
X
Abbreviations:  CxDx = Cycle x, Day x; ECG = electrocardiogram; PK = pharmacokinetic(s).
When the timing of a blood sample for PK or safety laboratory analysis coincides with the timing of ECG measurements, the ECG will be completed before 
the collection of the blood sample.  The triplicate ECG measurements should be completed immediately before the corresponding blood sample for PK or 
safety laboratory analysis.  
See Section 7.4.16 for information regarding fasting periods that are required in advance of PK/ECG testing.
a Holter monitors will be used to collect triplicate ECG measurements.  Holter ECG measurements will be performed over the course of 15 minutes (at 
least 5 min supine prior to the first ECG measurement, and then a 10-minute period of extracting the triplicate ECG measurements at approximately 
2- to 5-minute intervals).  Timing of ECG collection on Screening; Day -1 should match PK/ECG collection on C1D1 to enable appropriate baseline 
correction.
b MLN0128 will be administered to patients at the clinic on C1D1.  If a patient is deemed not evaluable by the sponsor, the postdose C1D1 Holter ECG 
monitoring and PK sampling procedures need not be performed.  Refer to Section 7.6 for additional information.  
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
12
TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................14
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................15
1. BACKGROUND AND STUDY RATIONALE..............................................................18
1.1 Scientific Background ..............................................................................................18
1.1.1 Disease Under Treatment...................................................................................18
1.1.2 Study Drug ........................................................................................................18
1.2 Nonclinical Experience.............................................................................................19
1.3 Clinical Experience ..................................................................................................21
1.4 Study Rationale ........................................................................................................21
1.5 Potential Risks and Benefits .....................................................................................23
2. STUDY OBJECTIVES ..................................................................................................23
2.1 Primary Objective.....................................................................................................23
2.2 Secondary Objectives ...............................................................................................23
3. STUDY ENDPOINTS....................................................................................................24
3.1 Primary Endpoint .....................................................................................................24
3.2 Secondary Endpoints................................................................................................24
4. STUDY DESIGN...........................................................................................................24
4.1 Overview of Study Design........................................................................................24
4.2 Number of Patients...................................................................................................27
4.3 Duration of Study.....................................................................................................27
5. STUDY POPULATION.................................................................................................27
5.1 Inclusion Criteria......................................................................................................27
5.2 Exclusion Criteria.....................................................................................................29
6. STUDY DRUG..............................................................................................................32
6.1 Study Drug Administration.......................................................................................32
6.2 Reference/Control Therapy.......................................................................................33
6.3 Definitions of Dose-Limiting Toxicity......................................................................33
6.4 Dose-Modification Guidelines..................................................................................34
6.4.1 Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................35
6.4.2 Criteria for Dose Interruption During a Cycle ....................................................35
6.4.3 Criteria for Dose Reduction ...............................................................................35
6.4.4 Criteria for Discontinuation................................................................................35
6.5 Excluded Concomitant Medications and Procedures.................................................36
6.6 Permitted Concomitant Medications and Procedures.................................................37
6.7 Precautions and Restrictions .....................................................................................37
6.8 Management of Clinical Events................................................................................38
6.8.1 Management of Nausea and/or Vomiting ...........................................................38
6.8.2 Management of Hyperglycemia .........................................................................39
6.8.3 Management of Hyperlipidemia.........................................................................41
6.8.4 Management of Oral Mucositis ..........................................................................42
6.8.5 Management of Rash .........................................................................................42
6.8.6 Blinding and Unblinding....................................................................................43
6.9 Description of Investigational Agents.......................................................................43
6.10 Preparation, Reconstitution, and Dispensation ........................................................43
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6.11 Packaging and Labeling..........................................................................................44
6.12 Storage, Handling, and Accountability....................................................................44
7. STUDY CONDUCT ......................................................................................................45
7.1 Study Personnel and Organizations...........................................................................45
7.2 Arrangements for Recruitment of Patients ................................................................45
7.3 Treatment Group Assignments .................................................................................45
7.4 Study Procedures......................................................................................................45
7.4.1 Informed Consent ..............................................................................................45
7.4.2 Patient Demographics ........................................................................................46
7.4.3 Medical History.................................................................................................46
7.4.4 Physical Examination.........................................................................................46
7.4.5 Patient Height and Weight .................................................................................46
7.4.6 Vital Signs .........................................................................................................46
7.4.7 Pregnancy Test ..................................................................................................46
7.4.8 Eastern Cooperative Oncology Group Performance Status.................................46
7.4.9 Echocardiogram or Multiple Gated Acquisition Scan.........................................47
7.4.10 Concomitant Medications and Procedures........................................................47
7.4.11 Adverse Events ................................................................................................47
7.4.12 Enrollment .......................................................................................................47
7.4.13 Electrocardiogram............................................................................................47
7.4.14 Disease Assessment .........................................................................................49
7.4.15 Clinical Laboratory Evaluations.......................................................................49
7.4.16 Requirements for Fasting Periods.....................................................................50
7.4.17 Fasting Glucose ...............................................................................................51
7.4.18 In-Home Daily Fasting Glucose Monitoring.....................................................51
7.4.19 Pharmacokinetic Measurements .......................................................................51
7.5 Completion of Treatment/Completion of Study ........................................................51
7.6 Discontinuation of Treatment with Study Drug and Patient Replacement..................52
7.7 Study Compliance ....................................................................................................52
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................53
8.1 Statistical Methods ...................................................................................................53
8.1.1 Determination of Sample Size............................................................................53
8.1.2 Randomization and Stratification .......................................................................53
8.1.3 Populations for Analysis ....................................................................................53
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................53
8.1.5 Demographic and Baseline Characteristics.........................................................54
8.1.6 Efficacy Analysis...............................................................................................54
8.1.7 Electrocardiogram Analysis ...............................................................................54
8.1.8 Pharmacokinetics...............................................................................................55
8.1.9 Safety Analysis ..................................................................................................56
8.1.10 Interim Analysis...............................................................................................57
8.2 Pharmacokinetic Modeling .......................................................................................57
9. ADVERSE EVENTS .....................................................................................................57
9.1 Definitions................................................................................................................57
9.1.1 Pretreatment Event Definition............................................................................57
9.1.2 Adverse Event Definition...................................................................................57
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9.1.3 Serious Adverse Event Definition ......................................................................58
9.2 Procedures for Recording and Reporting Adverse Events and Serious Adverse 
Events...............................................................................................................59
9.3 Monitoring of Adverse Events and Period of Observation.........................................60
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........60
10. ADMINISTRATIVE REQUIREMENTS .....................................................................61
10.1 Good Clinical Practice............................................................................................61
10.2 Data Quality Assurance ..........................................................................................61
10.3 Electronic Case Report Form Completion...............................................................61
10.4 Study Monitoring ...................................................................................................62
10.5 Ethical Considerations............................................................................................62
10.6 Patient Information and Informed Consent..............................................................62
10.7 Patient Confidentiality............................................................................................63
10.8 Investigator Compliance.........................................................................................63
10.9 On-site Audits ........................................................................................................63
10.10 Investigator and Site Responsibility for Drug Accountability................................63
10.11 Product Complaints ..............................................................................................64
10.12 Closure of the Study .............................................................................................64
10.13 Record Retention..................................................................................................65
11. USE OF INFORMATION............................................................................................65
12. INVESTIGATOR AGREEMENT................................................................................66
13. REFERENCES.............................................................................................................67
14. APPENDICES .............................................................................................................69
14.1 Eastern Cooperative Oncology Group Scale for Performance Status.......................69
14.2 New York Heart Association Classification of Cardiac Disease ..............................69
14.3 Cockcroft-Gault Equation.......................................................................................70
14.4 List of Relevant Cytochrome P450 Inhibitors and Inducers.......................................70
14.5 Exclusionary QT-Prolonging Drugs........................................................................70
14.6 Amendment 2 Detailed Summary of Changes.........................................................76
LIST OF TABLES
Table 6-1   
Dose Reduction Schedule for MLN0128 .....................................................35
Table 6-2   
Management of Nausea and/or Vomiting ....................................................39
Table 6-3   
Management of Hyperglycemia...................................................................40
Table 6-4   
Management of Hyperlipidemia ..................................................................41
Table 6-5   
Management of Oral Mucositis ...................................................................42
Table 6-6   
Management of Rash...................................................................................43
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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
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUCinf
area under the plasma concentration versus time curve from zero to infinity
AUCt
area under the plasma concentration versus time curve from zero to the last 
measurable concentration
BCRP
breast cancer-resistant protein
Cmax
single-dose maximum (peak) concentration  
CT
computed tomography
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
End of Study (visit)
ER
estrogen receptor
ER/HER2
estrogen receptor positive/human epidermal growth factor receptor-2 negative
FBG
fasting blood glucose
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
GI
Gastrointestinal
hERG
human ether-à-go-go related gene
HDPE
high-density polyethylene
HER2
human epidermal growth factor receptor 2
IB
Investigator’s Brochure
IC
informed consent
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Abbreviation
Term
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IV
intravenous; intravenously
LQTS
long QT syndrome
LVEF
left ventricular ejection fraction
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
P-gp
P-glycoprotein
PI3K
phosphoinositide 3-kinase
PK
pharmacokinetic(s)
PPI
proton pump inhibitor
PR
progesterone receptor
QD
quaque die; every day; once daily
QT
measure of the time between the start of the Q wave and the end of the T wave 
in the electrical cycle of the heart; electrical depolarization and repolarization of 
the left and right ventricles of the heart
QTc
rate-corrected QT interval (millisec)
QTcB
rate-corrected QT interval (millisec) with Bazett correction
QTcF
rate-corrected QT interval (millisec) Fridericia correction
QTcI
individual baseline corrected rate-corrected QT interval (millisec)
QW
every week; once weekly
S473
Serine 473
S6K
ribosomal protein S6 kinase
SAE
serious adverse event
t1/2
terminal disposition half-life
T308
Threonine 308
TdP
torsades de pointes
TEAE
treatment-emergent adverse events
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Abbreviation
Term
Tmax
single-dose first time of occurrence of maximum (peak) concentration
TORC1
mammalian (or mechanistic) target of rapamycin complex 1
TORC2
mammalian (or mechanistic) target of rapamycin complex 2
ULN
upper limit of normal
US
United States
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 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
mTOR Inhibitors
The mTOR serine/threonine kinase has a central role in regulating cellular growth and 
metabolism in response to external environmental factors.(1, 2)  The mTOR kinase binds with 
other proteins to form 2 distinct multiprotein complexes, TORC1 and TORC2.  The TORC1 
complex is stimulated by growth factors and amino acids and regulates cell growth by 
controlling the activity of the ribosomal protein S6 kinase (S6K) and eukaryotic initiation 
factor 4-binding protein (4E-BP1).(3)  The TORC2 complex is activated by growth factors 
and promotes cell survival, proliferation, and actin cytoskeleton organization by 
phosphorylating and activating kinases, such as serine/threonine-specific protein kinase 
(AKT; also known as protein kinase B), which is a regulator of apoptosis.(4, 5)  
Two major classes of mTOR inhibitors are under development:  allosteric inhibitors and 
adenosine triphosphate (ATP)-competitive inhibitors.  The first-generation, or allosteric, 
inhibitors include rapamycin and the related analogs or rapalogs temsirolimus, everolimus, 
and ridaforolimus.  The rapalogs effectively inhibit phosphorylation of S6K but only 
partially inhibit the phosphorylation of 4E-BP1, which regulates cap-dependent translation 
of transcripts for cell survival, proliferation, and angiogenesis.(2)  Thus, rapamycin and the 
rapalogs are only partial inhibitors of TORC1.(2)  
The ATP-competitive inhibitors (also known as mTOR kinase inhibitors or TORKinibs), 
such as MLN0128, bind to the catalytic domain of mTOR and thus inhibit both TORC1 and 
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TORC2 complexes, including the rapamycin-insensitive or -resistant actions of TORC1, 
such as phosphorylation of 4E-BP1.(6, 7, 8)
The rapalogs temsirolimus and everolimus have been approved by the United States (US) 
Food and Drug Administration (FDA) as monotherapy for patients with advanced renal cell 
carcinoma (temsirolimus and everolimus), advanced pancreatic neuroendocrine tumors 
(everolimus), and subependymal giant cell astrocytoma associated with tuberous sclerosis 
(everolimus).  However, resistance to single-agent rapalog therapy occurs and may be 
related to either incomplete inhibition of the targeted pathway (such as phosphorylation of 
4E-BP1 as discussed above) or loss of S6K-mediated feedback inhibition of growth factor 
receptor signaling leading to paradoxic hyperactive signaling.  The normal feedback loop 
involves activated S6K, which phosphorylates and inactivates insulin receptor substrate-1 
and inhibits signaling through the phosphoinositide 3-kinase (PI3K) pathway.(5, 9)  In the 
presence of rapalogs, the feedback loop is abrogated, leading to continued PI3K signaling, 
TORC2 activation, and subsequent phosphorylation of AKT at Threonine 308 (T308) and 
Serine 473 (S473), which markedly enhances the activity of AKT.(2, 5, 9)   
The loss of feedback inhibition by rapalogs has been demonstrated in clinical trials.  In an 
analysis of either paired fresh tumor samples or skin biopsies obtained from 55 patients who 
received different doses of everolimus either daily or weekly in a phase 1 trial, everolimus 
inhibited TORC1 in a dose- and schedule-dependent manner with near complete inhibition 
of S6K.(10)  Half the paired tumor samples had a posttreatment increase in the 
phosphorylation of AKT at S473.(10)  These results provide direct evidence that loss of S6K 
feedback and subsequent PI3K/TORC2-induced activation of AKT occurs commonly in 
patients with solid tumors receiving single-agent everolimus.
MLN0128 is a potent, highly selective, ATP-competitive inhibitor of mTOR.  MLN0128 is 
mechanistically distinct from the allosteric inhibitors of mTOR (rapamycin and its 
derivatives, referred to as rapalogs).  The rapalogs only partially inhibit TORC1, whereas 
MLN0128 inhibits both TORC1 (more completely S6K and 4E-BP1) and TORC2.  Dual 
TORC1/2 inhibition mitigates feedback activation of PI3K and AKT, known to cause 
resistance to TORC1-only inhibitors.(11)
1.2   
Nonclinical Experience
MLN0128 inhibited the human ether-à-go-go related gene (hERG) potassium ion channel 
with a concentration producing 50% inhibition (IC50) of approximately 175 μM.  Given an 
in vitro mTOR kinase IC50 of 1.1 nM, MLN0128 it is not expected to have an effect on the 
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hERG channel at efficacious exposures in humans.  Additionally, a Good Laboratory 
Practice (GLP)-compliant cardiovascular safety study in telemeterized monkeys 
demonstrated no effects on the body temperature, blood pressure, heart rate, or 
electrocardiogram (ECG) endpoints.  There were also no effects on cardiovascular or 
respiratory parameters with MLN0128 in GLP-compliant toxicology studies.  In the 
GLP-compliant, single-agent study of MLN0128 in Sprague-Dawley rats, gait effects were 
observed on Day 28; however, no similar effects have been observed in humans. 
The toxicity profile of MLN0128 in rats and monkeys, as established in GLP-compliant 
repeat-dose studies, is consistent with pharmacologic inhibition of mTORC1/2 activity.  The 
dose limiting toxicities (DLTs) of MLN0128 in rats and monkeys were secondary to an 
exaggerated pharmacologic response and consisted of body weight loss and associated 
clinical observations that included gastrointestinal (GI) distress and decreased activity, 
appetite, and body temperature.  Additional findings in rat and monkey repeat-dose 
toxicology studies with MLN0128 included bone marrow and lymphoid depletion, GI and 
skin effects, and effects on glucose and insulin levels, all of which can be monitored in 
clinical trials.  The toxicities seen in the repeat-dose toxicology studies, such as GI effects 
and glucose and insulin increases, are consistent with the treatment-emergent adverse events 
(TEAEs), including mucositis and hyperglycemia, which have been observed to date in 
patients receiving MLN0128.
MLN0128 was negative in the Ames assay, in vivo comet assay, and in vivo micronucleus 
assay.  An in vitro chromosomal aberration assay was positive.  Thus, current evidence 
supports a low risk for genotoxicity for MLN0128.
Recently completed in vitro metabolism experiments in human hepatocytes using 
14C-labeled MLN0128 suggest that MLN0128 is metabolized primarily via CYP1A2 
(approximately 31% to 40%), with a minor contribution from CYP3A4 (approximately 11% 
to 22%).  These data suggest that MLN0128 is also metabolized by direct glucuronidation 
(approximately 22%) and an unidentified non-uridine diphosphate glucuronosyltransferase 
pathway (approximately 18%).  The new data differ from the previous in vitro CYP 
phenotyping data obtained using recombinant CYP enzymes, which suggested the 
involvement of CYP2C9 (approximately 35%), CYP2C19 (approximately 28%), and 
CYP3A4 (approximately 28%) in MLN0128 metabolism.
In addition, physiologically based PK modeling and simulation using the new metabolism 
data for MLN0128 suggest that the risk for a metabolism-based drug-drug interaction with 
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MLN0128 appears to be low.  Therefore, strong CYP1A2 inhibitors and CYP inducers (see 
Section 14.4) should only be administered with caution and at the discretion of the 
investigator during the study. Alternative treatments, if available, should be considered.
MLN0128 exhibits an inverse pH dependent aqueous solubility, having low solubility at 
high pH.  pH modifying agents such as proton pump inhibitors (PPIs), H2-receptor 
antagonists, or neutralizing antacids that can increase stomach pH can reduce MLN0128 
absorption.  In this study PPIs are not permitted; however, restricted use of H2-receptor 
antagonists and neutralizing antacids is permitted (refer to Section 6.5 and Section 6.6).
Detailed information regarding the nonclinical pharmacology and toxicology of MLN0128
may be found in the Investigator’s Brochure (IB).
1.3   
Clinical Experience
Single-agent MLN0128 is in clinical development with 2 phase 1 studies:  a study in patients 
with advanced solid malignancies (INK128-001) and a study in patients with relapsed or 
refractory multiple myeloma or Waldenstrom macroglobulinemia (INK128-002).  A third 
phase 1 study of MLN0128 is in combination with paclitaxel with or without trastuzumab in 
patients with advanced solid tumors (INK128-003).  These studies have been designed to 
investigate the safety, pharmacokinetics (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 (HER2)-targeting agents.  A phase 1b/2 study of MLN0128 in 
combination with exemestane or fulvestrant therapy in women with estrogen receptor 
positive (ER+)/HER2 negative (HER2) advanced or metastatic breast cancer (Study 
C31001) is enrolling patients.  Additionally, the combination of MLN0128 with MLN1117 
(an oral PI3Kα inhibitor) is being evaluated in a phase 1b study in adult patients with 
advanced nonhematologic malignancies (Study C32001).
Further details on these studies are provided in the IB.
1.4   
Study Rationale
MLN0128 is currently in phase 1 clinical investigation.  In May 2012, the US FDA 
recommended that the effect of MLN0128 on rate-corrected QT interval (millisec) of 
electrocardiograph (QTc) be investigated before initiating phase 3 studies.  
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Assessment of the potential of an investigational agent to cause QTc prolongation as a 
biomarker for ventricular tachycardia is an essential component of new drug development, 
as drugs that prolong the QTc interval pose an increased risk for ventricular tachycardia and 
sudden cardiac death.  While ECG data are collected during early clinical studies, often 
these data are not sufficient to provide a high degree of confidence in evaluation of the 
potential of a study drug to prolong the QT interval.  Dedicated QTc studies are 
advantageous because extensive ECG data is collected prior to and immediately following 
dosing of the investigational agent.  ECG measurements can be made to coincide with 
clinically relevant maximal concentrations of the investigational agent to provide a more 
robust assessment of the effect of the investigation agent on QTc interval. 
The primary objective of this dedicated QT study is to characterize the effect of a single 
dose of 40 mg MLN0128 on the QTc interval in patients with advanced solid tumors.  Two 
doses and schedules of MLN0128 are currently being investigated:  5 mg every day (QD) 
and 40 mg QW.  The 40 mg QW is currently the highest dose of MLN0128 under clinical 
investigation.  The 40 mg dose of MLN0128 is also the single agent maximum tolerated 
dose (MTD) of MLN0128 in the QW dosing schedule.  MLN0128 does not accumulate in 
plasma to any meaningful extent with QD dosing and the maximum plasma concentration of 
MLN0128 with 5 mg QD dosing is unlikely to exceed those expected at the 40 mg QW dose 
of MLN0128.  The 40 mg dose of MLN0128 will allow for the assessment of the effect of 
MLN0128 on QTc interval at its highest anticipated plasma concentration.
Since this study will be conducted in patients with advanced solid tumors, the study does not 
include placebo or a positive control (ie, moxifloxacin).  In addition, since the 40 mg dose of 
MLN0128 represents its single agent MTD in the QW dosing schedule and is the highest 
dose of MLN0128 administered in clinical studies, the design of this dedicated QT study 
does not include a supratherapeutic dose of MLN0128.  The collection of serial 
time-matched baseline ECGs should account for circadian changes, within patient 
inter-occasion variability in ECGs, and the determination of individual baseline corrected 
QTc (QTcI).  ECGs will be collected in triplicate to further minimize variability.  
Time-matched collection of serial PK data of MLN0128 for concentration-QTc analysis will 
enable the understanding of changes in QTc with plasma concentration and projection of the 
effect of MLN0128 on QTc at doses that were not evaluated in this study.
MLN0128 is known to induce nausea and vomiting at the 40 mg dose.  To mitigate this 
effect, patients will receive an antiemetic agent (0.25 mg palonosetron) before receiving the 
single dose of MLN0128.  No significant effect of palonosetron on QT interval has been 
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observed at doses up to 2.25 mg in a thorough QT assessment;(12) thus, no effect on QT 
interval is anticipated with the prophylactic use of palonosetron during this study.
1.5   
Potential Risks and Benefits
The most common TEAEs observed with MLN0128 are consistent with the 
pharmacodynamic mechanism of mTOR inhibition that is also seen with rapalogs (TORC1 
inhibition) or other dual mTORC1/2 inhibitors.  The TEAEs observed across the MLN0128 
single-agent studies include diarrhea, fatigue, vomiting, rash, mucosal inflammation, 
asthenia, dysgeusia, thrombocytopenia, stomatitis, and blood creatinine increased.  In 
general, toxicities observed to date have been mostly Grade 1 or Grade 2 and are 
manageable with supportive care and/or dose interruption or dose reduction of MLN0128.
Risk mitigation strategies for potential adverse events (AEs) include, but are not limited to, 
strict application of the study inclusion and exclusion criteria, frequent monitoring of 
clinical and laboratory results, guidelines for management and prophylaxis of potential 
toxicities, criteria for dose modification, and regular monitoring of AEs and serious adverse 
events (SAEs) by the sponsor.  Refer to Section 6.8 for additional information.
The benefits of MLN0128 are discussed in Section 1.1.
Further details are presented in the MLN0128 IB.
2.   
STUDY OBJECTIVES
2.1   
Primary Objective
The primary objective is:

To characterize the effect of a single dose of 40 mg MLN0128 on the 
electrocardiographic QT/QTc interval in patients with advanced solid tumors
2.2   
Secondary Objectives
The secondary objectives are:

To evaluate the safety, tolerability, and pharmacokinetics of MLN0128 in patients 
with advanced solid tumors
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3.   
STUDY ENDPOINTS
3.1   
Primary Endpoint
The primary endpoint is:

Change in QTcI from time-matched baseline (Screening; Day -1) to Cycle 1, Day 1
3.2   
Secondary Endpoints
The secondary endpoints are:

AEs, SAEs, assessments of clinical laboratory values, and vital sign measurements

Change from time-matched baseline (Screening; Day -1) in QTc with Bazett 
correction (QTcB), QTc with Fridericia correction (QTcF), QRS, PR, and heart rate 
on Cycle 1, Day 1

PK parameters, including, but not limited to, single-dose maximum (peak) 
concentration (Cmax), single-dose first time of occurrence of maximum (peak) 
concentration (Tmax), area under the plasma concentration versus time curve from 
zero to the last measurable concentration (AUCt), area under the plasma 
concentration versus time curve from zero to infinity (AUCinf), and terminal 
disposition half-life (t1/2)
4.   
STUDY DESIGN 
4.1   
Overview of Study Design
This is an open label, single-arm, multicenter study to evaluate the effect of a single dose of 
40 mg MLN0128 on the electrocardiographic QT/QTc interval in patients with advanced 
solid tumors.
The study will enable collection of time-matched PK and ECG data before and after 
MLN0128 administration at the time points specified in the Schedule of Events.  A central 
ECG reader will be used and continuous 12-lead digital ECGs will be obtained using a 
Holter H12+ ECG recorder.  All planned 12-lead ECG collections will be obtained in 
triplicate.
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On the morning of Screening; Day -1 baseline measurements of serial triplicate ECGs 
(0-10 hours) will be obtained.  Three Holter ECGs will be extracted at the time points 
matching the Cycle 1, Day 1 PK/ECG sampling times.  As the Screening; Day -1 baseline 
evaluations serve as the time-matched baseline for the corresponding Cycle 1, Day 1 
PK/ECG assessments, the 0-hour time point on Screening; Day -1 should coincide with the 
clock time of MLN0128 dosing on Cycle 1, Day 1 (the 0-hour time point on Cycle 1, 
Day 1).  The clock time of all other ECG assessments on Screening; Day -1 should also 
coincide with the clock time of PK/ECG assessments for Cycle 1, Day 1.  After collection of
the planned 10-hour ECG sample on Cycle 1, Day 1, the Holter recorders will not be 
removed and patients will be furloughed from the study site.  
On Screening; Day -1 and Cycle 1, Day 1, patients will be given the option to report to the 
site fasted or after having a light morning meal as long as the meal has been completed at 
least 2 hours before the scheduled baseline triplicate ECG on each day.  If patients report to 
the site fasted, they should do so with adequate time (approximately 3 hours before the
scheduled baseline triplicate ECG) in order to eat standard, light breakfast provided by the 
site that must be completed at least 2 hours before the scheduled baseline triplicate ECG on 
each day.  Patients will be instructed not to eat for the next 6 hours (ie, 2 hours before the 
0-hour, predose time point and until completion of the collection of the 4-hour postdose 
PK/ECG assessments).  A standard, light lunch will be provided.  Light meals will be 
administered at the same times on Screening; Day -1 and Cycle 1, Day 1.  
For the Screening; Day -1 and Cycle 1, Day 1 study visits, fasting serum glucose will be 
measured at the clinical facility.  In addition, all patients will be issued a glucometer and 
trained to use it to monitor their daily predose fasting blood glucose (FBG) levels at home 
for the days on which glucose is not measured at the clinic.  Patients will be instructed to 
notify the study staff immediately with any abnormal readings (ie, ≥ 150 mg/dL) for further 
instructions on the management of hyperglycemia.  In-home glucose monitoring is not 
required on days when fasting glucose is measured in the clinic.
To mitigate nausea and vomiting known to occur at a 40 mg dose of MLN0128, patients will 
be administered an antiemetic agent (0.25 mg palonosetron) on Cycle 1, Day 1.  
After collection of the 10-hour postdose PK/ECG assessment on Cycle 1, Day 1, patients 
will be furloughed from the study site.  The Holter recorders will not be removed during this 
furlough period.
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On Cycle 1, Day 2 and Cycle 1, Day 3, patients may eat and drink up to approximately 
2 hours before arriving at the study site for PK/ECG evaluations.  
On Cycle 1, Day 2, patients will report to the clinical facility at least 1 hour before the 
24-hour postdose PK/ECG (triplicate) assessments.  After the PK/ECG assessments are 
completed, the Holter recorders will be removed and patients will be furloughed from the 
study site.  
On Cycle 1, Day 3, patients will report to the clinical facility at least 1 hour before the 
48-hour postdose assessments, which will represent the final study endpoint-specific 
planned PK/ECG assessments.  
Patients may continue to receive MLN0128 if, in the opinion of the investigator, the patients 
are deriving clinical benefit, until they experience disease progression.  Patients continuing 
treatment with MLN0128 at the discretion of the investigator will receive a dose of 
MLN0128 up to 30 mg QW.  Dose escalation will not be permitted, and a maximum of 
2 dose reductions (for patients experiencing study drug-related toxicity) will be permitted.  
Patients will return to the study site for follow-up visits at the time points in the Schedule of 
Events.  Treatment may continue until disease progression, unacceptable MLN0128-related 
toxicity, withdrawal of consent, or for up to 12 months (whichever occurs first).  
All patients enrolled in the study will attend the End-of-Study (EOS)/Early Termination visit 
30 (to 40) days after receiving their last dose of study drug.
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.(13)  
DLTs are defined in Section 6.3.  
AEs will be assessed, and laboratory values, vital signs, and ECGs will be obtained to 
evaluate the safety and tolerability of MLN0128.
Radiological evaluations (computed tomography [CT] scan or magnetic resonance imaging 
[MRI] as clinically indicated) will be obtained at baseline and Cycle 3, Day 28, after which 
point CT (with contrast) or MRI may be performed every 3 cycles at the investigator’s 
discretion as clinically indicated, according to standard of care.
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4.2   
Number of Patients
Approximately 30 patients will be enrolled in this study.  Patients will be enrolled from 
approximately 6 study centers in the US.  Enrollment is defined as the time of the initiation 
of the first dose of study drug.
Patients who are withdrawn from treatment before completing study-required PK/ECG 
assessments for reasons other than DLTs will be replaced.
4.3   
Duration of Study
Patients may receive MLN0128 until they experience disease progression.  Patients will 
discontinue treatment if they have an unacceptable MLN0128-related toxicity.  The 
maximum duration of treatment will be 12 months unless, after discussion between the 
investigator and sponsor, it is determined that a patient would derive benefit from continued 
therapy beyond 12 months.
Patients will attend an EOS/Early Termination visit 30 (to 40) days after receiving their last 
dose of study drug to permit the detection of any delayed treatment-related AEs. 
It is anticipated that this study will last for approximately 12 months.
5.   
STUDY POPULATION
5.1   
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Men or women patients 18 years or older.
2. Patients must have a radiographically or clinically evaluable solid tumor for which 
standard-of-care therapy has failed; however, measurable disease as defined by 
modified Response Evaluation Criteria in Solid Tumors criteria (Version 1.1)(14) is 
not required for participation in this study.
3. Patients with a history of brain metastasis may be eligible for the study provided all 
of the following criteria are met: 

Brain metastases which has been treated
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
No evidence of disease progression or hemorrhage after treatment

Off-treatment with dexamethasone for 28 days before administration of the first 
dose of MLN0128

No ongoing requirement for dexamethasone or anti-epileptic drugs
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (refer to 
Section 14.1).
5. 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  
through 3 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the subject.  (Periodic abstinence (eg, calendar, ovulation, 
symptothermal, postovulation methods] and withdrawal are not acceptable 
methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment  
period and through 3 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception.)
6. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care.
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7. Clinical laboratory values as specified below within 28 days before the first dose of 
study drug:

Total bilirubin must be 1.5 the upper limit of normal (ULN)

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 2.5 
the ULN.  ALT and AST may be 5 the ULN if the elevation can be 
reasonably ascribed to the presence of metastatic disease in liver.

Creatinine clearance ≥ 50 mL/min based either on Cockroft Gault estimate or 
based on a 12- or 24-hour urine collection. (refer to Section 14.3)

Absolute neutrophil count ≥ 1.5 109/L; platelet count ≥ 100 109/L; 
hemoglobin 10 g/dL

Fasting glucose ≤ 120 mg/dL and fasting triglycerides ≤300 mg/dL
8. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of 
institutional standard of normal, as measured by echocardiogram or multiple gated 
acquisition (MUGA) scan, within 28 days before the first dose of study drug (ie, if 
the institutional normal is 50%, LVEF may be as low as 45% to be eligible).
9. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, 
and suitable venous access for the study-required blood sampling.
10. Patients requiring chronic treatment with H2-receptor antagonists or neutralizing 
antacids are eligible; however, the most recent dose must have been more than 
48 hours with H2-receptor antagonists and more than 4 hours with neutralizing 
antacids before receiving the first dose of MLN0128.  Treatment with H2-receptor 
antagonists or neutralizing antacids is permitted after completing the required 
PK/ECG assessments on Cycle 1, Day 3 within the specified windows (refer to 
Section 6.6).
5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Female patients who are lactating and breastfeeding or have a positive serum 
pregnancy test during the screening period.
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2. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.
3. Treatment with any investigational products within 14 days before the first dose of 
study drug and systemic anticancer therapy within 28 days before the first dose of 
study drug
4. Untreated brain metastasis or history of leptomeningeal disease or spinal cord 
compression.
5. Tumors with involvement of the mediastinum.
6. Failure 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.
7. Systemic corticosteroid (inhalers are allowed) within 7 days before the first dose of 
study drug.
8. Manifestations of malabsorption due to prior GI surgery, GI disease, or for an 
unknown or other reason that may alter the absorption of MLN0128.
9. Diagnosis of diabetes mellitus; patients with a history of transient glucose 
intolerance due to corticosteroid administration may be enrolled if all other 
inclusion/exclusion criteria are met.
10. History of any of the following within 6 months before study entry:

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
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
New York Heart Association Class III or IV heart failure 

Pulmonary embolism
11. Significant active cardiovascular or pulmonary disease at study entry, including:

Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mmHg, 
diastolic blood pressure > 95 mmHg)

Resting pulse rate of < 50 beats per minute or > 100 beats per minute at 
screening or predose

Pulmonary hypertension

Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or 
pulse oximetry on room air 

Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention, or history of valve 
replacement

Medically significant (symptomatic) bradycardia

History of arrhythmia requiring an implantable cardiac defibrillator 
12. Requirement for QT-prolonging drugs with a risk of causing torsades de pointes 
(TdP).  Patients on a stable dose of drugs with a conditional or possible risk of QT 
prolongation may be considered. 
13. Baseline prolongation of QTc (eg, repeated demonstration of QTcF > 430 ms for 
men and QTcF > 450 ms for women, or TdP); other abnormal ECG findings deemed 
clinically significant by the investigator or which would interfere with determination 
of the QT interval, such as bundle branch block, abnormal T waves or pathological U 
waves. 
14. History of thoracic surgery, Brugada syndrome, history of congenital long QT 
syndrome (LQTS; or family history of LQTS), or major surgery within 14 days 
before the first dose of study drug
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15. Clinically significant comorbidities such as uncontrolled pulmonary disease, active 
central nervous system disease, active infection, serious infection within 14 days 
before the first dose of study drug, or any other condition that could compromise 
study participation by the patient.
16. Patients requiring daily or chronic use of PPI and/or having taken a PPI within 
7 days before receiving the first dose of study drug.  
6.   
STUDY DRUG
6.1   
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration.  Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified sub-investigator(s).
MLN0128 is administered once weekly (QW) in continuous cycles of 28 days.  MLN0128 
will be supplied as capsules of 5 mg dose strength.  All capsules will be swallowed whole.  
It is recommended that each dose of MLN0128 be given orally with 8 ounces (240 mL) of 
water.  
Cycle 1, Day 1
During Holter ECG monitoring (Screening; Day -1 and Cycle 1, Day 1), patients will be 
given the option to report to the site fasted or after having a light morning meal, as long as 
the meal has been completed at least 2 hours before the scheduled baseline triplicate ECG on 
each day.  If patients report to the site fasted, they should do so with adequate time 
(approximately 3 hours before the scheduled baseline triplicate ECG) to eat a light, standard 
breakfast provided by the site that will need to be completed at least 2 hours before the 
scheduled baseline triplicate ECG on each day.  Patients will be instructed not to eat for the 
next 6 hours (ie, 2 hours before the 0-hour, predose time point and until completion of the 
collection of the 4-hour postdose PK/ECG assessments).  A light, standard lunch will be 
provided at the same times on Screening; Day -1 and Cycle 1, Day 1.  
On Cycle 1, Day 2 and Cycle 1, Day 3, patients may eat and drink up to approximately 
2 hours before arriving at the study site for PK/ECG evaluations.
Patients will be required to swallow 8, 5mg capsules for a total dose of 40 mg MLN0128 on 
Cycle 1, Day 1.  To mitigate nausea and vomiting known to occur at a 40 mg dose of 
MLN0128, patients will be administered an antiemetic agent (0.25 mg palonosetron), on 
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Cycle 1, Day 1, as an intravenous infusion over 30 seconds, at least 30 minutes before study 
drug administration.
Palonosetron is a commercially available drug; instructions are provided in the 
manufacturer’s package insert.(12)
After Cycle 1, Day 3
After completing the required PK/ECG assessment period (Cycle 1, Day 3), patients may 
continue treatment with MLN0128 at the discretion of the investigator at a dose of 
MLN0128 30 mg QW.  If patients experience severe emesis or mucositis preventing them 
from taking an MLN0128 dose, that dose will be skipped.  If emesis occurs after study 
medication ingestion and whole capsule(s) are visible in the vomitus, replacement capsule(s) 
should be taken; otherwise the dose will not be re-administered, and patients should 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 cards (see the 
Study Manual).  Under no circumstance should a patient repeat a dose or double-up doses.  
Patients should be instructed to take their study medication at approximately the same time 
each week and not to take more than the prescribed dose at any time.  Patients should 
swallow the study medication whole and not chew it, open it, or manipulate it in any way 
before swallowing.  In the event, that, a patient fails to take the MLN0128 dose within the 
time frame specified (± 12 hours), that dose should be skipped.  Patients should record any 
skipped doses in their dosing diary cards (see the Study Manual) and resume dosing at the 
next scheduled time with the prescribed dosage.
Starting at Cycle 1, Day 8, patients are advised to take their doses of study drug with a light 
meal.
6.2   
Reference/Control Therapy
No reference or placebo treatment will be used in this study.  All patients will receive 
treatment with MLN0128.
6.3   
Definitions of Dose-Limiting Toxicity 
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 14 June 
2010.(13)  These criteria are provided in the Study Manual.  DLT 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:
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
Grade 3 or higher nonhematologic toxicity, despite adequate treatment, except for 
the following:
o
Grade 3 hyperglycemia lasting ≤ 14 days (all patients should receive optimal 
antiglycemic treatment, including insulin).
o
Grade 3 rash lasting ≤ 3 days (all patients should receive topical steroid 
treatment, oral antihistamines, and oral steroids, if necessary).

Grade 4 neutropenia lasting > 7 days in the absence of growth factor support.

Grade 4 neutropenia of any duration accompanied by fever ≥ 38.5°C and/or systemic 
infection.

Any other ≥ Grade 4 hematologic toxicity.

Inability to administer at least 75% of planned doses of study drug within Cycle 1 
due to treatment-related toxicity or delay in the initiation of the subsequent cycle of 
therapy by more than 14 days due to treatment-related toxicity (lack of adequate 
recovery of treatment-related hematological or nonhematological toxicities).

Any clinically significant occurrence that the investigator and sponsor agree would 
place patients at an undue safety risk.
6.4   
Dose-Modification Guidelines
MLN0128 is administered QW in continuous cycles of 28 days.  Study drug should be 
administered continuously unless a ≥ Grade 3 MLN0128-related event occurs.
For management of toxicity for individual patients, dose adjustments may include 
interruption of treatment with study drug and a dose reduction.  If continued treatment with 
MLN0128 is thought to be beneficial by the investigator, and with the sponsor’s approval, 
dose reductions should be based on the guidelines provided below and in Table 6-1.  
Patients whose dose is reduced will not be allowed to re-escalate.
Dosing should be interrupted for ≥ Grade 3 MLN0128-related toxicities.  If the event 
resolves to Grade 1 or baseline values within 14 days of interrupting treatment, depending 
on the severity of the toxicities, the patient may resume study drug as follows:

Resume study treatment at 30 mg QW dose, or
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
Resume study treatment at 20 mg QW (33% reduction)
If the toxicity recurs at the 20 mg QW dose, dosing should be interrupted.  If the event 
resolves to Grade 1 or baseline values within 14 days of interrupting treatment, depending 
on the severity of the toxicity, the patient may resume study drug as follows:

Resume study treatment at 20 mg QW, or

Resume study treatment at 15 mg QW (25% dose reduction)
The sponsor’s project clinician should be contacted before any dose modification of 
MLN0128 for any patient in the study.
Table 6-1   
Dose Reduction Schedule for MLN0128
Dose Level
Percent Reduction
Dose
0
0%
30 mg QW
-1
33%
20 mg QW
-2
25%
15 mg QW
Abbreviation:  QW = once weekly.
6.4.1   
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
MLN0128 is administered in continuous cycles; therefore, study drug should be 
administered continuously unless a Grade 3 MLN0128-related event occurs.  Patients who 
experience an AE meeting the definition for a DLT after Cycle 1, Day 3 should have their 
study drug treatment interrupted and reduced as outlined in Section 6.4.
6.4.2   
Criteria for Dose Interruption During a Cycle
See Section 6.4 for dose modification guidelines.
6.4.3   
Criteria for Dose Reduction
See Section 6.4 for dose modification guidelines.
6.4.4   
Criteria for Discontinuation
Grade 4 nonhematologic toxicities will in general require that treatment with MLN0128 be 
permanently discontinued.  If, in the opinion of the investigator and the project clinician, it 
is in the best interest of the patient to continue treatment with MLN0128, then the dose of 
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MLN0128 should be reduced by at least 1 dose level after recovery of the toxicity and/or 
intolerability to Grade 1 or to baseline values.
If dosing is delayed for > 14 consecutive days for MLN0128-related toxicities despite 
supportive treatment per standard clinical practice, or more than 2 dose reductions of 
MLN0128 are required for a patient, treatment should be stopped, the patient discontinued 
from the study, and the follow-up visit completed within 30 days of the last dose of 
MLN0128.
6.5   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

During the required PK/ECG assessment period (Cycle 1, Day 3), QT-prolonging 
drugs with a risk of causing TdP are prohibited.  Patients on a stable dose of drugs 
with a conditional or possible risk of QT prolongation may be considered. (see 
Section 14.5).

Radiation therapy for disease under study.

Any investigational agent other than MLN0128 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 intravenous [IV] or oral steroids, excluding 
inhalers), unless necessary for treatment of an MLN0128-related AE (eg, rash).

Anti-epileptic drugs for patients with a history of treated brain metastasis.

Anti-emetic agents (eg, 5-HT3 receptor antagonists) associated with a risk for QT 
prolongation, including ondansetron and granisetron.  After completing the required 
PK/ECG assessment period (Cycle 1, Day 3), treatment with granisetron is permitted 
according to standard of care.

PPIs; examples of PPIs include:  omeprazole, esomeprazole, lansoprazole, and 
pantoprazole.
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
Strong cytochrome P450 (CYP) 1A2 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.
6.6   
Permitted Concomitant Medications and Procedures
Restricted use of H2-receptor antagonists or neutralizing antacids is permitted after 
completion of the required PK/ECG assessments on Cycle 1, Day 3, for patients continuing 
to receive treatment with MLN0128, under the following conditions:

Treatment with H2-receptor antagonist is not permitted less than 24 hours before and 
within 6 hours after receiving a dose of MLN0128.  Examples of H2-receptor 
antagonist include:  ranitidine, cimetidine, and nizatidine.  

Treatment with neutralizing antacids is not permitted less than 4 hours before and 
within 6 hours after receiving a dose of MLN0128.
Other medications considered necessary for the safety and well-being of the patient may be 
administered at the discretion of the investigator.  Any concomitant medications added or 
discontinued during the study should be recorded on the electronic case report form (eCRF).
6.7   
Precautions and Restrictions 
Dietary restrictions include periods of fasting as described in Section 7.4.16, and in-home 
daily fasting glucose monitoring (refer to Section 7.4.18).
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, female patients participating in this study should avoid 
becoming pregnant, and male patients should avoid impregnating a female partner.  Non-
sterilized female patients of reproductive age group and male patients 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
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
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 
3 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] 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 3 months after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner] and withdrawal are not acceptable 
methods of contraception.)
6.8   
Management of Clinical Events
6.8.1   
Management of Nausea and/or Vomiting
This study will employ prophylactic anti-emetic on Cycle 1, Day 1.  
For patients remaining in the study after completing the required PK/ECG assessment period 
(Cycle 1, Day 3), guidance for the management of nausea and/or vomiting is provided in 
Table 6-2.
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Table 6-2   
Management of Nausea and/or Vomiting
Grade
Description
Treatment
MLN0128 Dose Modification
2
Loss of appetite with or 
without decreased oral 
intake; 1-5 episodes of 
vomiting within 24 hours
Maximize 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; IVF = intravenous fluids; TPN = total parenteral nutrition.
6.8.2   
Management of Hyperglycemia
In addition to obtaining fasting glucose levels at the clinic visits as outlined in the Schedule 
of Events, all patients will be provided with a glucometer and trained to use it to monitor 
their daily predose FBG levels at home.  Patients will be instructed to notify the study staff 
immediately of any abnormal readings (ie, ≥150 mg/dL) for further instructions on the 
management of their hyperglycemia.  Hyperglycemia observed during home glucose 
monitoring should be confirmed in the clinic.  Investigators will be responsible for 
reviewing the home glucose monitoring logs for hyperglycemia.  If no irregularities in the 
FBG level are observed during a minimum of 6 consecutive months, then the frequency of 
in-home fasting glucose testing may be reduced to twice weekly if the investigator approves.  
Patients will continue to notify the investigator of FBG levels ≥150 mg/dL, and if blood 
glucose levels are not well controlled, or if they require either oral hypoglycemic agents or 
insulin to control blood glucose levels, then the frequency of in-home testing of FBG levels 
will be reinstated to daily.  Guidelines for management of hyperglycemia are presented in 
Table 6-3.
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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 by 20%

2 weeks:  stop MLN0128 and 
discontinue patient from the study
Prevention/Prophylaxis

Follow fasting glucose levels during clinic visits.

Monitor home glucometer test results.

Check HbA1c levels every 3 months during therapy.

Recommend lifestyle modifications, as appropriate (balanced diet, limited alcohol consumption, 
increased physical activity).

Most episodes of Grade 1 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 glucose reading performed at the site indicates hyperglycemia (fasting glucose 
> 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. 
Based on the clinical experience in MLN0128 trials, most episodes of hyperglycemia 
observed have been Grade 1 or Grade 2 and have responded quickly to oral metformin.  
Hyperglycemia has not been dose-limiting since instituting a standard regimen for early 
treatment of hyperglycemia.  All patients developing hyperglycemia on the study should 
have their glucose closely monitored by study staff.  The investigator may choose either to 
continue close monitoring of patients who develop Grade 1 hyperglycemia (fasting glucose 
> ULN ≤160 mg/dL) or consider initiating treatment with an oral hypoglycemic agent, such 
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as metformin.  All patients with ≥ Grade 2 hyperglycemia (fasting glucose > 160 mg/dL) 
must be treated aggressively with oral hypoglycemic agents and/or insulin as clinically 
indicated while continuing on MLN0128 treatment.  The investigator should consult an 
endocrinologist if needed to aid in optimizing the hyperglycemia treatment plan of the 
patient.
It is recommended that patients be treated initially with a fast-acting insulin sensitizer, such 
as metformin at 500 mg orally QD, and titrate up to a maximum of 1000 mg orally twice 
daily as needed.  Concurrent addition to metformin of dipeptidyl peptidase-4 inhibitors (eg, 
sitagliptin or vildagliptin) and/or insulin should also be considered.  Oral sulfonylureas (eg, 
glipizide or glyburide) should be used with caution due to the higher risk of inducing 
hypoglycemia in patients.  The dose of oral hypoglycemic agents should be adjusted in 
patients with renal insufficiency.
6.8.3   
Management of Hyperlipidemia
Guidance on study drug dose modification for patients with hyperlipidemia is provided in 
Table 6-4.
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 due to 
risk of pancreatitis.
Maintain dose if tolerable.  If 
toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤ Grade 1.  Reinitiate 
at same dose.
3
Cholesterol:
> 400-500 mg/dL
Triglycerides:
> 500-1000 mg/dL
Same as for Grade 2
Hold dose until recovery to 
≤Grade 1, then restart with a 20% 
dose reduction.
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).
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Table 6-4   
Management of Hyperlipidemia
Grade
Description
Treatment
MLN0128 Dose Modification
Abbreviation:  ULN = upper limit of normal.
6.8.4   
Management of Oral Mucositis
Guidance for the management of oral mucositis is provided in Table 6-5.
Table 6-5   
Management of Oral Mucositis
Grade
Description
Treatment
MLN0128 Dose Modification
1
Asymptomatic or mild 
symptoms 
Nonalcoholic mouth wash or 
0.9% salt water rinse; consider 
topical corticosteroids at earliest 
signs of mucositis.
None
2
Moderate pain not 
interfering with oral 
intake; modified diet 
indicated 
Topical analgesic mouth 
treatments; topical 
corticosteroids; initiate antiviral 
or antifungal therapy, if indicated.
Maintain dose if tolerable.  If toxicity 
becomes intolerable, interrupt 
MLN0128 dosing until recovery to 
≤Grade 1.  Reinitiate at same dose.
3
Severe pain interfering 
with oral intake
Same as for Grade 2; consider 
intralesional corticosteroids.
Hold dose until recovery to ≤Grade 
1, then restart with a 20% dose 
reduction.
4
Life-threatening 
consequences 
Same as for Grade 2; consider 
intralesional corticosteroids.
Discontinue treatment.
Prevention/Prophylaxis

Consider initiation of a nonalcoholic mouth wash or 0.9% salt water rinses 4-6 times daily with start of 
therapy before signs of mucositis develop.

Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis as they may worsen mouth ulcers.
6.8.5   
Management of Rash
Guidance for management of rash is provided in Table 6-6.
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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 dose by 20%
> 2 weeks:  stop MLN0128 and 
discontinue patient from the study 
6.8.6   
Blinding and Unblinding
This is an open-label study.
6.9   
Description of Investigational Agents
MLN0128 will be supplied as capsules for oral administration.  A dose strength containing 
5 mg of MLN0128, in addition to the following inactive ingredients:  microcrystalline 
cellulose (solid filler/diluents), magnesium stearate (lubricant), and hard gelatin capsule, will 
be used in this study.  The 5 mg dose strength is formulated into size 2 capsules and is a 
gray, opaque color. 
Refer to the MLN0128 IB for full details.
Palonosetron is a commercially available drug.(12)
6.10   
Preparation, Reconstitution, and Dispensation
MLN0128 study drug will be provided in 60-cc high-density polypropylene (HDPE) bottles 
with child-resistant caps and induction seal.  Study drug will be dispensed with dosing 
instructions for home use, including the requirement that capsules are stored in their original 
containers and that capsules be swallowed whole and not opened, chewed, or manipulated in 
any way.  Materials provided by the sponsor should be dispensed to patients with clear 
administration instructions from the investigator.  
MLN0128 is an anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling MLN0128 capsules.
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6.11   
Packaging and Labeling
MLN0128 study drug will be provided by Millennium and will be handled at the 
investigative site as open-label material.  MLN0128 capsules are packaged in 60-cc HDPE
bottles with child-resistant caps and induction seal.  Each bottle contains 30 capsules and 
will have a label containing pertinent study information, country-specific requirements, and 
a caution statement.
6.12   
Storage, Handling, and Accountability
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 to 86F).  All 
temperature excursions will be reported to the sponsor for assessment and authorization for 
continued use.  All investigational supplies must be stored in a secure area with controlled 
access.  All MLN0128 should be used before the shelf-life date.
A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the patients, will be provided and kept at the study site.  Storage area 
temperature conditions must be monitored and recorded daily.  A daily temperature log will 
also be kept at the study site.
Because MLN0128 is an investigational agent, it should be handled with due care.  In case 
of contact with broken capsules, raising dust should be avoided during the clean-up 
operation.  The product may be harmful if inhaled, ingested, or absorbed through the skin.  
Gloves and protective clothing should be worn during the clean-up operation.  The area 
should be ventilated and the spill site washed after material pick-up is complete.  The spilled 
material should be disposed of as hazardous medical waste in compliance with federal, state, 
and local regulations. In case of contact with the powder (eg, from a broken capsule), skin 
should be washed immediately with soap and copious amounts of water for at least 
15 minutes.  In case of contact with the eyes, copious amounts of water should be used to 
flush the eyes for at least 15 minutes.  Medical personnel should be notified.
Patients will receive instructions for home storage and administration of MLN0128.  
Patients will also receive diary cards to record dosing compliance of MLN0128 and 
instructions for their completion. 
Patients will be instructed to return any unused study drug in the original packaging along 
with their completed diary cards at the appropriate visits.
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Please refer to the Study Manual for additional instructions.
Palonosetron should be stored according to instructions provided in the manufacturer’s 
package insert.(12)
7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
7.1   
Study Personnel and Organizations
The contact information for the Millennium Study Monitor for this study, the local 
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 
This is a single-dose, open label study.
7.4   
Study Procedures
Refer to the Schedule of Events for timing of assessments.  Additional details are provided 
as necessary in the sections that follow.
7.4.1   
Informed Consent
Each patient must provide written informed consent (IC) before any study-required 
procedures are conducted, unless those procedures are performed as part of the patient’s 
standard care.  
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7.4.2   
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
7.4.3   
Medical History
During the Screening period, a complete medical history will be compiled for each patient.   
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for it.  In addition, concomitant medications will be 
recorded as specified in Section 7.4.10. 
7.4.4   
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.  
7.4.5   
Patient Height and Weight
Height will be measured only during screening only.  Weight will be measured at the time 
points specified in the Schedule of Events.
7.4.6   
Vital Signs 
Vital sign measurements include supine (after 3-5 minutes in this position) measurements of 
diastolic and systolic blood pressure, heart rate, and oral temperature.  When the timing of 
vital sign measurements coincides with the timing of a blood sample (eg, for PK), the vital 
sign measurements should be completed before the blood sample.
7.4.7   
Pregnancy Test
A serum pregnancy test will be completed as specified in the Schedule of Events by all 
women of childbearing potential; this test must be negative for the patient to be enrolled.  
Pregnancy tests may also be repeated during the study if requested by an IEC/IRB or if 
required by local regulations.
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 Schedule of Events.
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7.4.9   
Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan or ECHO will be administered at the time points specified in the Schedule of 
Events.
7.4.10   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will 
recorded in the eCRF throughout the study as specified in the Schedule of Events.  See 
Section 6.5 and Section 6.6 for a list of medications and therapies that are prohibited and/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 Schedule of Events.  Refer to Section 9 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.  
7.4.12   
Enrollment
A patient is considered to be enrolled in the study when the first dose of MLN0128 is 
administered.  Procedures for completion of the enrollment information are described in the 
Study Manual.
7.4.13   
Electrocardiogram
There are 2 types of ECGs acquired in this study:  single, 12-lead safety ECGs and triplicate, 
12-lead Holter monitoring.  All ECGs will be administered at the time points specified in the 
Schedule of Events.
7.4.13.1   Single, 12-Lead Safety Electrocardiograms
The first type of ECG acquired for this study consists of ECG tracings that are acquired 
using a standard 12-lead digital ECG machine.  These tracings will be reviewed by the 
investigator or trained designee at the study center.  The ECG printout of parameters 
including PR, QRS, QT, QTcB, and QTcF intervals is acceptable for purposes of safety 
before dosing.  All machine-generated tracings should be acquired in the supine position 
after the patient has been resting for 5 minutes.  These ECGs are not included in the final QT 
analysis of this study.
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7.4.13.2   Serial, Triplicate, 12-Lead Holter Monitoring Electrocardiograms
The study ECGs that are included in the final statistical analysis will be acquired from the 
12-lead continuous ECG (Holter) recorders using the H-12 Plus ambulatory 
electrocardiograph recorder (Mortara Instruments, Milwaukee, WI), with high-frequency 
flashcards at a sampling rate of 1000 samples per second.
On Screening; Day -1, Holter ECG monitoring (0-10 hours) will be performed for baseline 
measurements.  Three serial triplicate ECGs will be extracted at prespecified time points at 
times that match the times of Cycle 1, Day 1 postdose PK/ECG sampling.
As the Screening; Day -1 baseline evaluations are intended to serve as a time-matched 
baseline for corresponding Cycle 1, Day 1 ECG evaluations, it is critical to ensure that the 
0-hour time point on Screening; Day -1 is timed to coincide with the clock time of the time 
of dosing of MLN0128 on Cycle 1, Day 1 (which will be considered the 0-hour time point 
on Cycle 1, Day 1). 
Before each nominal ECG time point, the patient must have been supine in bed for 
5 minutes.  The triplicate ECGs will be extracted at approximately 2- to 5-minute intervals 
over a10-minute period following the rest period (the ECG extraction 15-minute window, 
ending at the nominal time point).  Blood samples for PK analysis will be obtained 
immediately following the completion of the ECG extractions.  
Additionally, patients will undergo Holter ECG monitoring on Cycle 1, Day 1 as described 
on Cycle 1, Day 1, and triplicate ECGs will be extracted at the matched PK time points over 
the steady-state dosing interval to contribute to analysis of the effect of steady-state 
concentrations of MLN0128 on QT/QTc intervals.  
The 12-lead ECGs are extracted in triplicate, free from artifact, wandering, and at a time that 
the heart rate has been stabilized.  All QT intervals will be measured using representative 
beats in the superimposed 12-lead “global” display.  The measurement of QT, RR, PR, and 
QRS intervals are initiated in the semi-automatic mode and then adjusted appropriately by 
cardiovascular physicians; thereby, they are visually validated or manually adjusted and 
diagnostic findings are determined.  The cardiovascular physicians are assigned in a subject-
specific manner.
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7.4.14   
Disease Assessment
For patients remaining in the study after completing the required PK/ECG assessment period 
(Cycle 1, Day 3), CT with contrast as appropriate, MRI, X-ray, and/or bone scanning may 
be performed at the investigator’s discretion as clinically indicated, according to standard of 
care.  Assessments will be performed at the time points specified in the Schedule of Events.  
Radiographic images will be maintained at the site, and test results and physician’s findings 
will be filed in patient source documents.
7.4.15   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally.  Clinical laboratory evaluations 
will be performed as outlined below:
Clinical Chemistry, Hematology, and Urinalysis
Clinical chemistry, hematology, and urinalysis laboratory evaluations must be available and 
reviewed by the investigator before enrollment and initial administration of MLN0128.
Blood samples for analysis of the following clinical chemistry and hematological 
parameters, urine samples for urinalysis, and prospective monitoring for hyperlipidemia 
through fasting lipid testing will be obtained as specified in the Schedule of Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])
Serum Chemistry

Blood urea 
nitrogen (BUN)

Creatinine

Bilirubin (total)

Urate

Lactate 
dehydrogenase 
(LDH)

Gamma glutamyl 
transferase (GGT)

Phosphate

Albumin

Alkaline phosphatase 
(ALP)

Aspartate 
aminotransferase (AST)

Alanine 
aminotransferase (ALT)

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon dioxide 
(CO2)

Magnesium

Glycosylated 
hemoglobin 
(HbA1c) – at the 
times specified in 
the Schedule of 
Events
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Urinalysis

Turbidity and Color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult Blood

Nitrite

Urobilinogen

Glucose

Leukocytes
Fasting Lipid Profile

Total cholesterol

Triglycerides

High-density 
lipoprotein 
cholesterol (HDL-C)

Low-density 
lipoprotein 
cholesterol 
(LDL-C)
7.4.16   
Requirements for Fasting Periods
On Screening; Day -1 and Cycle 1, Day 1, patients will be given the option to report to the 
site fasted or after having a light morning meal, as long as the meal has been completed at 
least 2 hours before the scheduled baseline triplicate ECG on each day.  If patients report to 
the site fasted, they should do so with adequate time (approximately 3 hours before the 
scheduled baseline triplicate ECG) in order to eat standard, light breakfast provided by the 
site that must be completed at least 2 hours before the scheduled baseline triplicate ECG on 
each day.  Patients will be instructed not to eat for the next 6 hours (ie, 2 hours before the 
0-hour, predose time point and until completion of the collection of the 4-hour postdose 
PK/ECG assessments).  A standard, light lunch will be provided.  Light meals will be 
administered at the same times on Screening; Day -1 and Cycle 1, Day 1.  
On Cycle 1, Day 2 and Cycle 1, Day 3, patients may eat and drink up to approximately 
2 hours before arriving at the study site for PK/ECG evaluations; see Section 7.4.19 and 
Section 7.4.13.2.  
Beginning with Cycle 1, Day 4, patients will be instructed to fast overnight (nothing except 
water and/or medications after midnight or for a minimum of 8 hours) for daily glucose 
monitoring; see Section 7.4.17 and Section 7.4.18.  Starting with Cycle 1, Day 8, patients 
are advised to take their doses of study drug with a light meal.
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7.4.17   
Fasting Glucose
Fasting glucose will be measured at the time points specified in the Schedule of Events
before administration of MLN0128.  Patients are required to fast overnight (nothing except 
water and/or medications after midnight or for a minimum of 8 hours) for each of these 
measurements beginning on Cycle 1, Day 4; see Section 7.4.16.
7.4.18   
In-Home Daily Fasting Glucose Monitoring
Patients will be instructed to complete daily glucose monitoring at home after fasting 
overnight (nothing except water and/or medications after midnight or for a minimum of 
8 hours) for each of these measurements beginning on Cycle 1, Day 4; see Section 7.4.16 for 
fasting requirements.  Patients will be instructed to bring the glucometer with them to each 
study visit so that the data collected can be reviewed and recorded into source documents.  
Based on investigator judgment and upon the 6 consecutive months of well-controlled blood 
glucose levels, the frequency of in-home fasting glucose testing may be reduced to twice 
weekly.  During this period of reduced monitoring, patients will continue to notify the 
investigator of fasting blood glucose levels that exceed 150 mg/dL.  If blood glucose levels 
are not well controlled at any time during the study, or if the patient requires either oral 
hypoglycemic agents or insulin to control blood glucose levels, in-home testing of fasting 
blood glucose 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.
7.4.19   
Pharmacokinetic Measurements
During Cycle 1, serial blood samples for PK analysis of MLN0128 will be collected over a 
3-day period (0-48 hours) at the time points specified in the Schedule of Events.  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.
There is no protocol-specified PK sampling after Cycle 1.  
7.5   
Completion of Treatment/Completion of Study
Patients will be considered to have completed the study if they discontinue 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 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 EOS visit will 
be completed as specified in the Schedule of Events.  The primary reason for study drug 
discontinuation will be recorded on the eCRF.
If a patient is deemed not evaluable by the sponsor, the postdose Cycle 1, Day 1 Holter ECG 
monitoring and PK sampling procedures need not be performed, since the patient would 
need to be replaced for the purposes of the PK/QTc objective of the protocol.  
Patients who are withdrawn from treatment before completing study-required PK/ECG 
assessments for reasons other than DLT will be replaced.  The consequence of study 
withdrawal is that no new information will be collected from the withdrawn patient and 
added to the existing data or any database.
7.7   
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 
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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.  Separate analysis plans will be developed for 
ECG data derived from the triplicate, 12-lead Holter monitoring and for PK/QTc modeling.
8.1.1   
Determination of Sample Size
Based on historical data, the within-subject standard deviation in QTcF change from 
baseline is approximately 9 msec.  A sample size of 30 evaluable patients will provide a 
half-width of a 2-sided 90% confidence interval for the mean change from baseline in QTcF 
of 2.7 msec.
8.1.2   
Randomization and Stratification  
No randomization is planned for this study.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:

Safety population:  patients who receive at least 1 dose of MLN0128 will be used for 
all safety analyses, as well as efficacy analyses.

PK population:  patients who receive at least 1 dose of MLN0128 and have sufficient 
concentration-time data to calculate one or more PK parameters.

ECG population:  patients who receive at least 1 dose of MLN0128 and have at least 
1 post-baseline ECG on Cycle 1, Day 1 will be used for all analyses of ECGs.
8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations.  No 
imputation of values for missing data will be performed.  Data that are potentially spurious 
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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, primary diagnosis, and other parameters as appropriate.  No inferential 
statistics will be carried out.
8.1.6   
Efficacy Analysis
Investigator assessment of response will be provided in a data listing. 
8.1.7   
Electrocardiogram Analysis
Determination of QTcI
The QTcI will be based on the slope (exponent) of the QT-RR relationship derived from the 
acquisition of QT intervals from a 24-hour Holter recording on Screening; Day -1 (baseline) 
for each patient.  The patient-specific, individual correction is an improvement over the 
fixed formulas commonly deployed.  The patient-specific slope will be calculated using all 
pairs of QT and RR interval data on Screening; Day -1 separately for each patient.  The 
linear regression:  log (QT) = log (a) + b*log (RR) will be used to calculate the individual 
slope (b) for each patient.  The QTcI will be calculated as:  QTcI = QT/RRb.
Electrocardiogram Analysis
The primary analysis of ECG parameters from the 24-hour Holter recordings will be based 
on a repeated measures mixed effects linear model.  Mean changes (adjusted) and 1-sided 
95% upper confidence bounds in QTcI, QTcF, QTcB, and heart rate will be generated for 
each of the time-matched changes from baseline.  Descriptive statistics for the actual values 
of ECG intervals (QTcI, QTcF, QTcB, PR interval, RR interval, QRS duration) and heart 
rate will be tabulated by scheduled time point.
The following categorical analyses of QTc intervals (QTcI and QTcF), PR interval, and 
QRS duration will be performed at each scheduled time point and on the maximum value for 
each patient:

QTc interval > 450 msec

QTc interval > 480 msec
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
QTc interval > 500 msec

QTc interval increases from baseline > 30 msec 

QTc interval increases from baseline > 60 msec 

QRS interval > 110 msec and 25% increase from baseline 

PR interval > 200 msec and 25% increase from baseline
New ECG morphologies, not present at Screening; Day -1 (baseline), will be summarized.
8.1.8   
Pharmacokinetics
Pharmacokinetic Analysis
Individual and mean plasma concentration data will be plotted over time.  Descriptive 
statistics will be presented for plasma PK parameters including, but not limited to, Cmax, 
Tmax, AUCt, AUCinf, and t1/2.  Individual and mean MLN0128 plasma concentration-time 
data will be plotted.
PK/QTc Analysis
The relationship between plasma MLN0128 concentration and effects on heart rate and 
QTcI/QTcF will be analyzed using nonlinear mixed effects modeling.  It is expected that the 
relationship between plasma MLN0128 concentrations and change from time-matched 
baseline values of QTc will be described using a direct linear concentration-effect 
relationship; however, the selection of the final model and mathematical form of the 
concentration-effect relationship will be based on graphical assessment of the data (eg, 
visual examination of observed concentration-effect plots to rule out a hysteresis secondary 
to time-delayed effects on QTc) and exploration of alternate structural models (eg, 
maximum effect attributed to the drug [Emax] models).  The final model will be used to 
predict the population average change in QTc and its corresponding 1-sided 95% upper 
confidence bounds in the mean steady-state Cmax of MLN0128 after a single dose of 40 mg 
MLN0128.  A separate PK/QTc analysis plan will be developed and the results of these 
PK/QTc modeling analyses will be reported separately.
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8.1.9   
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
safety population.  Exposure to study drug and reasons for discontinuation will be tabulated.
TEAEs that occur after administration of the first dose of study drug and through 30 days 
after the last dose of study drug will be tabulated.  
AEs will be tabulated according to the Medical Dictionary for Regulatory Activities 
(MedDRA) and will include the following categories: 

TEAEs

Drug-related TEAEs

Grade 3 or higher TEAEs

Grade 3 or higher drug-related TEAEs

The most commonly reported TEAEs

SAEs
A listing of TEAEs resulting in study drug discontinuation will be provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change 
from baseline in clinical laboratory parameters) will be presented for all scheduled 
measurements over time.  Mean laboratory values over time will be plotted for key 
laboratory parameters.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs 
and weight over time will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE 
grade from baseline to the worst postbaseline value.  Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst postbaseline values, may be used 
to understand the MLN0128 safety profile.
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All concomitant medications collected from screening through the study period will be 
classified to preferred terms according to the World Health Organization (WHO) drug 
dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of MLN0128.
8.1.10   
Interim Analysis
Not applicable.
8.2   
Pharmacokinetic Modeling
Refer to Section 8.1.8.
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
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.  
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9.1.3   
Serious Adverse Event Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 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.(13)  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 
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function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell (WBC) count of 1000/mm3 to less than 2000 is considered 
Grade 3 (severe) but may not be considered serious.  Seriousness (not intensity) serves as a 
guide for defining regulatory reporting obligations.
9.2   
Procedures for Recording and Reporting 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.
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
Cognizant
US and Canada
Fax:  1-800-963-6290
Email: TakedaOncoCases@cognizant.com
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 
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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.(13)  The criteria are provided in the 
Study Manual.
Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question:  Is there a reasonable possibility that the AE is associated with the 
study drug?
9.3   
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from the first dose of 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.
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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.
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.
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The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible.  The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Millennium, or a designee, will retain the eCRF data and corresponding audit trails.  A copy 
of the final archival eCRF in the form of a compact disk or other electronic media will be 
placed in the investigator’s study file.
10.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation. During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory 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.
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10.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
10.8   
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies).  Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium.  Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients.  Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
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.
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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 MedComm 
Solutions (see below) and report the event.  Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance 
from a Millennium Quality representative.
For Product Complaints,
call MedComm Solutions at
877-674-3784 (877 MPI DRUG)
(US and International)
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed according to the procedures outlined in 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, and/or unevaluable data

Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
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event that any access devices for the EDC application have been provided, these will be 
returned to Millennium once the site’s participation in the study has concluded.
10.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.  
11.   
USE OF INFORMATION
All information regarding MLN0128 supplied by Millennium to the investigator is 
privileged and confidential information.  The investigator agrees to use this information to 
accomplish the study and will not use it for other purposes without consent from 
Millennium.  It is understood that there is an obligation to provide Millennium with 
complete data obtained during the study.  The information obtained from the clinical study 
will be used toward the development of MLN0128 and may be disclosed to regulatory 
authority(ies), other investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.
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12.   
INVESTIGATOR AGREEMENT
I have read Protocol C31002 Amendment 2:  A Phase 1 Study to Evaluate the Effect of 
MLN0128 on the QTc Interval in Patients With Advanced Solid Tumors, 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.   
REFERENCES
1.
Laplante M, Sabatini DM. mTOR Signaling. Cold Spring Harb Perspect Biol 
2012;4(2).
2.
Laplante M, Sabatini, DM. mTOR Signaling in Growth Control and Disease. Cell 
2012;149(2):274-93.
3.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nature 
Reviews. Cancer 2006;6(9):729-34.
4.
Benjamin D, Colombi M, Moroni C, Hall MN. Rapamycin passes the torch: a new 
generation of mTOR inhibitors. Nature Reviews. Drug Discovery 2011;10(11):868-
80.
5.
Vilar E, Perez-Garcia J, Tabernero J. Pushing the envelope in the mTOR pathway: 
the second generation of inhibitors. Molecular Cancer Therapeutics 2011;10(3):395-
403.
6.
Thoreen CC, Kang SA, Chang JW, Liu Q, Zhang J, Gao Y, et al. An ATP-
competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant 
functions of mTORC1. Journal of Biological Chemistry 2009;284(12):8023-32.
7.
Chresta CM, Davies BR, Hickson I, Harding T, Cosulich S, Critchlow SE, et al. 
AZD8055 is a potent, selective, and orally bioavailable ATP-competitive 
mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor 
activity. Cancer Research 2010;70(1):288-98.
8.
Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, 
Moskatel E, et al. mTOR kinase inhibition causes feedback-dependent biphasic 
regulation of AKT signaling. Cancer Discov 2011;1(3):248-59.
9.
O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR Inhibition 
Induces Upstream Receptor Tyrosine Kinase Signaling and Activates Akt. Cancer 
Res 2006;66(3):1500-8.
10.
Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, et al. Dose- and 
schedule-dependent inhibition of the mammalian target of rapamycin pathway with 
everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid 
tumors. J Clin Oncol 2008;26(10):1603-10.
11.
De P, Sun Y, Wu H, Rommel C, Yi L, Dey N, et al. Pre-clinical potency of INK128, 
a highly potent TORC1/2 kinase inhibitor in the HER2 amplified breast cancer 
model. Cancer Research 2012;72(Abstract 2240).
12.
ALOXI® (palonosetron HCl) injection for Intravenous Use [package insert]. 
Switzerland: Helsinn Healthcare SA; 2009.
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13.
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.
14.
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.
15.
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.
16.
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.
17.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
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14.   
APPENDICES
14.1  
Eastern Cooperative Oncology Group Scale for Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours.
3
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair
5
Dead
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.(15)
14.2   
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations 
of physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  
If any physical activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels.  9th Ed.  Boston, MA:  Little, Brown & Co; 1994:253-256.(16)
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14.3   
Cockcroft-Gault Equation
Creatinine Clearance  =
0.85 (140 - age [years]) weight [kg]
72 (serum creatinine [mg/dL])
OR
0.85 (140 - age [years]) weight [kg]
0.81 (serum creatinine [µmol/L])
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.(17)
14.4   
List of Relevant Cytochrome P450 Inhibitors and Inducers
Moderate CYP1A2 Inhibitors
cimetidine
methoxsalen 
Strong CYP1A2 Inhibitors
fluvoxamine
ciprofloxacin
Clinically Significant Enzyme Inducers
carbamazepine
rifabutin
St. John’s wort
phenobarbital
rifampin
phenytoin
rifapentine 
Source: fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm.
Note that these lists are not exhaustive.
14.5   
Exclusionary QT-Prolonging Drugs
The following table contains a list of QT-prolonging drugs according to the Arizona Center 
for Education and Research on Therapeutics.  QT-prolonging drugs with a risk of causing 
torsades de pointes (TdP) are exclusionary in this study.  Patients on a stable dose of drugs 
with a conditional or possible risk of QT prolongation or drugs that are to be avoided by 
patients with congenital long QT syndrome may be considered pending discussion and 
agreement with the project clinician.
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Exclusionary QT-Prolonging Drugs
Drug Class
Risk of TdPa
Name (Brand Name)
Conditional or Possible Risk of TdPb
Name (Brand Name)
Congenital QTc
Name (Brand Name)
Antianginal
ranolazine (Ranexa)
Antiarrhythmic
amiodarone (Cordarone, Pacerone)
bepridil (Vascor)
disopyramide (Norpace)
dofetilide (Tikosyn)
flecainide (Tambocor)
ibutilide (Corvert)
procainamide (Pronestyl, Procan)
quinidine (Cardioquin, Quinaglute)
sotalol (Betapace)
dronedarone (Multaq)
Antibiotic
azithromycin (Zithromax)
clarithromycin (Biaxin)
erythromycin (Erythrocin, EES)
moxifloxacin (Avelox)
pentamidine (NebuPent, Pentam)
sparfloxacin (Zagam)
ciprofloxacin (Cipro)
gatifloxacin (Tequin)
gemifloxacin (Factive)
levofloxacin (Levaquin)
ofloxacin (Floxin)
roxithromycin (Rulide)
telithromycin (Ketek)
trimethoprim-sulfa (Sulfa, Bactrim)
Anticancer
arsenic trioxide (Trisenox)
vandetanib (Caprelsaa)
Eribulin (Halaven)
lapatinib (Tykerb, Tyverb)
nilotinib (Tasigna)
sunitinib (Sutent)
Anticonvulsant/ Seizure
felbamate (Felbatrol)
fosphenytoin (Cerebyx)
Antidepressant
citalopram (Celexa)
amitriptyline (Elavil)
clomipramine (Anafranil)
desipramine (Pertofrane)
doxepin (Sinequan)
escitalopram (Lexapro, Cipralex)
fluoxetine (Prozac, Sarafem)
imipramine (Norfranil)
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Clinical Study Protocol C31002 Protocol Amendment 2
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Exclusionary QT-Prolonging Drugs
Drug Class
Risk of TdPa
Name (Brand Name)
Conditional or Possible Risk of TdPb
Name (Brand Name)
Congenital QTc
Name (Brand Name)
lithium (Eskalith, Lithobid)
nortriptyline (Pamelor)
paroxetine (Paxil)
protriptyline (Vivactil)
sertraline (Zoloft)
trazodone (Desyrel)
trimipramine (Surmontil)
venlafaxine (Effexor)
Antiemetic
domperidone (Motilium)
droperidol (Inapsine)
dolasetron (Anzemet)
granisetron (Kytril)
ondansetron (Zofran) 
tamoxifene (Nolvadex)
Antifungal
fluconazole (Diflucan)
itraconazole (Sporanox)
ketoconazole (Nizoral)
voriconazole (Vfend)
Antihistamine
astemizole (Hismanal)
terfenadine (Seldane)
diphenhydramine (Benadryl, Nytol)
Antihypertensive/
Diuretic
indapamide (Lozol)
isradipine (Dynacirc)
moexipril/HCTZ (Uniretic) 
nicardipine (Cardene)
Antilipemic/
Hypercholesterolemia
probucol (Lorelco)
Antimalarial
chloroquine (Aralen)
halofantrine (Halfan)
Antipsychotic
chlorpromazine (Thorazine)
haloperidol (Haldol)
mesoridazine (Serentil)
pimozide (Orap)
thioridazine (Mellaril)
amisulpride (Solian)
clozapine (Clozaril)
iloperidone (Fanapt)
paliperidone (Invega)
quetiapine (Seroquel)
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Exclusionary QT-Prolonging Drugs
Drug Class
Risk of TdPa
Name (Brand Name)
Conditional or Possible Risk of TdPb
Name (Brand Name)
Congenital QTc
Name (Brand Name)
risperidone (Risperdal)
sertindole (Serdolect, Serlect)
ziprasidone (Geodon)
Antiviral/
HIV infection
foscarnet (Foscavir)
Appetite suppressant/dieting, weight 
loss
fenfluramine (Pondimin)
phentermine (Adipex, Fastin)
sibutramine (Meridia)
Benign prostatic hyperplasia 
alfuzosin (Uroxatral)
ß2-receptor/asthma
albuterol (Proventil, Ventolin)
Bladder antispasmodic
Tolterodine (Detrol LA, Detrol)
Bronchodilator
ephedrine (Broncholate, 
Rynatuss)
levalbuterol (Xopenex)
metaproterenol (Alupent, 
Metaprel)
terbutaline (Brethine)
Catecholamine
epinephrine (Bronkaid, 
Primatene)
isoproterenol (Isupres, Medihaler-
Iso)
dobutamine (Dobutrex)
Cholinesterase inhibitor/
Dementia, Alzheimer's
galantamine (Reminyl)
CNS stimulant/ADHD
amphetamine (Adderall, 
Dexedrine)
dexmethylphenidate (Focalin)
lisdexamfetamine (Vyvanse)
methlphenidate (Concerta, 
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Clinical Study Protocol C31002 Protocol Amendment 2
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Exclusionary QT-Prolonging Drugs
Drug Class
Risk of TdPa
Name (Brand Name)
Conditional or Possible Risk of TdPb
Name (Brand Name)
Congenital QTc
Name (Brand Name)
Ritalin)
Decongestant/allergies, sinusitis, asthma
Phenylpropanolamine (Acutrim, 
Dexatrim)
pseudoephedrine (PediaCare, 
Sudafed)
Dopaminergic
amantadine (Symmetrel)
Endocrine
octreotide (Sandostatin)
Erectile dysfunction
vardenafil (Levitra)
GI stimulant/Heartburn
cisapride (Propulsid)
Imaging contrast agent/
Echocardiography
perflutren lipid microspheres (Definity)
Immunosuppressant
fingolimod (Gilenya)
tacrolimus (Prograf)
Inotropic agent/heart failure, 
hypotension, shock
dopamine (Intropine)
Local anesthetic
cocaine (Cocaine)
Muscarinic receptor anatagonist/
overactive bladder
solifenacin (VESIcare)
Muscle relaxant
tizanidine (Zanaflex)
Norepinephrine reuptake 
inhibitor/ADHD
atomoxetine (Strattera)
Opiate agonist
levomethadyl (Orlaam)
methadone (Dolophine, 
Methadose)
Oxytocic
oxytocin (Pitocin)
Peptic ulcer/GERD/
H2-receptor antagonist
famotidine (Pepcid)
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Clinical Study Protocol C31002 Protocol Amendment 2
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Exclusionary QT-Prolonging Drugs
Drug Class
Risk of TdPa
Name (Brand Name)
Conditional or Possible Risk of TdPb
Name (Brand Name)
Congenital QTc
Name (Brand Name)
Protease inhibitor/HIV
atazanavir (Reyataz)
ritonavir (Norvir)
Sedative
chloral hydrate (Noctec)
Sympathomimetic/asthma/ COPD
salmeterol (Serevent)
Uterine relaxant/prevent premature labor
ritodrine (Yutopar)
Vasoconstrictor, inotrope/shock, low 
blood pressure
norepinephrine (Levophed)
Vasoconstrictor, decongestant/ low 
blood pressure
phenylephrine (Neo-Synephrine)
midodrine (ProAmatine)
Source:  Based on Woosley RL.  Drugs That Prolong the QT Interval and/or Induce Torsades de Pointes. Arizona Center for Education and Research on 
Therapeutics.  azcert.org/medical-pros/drug-lists/printable-drug-list.cfm.  Last revised 24 June 2012.
Abbreviations:  ADHD = Attention deficit hyperactivity disorder; COPD = chronic obstructive pulmonary disorder; CNS = central nervous system; EES = 
erythromycin ethylsuccinate; GERD = gastroesophageal reflux disease; TdP = Torsades de Pointes.
Exclusions applicable only to listed drugs.  Names in parenthesis are United States trade names.  Drugs often have more than one brand name.  For this table, 
only the 2 most common brand names are included.
a Drugs that are generally accepted by authorities to have a risk of causing TdP.
b Drugs that may prolong the QT interval but at this time lack substantial evidence for causing TdP.
c Drugs to be avoided, if possible, by patients with Congenital Long QT Syndrome.
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14.6   
Amendment 2 Detailed Summary of Changes
The primary section(s) of the protocol affected by the changes in Amendment 2 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:
Deleted 
text:
16. Patients requiring treatment with strong CYP3A4 and CYP2C19 inducers 
and/or inhibitors and moderate inhibitors of CYP2C9.  Treatment with strong 
CYP3A4 and CYP2C19 inducers and/or inhibitors must be discontinued at least 
14 days before the first dose of study drug.  Treatment with moderate inhibitors 
of CYP2C9 must be discontinued at least 7 days before the first dose of study 
drug. 
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 6.5 Excluded Concomitant Medications and 
Procedures:
Previous text:
Strong CYP3A4 and CYP2C19 inducers and/or inhibitors and moderate 
inhibitors of CYP2CP. After completing the required PK/ECG assessment 
period (Cycle 1, Day 3), treatment with 1 or more of the strong CYP3A4 
or CYP2C19 inhibitors and/or inducers and moderate inhibitors of 
CYP2CP may be considered after consultation with the project clinician.  
A list of strong inhibitors and strong inducers of CYP2C9, CYP2C19, and 
CYP3A4 is included in Section 14.4.
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
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Amended or 
new wording:
Strong cytochrome P450 (CYP) 1A2 inhibitors and CYP CYP3A4 and 
CYP2C19 inducers and/or inhibitors and moderate inhibitors of CYP2CP. 
After completing the required PK/ECG assessment period (Cycle 1, 
Day 3), inducers should be administered with caution and at the 
discretion of the investigator.  See treatment with 1 or more of the strong 
CYP3A4 or CYP2C19 inhibitors and/or inducers and moderate inhibitors 
of CYP2CP may be considered after consultation with the project clinician.  
A list of strong inhibitors and strong inducers of CYP2C9, CYP2C19, and 
CYP3A4 is included in.  Refer to Section 14.4 for a list of these agents.  
Alternative treatments, if available, should be considered.
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 description of potential drug-drug interactions.
The primary change occurs in Section 1.2 Nonclinical Experience
Initial 
wording:
In-vitro, MLN0128 is metabolized by various cytochrome P450 (CYP) enzymes, 
including 2C19 (35%), 3A4 (28%), and 2C9 (28%); MLN0128 neither inhibited 
nor induced any of the major CYP enzymes.  Additionally, MLN0128 did not 
inhibit P-glycoprotein (P-gp) but did inhibit breast cancer resistance.  At the 
plasma concentrations expected with the 40 mg dose of MLN0128, there exists a 
risk for a drug-drug interaction (DDI) with substrates of breast cancer-resistant 
protein (BCRP) (eg, methotrexate, irinotecan, rosuvastatin, topotecan, lapatinib, 
imatinib, etc.).  Such agents should be avoided from co-administration with 
MLN0128.  Since MLN0128 is metabolized by various CYP enzymes, the risk 
for clinically significant DDI (2-fold or greater) is considered low; however, 
given that the 40 mg dose of MLN0128 is the single agent MTD in the every 
week (QW) dosing schedule, potent inhibitors of CYP3A4 and CYP2C19 
enzymes and strong inducers of CYP enzymes should not be administered 
concomitantly with MLN0128.
Amended 
or new 
wording:
Recently completed in-vitro metabolism experiments in human hepatocytes 
using14C-labeled MLN0128 suggest that, MLN0128 is metabolized by various
primarily via CYP1A2 (approximately 31% to 40%), with a minor 
contribution from CYP3A4 (approximately 11% to 22%). These data 
suggest that MLN0128 is also metabolized by direct glucuronidation 
(approximately 22%) and an unidentified non-uridine diphosphate 
glucuronosyltransferase pathway (approximately 18%). The new data 
differ from the previous in vitro CYP phenotyping data obtained using 
recombinant CYP enzymes, which suggested the involvement of CYP2C9 
(approximately 35%), CYP2C19 (approximately 28%), and CYP3A4 
(approximately 28%) in MLN0128 metabolism. cytochrome P450 (CYP) 
enzymes, including 2C19 (35%), 3A4 (28%), and 2C9 (28%); MLN0128 neither 
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
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inhibited nor induced any of the major CYP enzymes.  Additionally, MLN0128 
did not inhibit P-glycoprotein (P-gp) but did inhibit breast cancer resistance.  At 
the plasma concentrations expected with the 40 mg dose of MLN0128, there 
exists a risk for a drug-drug interaction (DDI) with substrates of breast cancer-
resistant protein (BCRP) (eg, methotrexate, irinotecan, rosuvastatin, topotecan, 
lapatinib, imatinib, etc.).  Such agents should be avoided from co-administration 
with MLN0128.
Since MLN0128 is metabolized by various CYP enzymes, the risk for clinically 
significant DDI (2-fold or greater) is considered low; however, given that the 40 
mg dose of MLN0128 is the single agent MTD in the every week (QW) dosing 
schedule, potent inhibitors of CYP3A4 and CYP2C19 enzymes and strong 
inducers of CYP enzymes should not be administered concomitantly with 
MLN0128. In addition, physiologically based PK modeling and simulation 
using the new metabolism data for MLN0128 suggest that the risk for a 
metabolism-based drug-drug interaction with MLN0128 appears to be low.  
Therefore, strong CYP1A2 inhibitors and CYP inducers (see Section 0) 
should only be administered with caution and at the discretion of the 
investigator during the study.  Alternative treatments, if available, should 
be considered.
Rationale for Change:
This paragraph was amended to describe updated data on MLN0128 metabolism by specific 
CYP isoforms.
Change 4: Update the list of relevant CYP inhibitors and inducers.
The primary change occurs in Section 14.4 List of Relevant Cytochrome P450 Inhibitors and 
Inducers:
Description 
of the 
change:
The list of relevant CYP inhibitors and induces was updated to remove 
sections listing strong CYP2C19 inhibitors and strong CYP3A4 inhibitors; to 
add 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 5: Remove the dietary restrictions related to CYP inhibitors and inducers.
The primary change occurs in Section 6.7 Precautions and Restrictions:
Deleted 
text:
Dietary restrictions include periods of fasting as described in Section 7.4.16, 
and in-home daily fasting glucose monitoring (refer to Section 7.4.18). not 
consuming food or beverages containing the fruit or juices listed in Section 
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MLN0128
Clinical Study Protocol C31002 Protocol Amendment 2
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14.4 within 1 week before first dose of study drug and throughout the study.
Rationale for Change:
This change was made for consistency with new data that removes the necessity for 
restrictions concerning CYP2C9 and 2C19.
Section 14.4 List of Relevant Cytochrome P450 Inhibitors and Inducers also contains this 
change.
Change 6: 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 “f” in the 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:
The change was made to reduce the burden and to minimize radiation exposure for long-term 
patients.
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E L E C T R O NI C S I G N A T U R E S 
Si g ne d b y 
Me a ni n g of Si g n at ure 
Ser ver D ate 
( d d- M M M- y y y y H H: m m ‘ U T C’) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0 9 0 1 0 1 d 6 8 0 7 5a 3 4 6
A P h a s e 1 St u d y t o E v al u at e t h e Eff e ct of M L N 0 1 2 8 o n t h e Q T c I nt er v al i n P ati e nt s Wit h A d v a n c e d S oli d T u m or s
P P D
Cli nical A p pr o val
0 4- Dec- 2 0 1 7 1 9: 1 4 U T C
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e

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:  Phase 1 Study to Evaluate the Effect of MLN0128 on the QTc Interval in Patients With 
Advanced Solid Tumors
NCT Number: NCT02197572
SAP Approve Date: February 18, 2015
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.


P P D
Pr o p ert y of T a k e d a: F or n o n- c o m m er ci al u s e o nl y a n d s u bj e ct t o t h e a p pli c a bl e T er m s of U s e


MLN0128
Statistical Analysis Plan, Study C31002
2
TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.........................................3
1. INTRODUCTION............................................................................................................5
1.1 Study Design..............................................................................................................5
1.2 Study Objectives ........................................................................................................5
2. POPULATIONS FOR ANALYSIS..................................................................................6
2.1 Safety Population .......................................................................................................6
2.2 PK Population ............................................................................................................6
3. HYPOTHESES AND DECISION RULES.......................................................................6
4. INTERIM ANALYSIS.....................................................................................................6
5. STATISTICAL METHODOLOGY .................................................................................6
5.1 Sample Size Justification............................................................................................7
5.2 Randomization and Stratification................................................................................7
5.3 Unblinding .................................................................................................................7
5.4 Data Handling ............................................................................................................7
5.4.1 Methods for Handling Missing Data.....................................................................7
5.4.2 Definition of Baseline Values ..............................................................................8
5.4.3 Windowing of Visits............................................................................................8
5.4.4 Justification of Pooling ........................................................................................8
5.4.5 Withdrawals, Dropouts, Lost to Follow-up...........................................................8
5.5 Patient Disposition .....................................................................................................8
5.6 Demographics and Baseline Disease Characteristics...................................................8
5.6.1 Demographics......................................................................................................8
5.6.2 Medical History...................................................................................................8
5.7 Treatments and Medications .......................................................................................9
5.7.1 Concomitant Medications ....................................................................................9
5.7.2 Study Treatments.................................................................................................9
5.8 Efficacy Analyses.....................................................................................................10
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis .................................10
5.9.1 Pharmacokinetic Analyses .................................................................................10
5.9.2 Pharmacodynamic Analyses...............................................................................10
5.9.3 Biomarker Analysis ...........................................................................................11
5.10 Safety Analyses ......................................................................................................11
5.10.1 Adverse Events................................................................................................11
5.10.2 Laboratory Data...............................................................................................14
5.10.3 Electrocardiograms ..........................................................................................15
5.10.4 Vital Signs .......................................................................................................15
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL .....................................15
7. PROGRAMMING CONSIDERATIONS .......................................................................16
7.1 Statistical Software...................................................................................................16
7.2 Rules and Definitions ...............................................................................................16
8. REFERENCES...............................................................................................................16
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MLN0128
Statistical Analysis Plan, Study C31002
3
List of Abbreviations and Definitions of Terms
Abbreviation
Term
AE(s)
adverse event (or events)
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATCC
Anatomical Therapeutic Chemical Classification
ATP
adenosine triphosphate
AUCinf
area under the plasma concentration versus time curve from zero to infinity
AUCt
area under the plasma concentration versus time curve from zero to the last 
measurable concentration
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
Cmax
maximum (peak) plasma concentration
CO2
carbon dioxide
CRF
case report form
DLT
dose limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
FDA
Food and Drug Administration
GGT
gamma glutamyl transferase
ICF
informed consent form
IV
intravenous
LDH
lactate dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
PK
pharmacokinetic
QT
measure of the time between the start of the Q wave and the end of the T wave 
in the electrical cycle of the heart; electrical depolarization and repolarization 
of the left and right ventricles of the heart
QTc
rate-corrected QT interval (millisec) 
QTcB
rate-corrected QT interval (millisec) with Bazett correction
QTcF
rate-corrected QT interval (millisec) Fridericia correction
QTcI
individual baseline corrected rate-corrected QT interval (millisec)
QW
every week; once weekly
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
t1/2
terminal disposition half-life
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MLN0128
Statistical Analysis Plan, Study C31002
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Abbreviation
Term
TEAE
treatment emergent adverse event
Tmax
first time to maximum plasma concentration
ULN
upper limit of the normal range
US
United States
WHO
World Health Organization
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MLN0128
Statistical Analysis Plan, Study C31002
5
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.
This SAP only covers the analyses to be performed for the clinical data collected at the sites
in the eCRF.  The ECG QTc analyses from the Holter monitor will be in a separate SAP 
prepared by CardioCore.  The QTc-PK analyses will be in a SAP prepared by Metrum 
Research Group.
1.1   
Study Design
This is an open label, single-arm, multicenter study to evaluate the effect of a single dose of 
40 mg MLN0128 on the electrocardiographic QT/QTc interval in patients with advanced 
solid tumors.  The study will collect time-matched PK and ECG data before and after 
MLN0128 administration at the time points specified in the Schedule of Events in the
protocol.
Patients may continue to receive MLN0128 if, in the opinion of the investigator, the patients 
are deriving clinical benefit.  Treatment may continue until disease progression, 
unacceptable MLN0128-related toxicity, withdrawal of consent, or for up to 12 months 
(whichever occurs first). 
Approximately, 30 patients will be enrolled from approximately 6 study centers in the US.  
1.2   
Study Objectives
Primary objective:

To characterize the effect of a single dose of 40 mg MLN0128 on the 
electrocardiographic QT/QTc interval in patients with advanced solid tumors.
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MLN0128
Statistical Analysis Plan, Study C31002
6
Secondary objective:

To evaluate the safety, tolerability, and pharmacokinetics of MLN0128 in patients 
with advanced solid tumors.
2.   
POPULATIONS FOR ANALYSIS
2.1   
Safety Population
All patients who receive at least 1 dose of MLN0128 will be included in the safety 
population.  This population will be used for safety analyses.
2.2   
PK Population
All patients who receive at least 1 dose of MLN0128 and have sufficient concentration-time 
data to calculate one or more PK parameters will be included in the PK population.  All PK 
analyses will be performed using the PK population.
3.   
HYPOTHESES AND DECISION RULES
Not applicable.
4.   
INTERIM ANALYSIS
Not applicable.
5.   
STATISTICAL METHODOLOGY
Statistical analyses will be primarily descriptive and graphical in nature.
In general, the number of observations, mean, standard deviation (SD), median, minimum, 
and maximum will be displayed for continuous variables, and the number and percent for 
categorical data, unless specified otherwise.  For PK related parameters, the geometric mean 
and coefficient of variation will also be presented.
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MLN0128
Statistical Analysis Plan, Study C31002
7
5.1   
Sample Size Justification
Based on historical data, the within-subject standard deviation in QTcF change from baseline 
is approximately 9 msec.  A sample size of 30 evaluable patients will be needed to detect a 
half-width of 2.7 msec of a 2-sided 90% CI for the mean change from baseline in QTcF.
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 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.
5.4.1.1   Missing/Partial Dates in Adverse Events/Concomitant Therapies
Missing and incomplete start dates will be imputed based on the algorithm described below.
The algorithm will be used only if the end date indicates that the adverse event was not 
resolved or the therapy was not ended before the first administration of study drug.
Adverse events or concomitant therapies 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 adverse event will be considered
treatment-emergent or the therapy concomitant if both the month and year of the start date 
are on or after the month and year of the date of the first dose of MLN0128 and on or before 
the month and year of the date of the last dose of MLN0128 plus 30 days.
If the start date has year, but day and month are missing, the adverse event will be 
considered treatment -emergent or the therapy concomitant if the year of the start date is on 
or after the year of the date of the first dose of MLN0128 and on or before the year of the 
date of the last dose of MLN0128 plus 30 days.
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MLN0128
Statistical Analysis Plan, Study C31002
8
If the start date of an adverse event or therapy is completely missing, then the event is 
assumed to be treatment-emergent or the therapy concomitant.
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 who are withdrawn from treatment before completing study-required PK/ECG 
assessments for reasons other than DLTs will be replaced.
5.5   
Patient Disposition
Patient disposition will be summarized as the number and percentage of patients in the 
safety and PK populations, and the reason study drug was discontinued.  All percentages 
will be based on the number of patients enrolled.
5.6   
Demographics and Baseline Disease Characteristics
5.6.1   
Demographics
Demographic and baseline characteristics will be summarized.  These include age, gender, 
ethnicity, race, height, weight and body mass index (BMI).  
BMI = weight / height2, where weight is in kilograms and height in meters.
5.6.2   
Medical History
5.6.2.1   General Medical History
Medical history will be presented in by-patient listings. 
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5.6.2.2   Disease-Specific History
The following disease-specific characteristics will be summarized: tumor type, stage, 
Eastern Cooperative Oncology Group (ECOG) performance status and site of cancer 
involvement. Percents are based on the number of patients in the safety population.
ECHO data collected at Baseline and Prior Therapies will be presented in by-patient listings.
5.7   
Treatments and Medications
5.7.1   
Concomitant Medications
Concomitant medications will be coded using the March 2014 version of the World Health 
Organization (WHO) Drug Dictionary Enhanced.  The number and percentage of patients
taking concomitant medications from the date of the first dose of study drug will be 
tabulated by generic term.  
5.7.2   
Study Treatments
Patients will be required to swallow 8, 5-mg capsules for a total dose of 40 mg MLN0128 on 
Cycle 1, Day 1.  To mitigate nausea and vomiting, patients will be administered an 
antiemetic agent on Cycle 1, Day 1 as an intravenous infusion (IV) over 30 seconds, at least 
30 minutes before study drug administration. After completing the required PK/ECG 
assessments at Cycle 1, Day 3, patients may continue treatment with MLN0128.  For 
patients continuing treatment with MLN0128, the drug is administered at a dose of 30 mg 
once weekly (QW) in continuous cycles of 28 days.   
5.7.2.1   Extent of Exposure
The total amount of dose taken in mg, number of treated cycles and the relative dose 
intensity will be summarized in each cycle and overall.  A treated cycle is defined as a cycle 
in which the patient received any amount of study drug.  The numbers and percentages of 
patients who had 1, 2, 3 …..etc. treated cycles will also be presented.
Relative dose intensity (%) for MLN0128 is defined as 100x(total amount of dose taken 
((mg))/(prescribed dose per day*total number of treated days in cycle*number of treated 
cycles).
5.7.2.2   Treatment Compliance and Modifications
Action on study drug will be summarized across the cycles  
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5.8   
Efficacy Analyses
The investigator’s assessment of response including tumor lesion measurement (targeted and 
non-targeted), new lesions, will be provided in a data listing.
5.9   
Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis
5.9.1   
Pharmacokinetic Analyses
The PK population will be used for the description of the concentration-time profiles and for 
the estimation of the PK parameters. 
Descriptive statistics (number of patients, mean, SD, geometric mean, median, minimum,  
maximum, and coefficient of variation) will be presented for the plasma PK parameters 
listed below.  Individual and mean plasma concentration data will be plotted over time.
Data permitting, summary statistics for the following PK parameters will be provided:

Area under the plasma concentration-time curve from time 0 to time of last 
measurable concentration(AUClast)

Area under the plasma concentration-time curve from time 0 to infinity (AUCinf)

Area under the plasma concentration-time curve from time 0 to 48 hr (AUC48hr)

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 clearance (CL/F)

Apparent terminal phase volume of distribution (Vz/F)
QTc-PK analyses will be performed by Metrum Research Group.  The details are presented 
in a SAP prepared by Metrum Research Group.
5.9.2   
Pharmacodynamic Analyses 
Not applicable.
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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 weight, 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
AEs will be coded using the Medical Dictionary for Regulatory Activities ( MedDRA),
version 17.0 or higher.
A treatment-emergent AE (TEAE) is an AE that occurs on or after the date of the first dose 
of study drug and up through 30 days after the last dose of study drug.
The number and percentage of patients experiencing at least 1 TEAE will be tabulated by 
MedDRA primary system organ class, high-level term and preferred term.  For the number 
of patients with AEs, patients reporting the same event more than once will have that event 
counted only once within each body system, once within each high- level term, and once 
within each preferred term.  
Tabular summaries of the following TEAEs will also be provided:

TEAEs related to Study Drug

Grade 3 or greater TEAEs

Grade 3 or greater TEAEs related to Study Drug

Most common (>= 10% of patients) TEAEs by maximum severity grade
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The following adverse events of interest will be tabulated:
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)
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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
Asthenic Conditions
Asthenia, Fatigue, Lethargy, Listless, Malaise, 
Sluggishness, Muscle Weakness
Events will be considered related to study drug if the investigator answered “yes” to the 
following question: “Is there a reasonable possibility that the adverse event was associated 
with the study medication?”  
Intensity is determined using the National Cancer Institute Common Toxicity Criteria (NCI 
CTC) version 4.03. 
By-patient listings will be produced for all DLTs.
All TEAEs will be presented in by-patient listings.
5.10.1.2   Serious Adverse Events  
The number and percentage of patients experiencing at least 1 treatment emergent serious 
AE (SAE) will be summarized by MedDRA primary system organ class, high-level term, 
and preferred term. Drug-related SAEs will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain 
all SAEs regardless of treatment emergent status).
5.10.1.3   Deaths
A by-patient listing of the deaths will be presented.  All deaths occurring on-study will be 
displayed (regardless of treatment emergent status). On-study death is defined as death that 
occurs during the period from the first dose of study drug through 30 days after the last dose 
of study drug.
5.10.1.4   Adverse Events Resulting in Discontinuation of Study Drug
A by-patient listing of TEAEs resulting in discontinuation of study drug will be presented.  
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5.10.2   Laboratory Data
All laboratory values will be converted to standardized units.  If a laboratory value is 
reported using a non-numeric qualifier (e.g., less than (<) a certain value, or greater than (>) 
a certain value), the given numeric value will be used in the summary statistics, ignoring the 
non-numeric qualifier.  
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results will be presented according to the scheduled sample collection time 
points.  Unscheduled laboratory test results will be included in the by-patient listings and in 
shift tables.
Descriptive statistics for the actual values of the clinical laboratory parameters and/or 
change from baseline will be presented for all scheduled time points.  Mean laboratory 
values over time (up to Cycle 6) will be plotted for hemoglobin, platelets, leucocytes, 
neutrophils, lymphocytes, creatinine, glucose, Alanine aminotransferase (ALT), urate, 
Aspartate aminotransferase (AST), phosphate, blood urea nitrogen (BUN), sodium, 
potassium, chloride, calcium, magnesium, glycosylated hemoglobin, total cholesterol, 
triglycerides, high density lipoprotein cholesterol, and low density lipoprotein cholesterol.  
Other graphical displays such as scatter plots of baseline versus worst post-baseline values 
will be presented.
Shift tables based on changes in NCI CTC AE grade from baseline to worst post-baseline 
value will be presented.
The parameters to be analyzed are as follows:

Hematology:  hemoglobin, hematocrit, platelets, leucocytes, neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils.

Clinical chemistries:  bilirubin, creatinine, alkaline phosphatase (ALP), glucose, 
ALT, urate, AST, phosphate, gamma-glutamyl-transferase (GGT), lactate 
dehydrogenase (LDH), albumin, BUN, sodium, potassium, carbon dioxide (CO2), 
chloride, calcium, magnesium and glycosylated hemoglobin.

Urinalysis:  turbidity, color, pH, nitrite, protein, leukocytes, glucose, ketones, 
bilirubin, occult blood, specific gravity and urobilinogen.
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
Fasting Lipid Profile: total cholesterol, triglycerides, high density lipoprotein 
cholesterol, low density lipoprotein cholesterol.
5.10.3   Electrocardiograms
The primary analysis of ECG parameters is from the continuous Holter Monitor recordings.
The ECG QTc analyses from the Holter monitor will be in a separate SAP prepared by 
CardioCore.
All ECG parameters and the overall interpretation from the single 12-lead ECG will be 
listed by patient.
5.10.4   Vital Signs
Vital sign results (diastolic and systolic blood pressure, temperature, heart rate) and body
weight will be summarized descriptively by scheduled time point 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.
By-patient listings will be produced.
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Not applicable.
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7.   
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.2 (or higher) will be used for all safety and efficacy analyses.  PK parameters 
will be estimated using non-compartmental analysis (NCA) with Phoenix WinNonlin 
Version 6.2 or newer.
7.2   
Rules and Definitions
Patient populations are defined in Section 2.
Baseline values are defined in Section 5.4.2.
Treatment-emergent AEs are defined in Section 5.10.1.1.
8.   
REFERENCES
Not applicable.
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