Clinical trial NCT01058707
Conditions: Advanced Solid Malignancies
Keywords: Solid tumors, MLN0128, TORC1/2 inhibitors
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2010-01-04; Completion date: 2019-02-07
Enrollment: 198 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a Phase I, open label, Dose Escalation study of oral administration of single agent MLN0128 in participants with Advanced Malignancies followed by an Expansion Phase in participants with renal cell carcinoma, endometrial cancer or urothelial cancer who have measurable disease.

Detailed description:
The drug being tested in this study is called MLN0128. MLN0128 is being tested to treat people who have Advanced Malignancies.

The study enrolled approximately 198 patients. Participants were assigned to one of the following dose regimens in the Dose Escalation Phase to establish the Maximum Tolerated Dose (MTD):

* MLN0128 QD
* MLN0128 QW
* MLN0128 QDx3dQW
* MLN0128 QDx5dQW

MLN0128 capsule, orally, once daily (QD) or Once weekly (QW) in the Dose Escalation Phase until MTD was established.

Once MTD was determined, participants were then enrolled in the Dose Expansion Phase to receive:

* MLN0128 5 mg QD
* MLN0128 30 mg QW
* MLN0128 40 mg QW

This multi-centre trial was conducted worldwide. The overall time to participate in this study was approximately 244 weeks. Participants will make multiple visits to the clinic, and were contacted by telephone OR plus a final visit after last dose of study drug for a follow-up assessment.

Arms: arm 1: MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). arm 2: MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). arm 3: MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). arm 4: MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks). arm 5: MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). arm 6: MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). arm 7: MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks).
Interventions: intervention 1: MLN0128
Intervention descriptions: intervention 1: MLN0128 capsules

Protocol documents:
Prot_000.pdf: 



Title: A Phase I, Open Label, Dose Escalation Study of Oral Administration of Single Agent 
INK128 in Subjects with Advanced Malignancies Followed by an Expansion in Subjects with 
Measurable Disease
NCT Number: NCT01058707
Protocol Approve Date: January 17, 2018
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
1
1.
CLINICAL STUDY PROTOCOL
Study Title:
A Phase I, Open Label, Dose Escalation Study of Oral 
Administration of Single Agent INK128 in Subjects with 
Advanced Malignancies Followed by an Expansion in Subjects 
with Measurable Disease
Protocol Number:
INK128-001
Investigational Product
MLN0128 (also known as TAK-228 and INK128)
US IND Number
104,801
EudraCT Number
2009-017284-42
Indication
Advanced Malignancies
Sponsor
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street, Cambridge, MA  USA  02139
Development Phase
Phase 1
Sponsor’s Responsible 
Medical Officer
Global Clinical Lead
Original Protocol Date:
November 3, 2009
Amendment 1 Date:
December 3, 2009
Amendment 2 Date:
January 28, 2010
Amendment 3 Date:
March 31, 2010
Amendment 4 Date:
July 20, 2010 (not implemented)
Amendment 5 Date:
August 12, 2010
Amendment 6 Date:
September 14, 2010
Amendment 7 Date:
October 27, 2010
Amendment 8 Date:
December 21, 2010
Amendment 9 Date:
March 25, 2011
Amendment 10 Date:
June 28, 2011
Amendment 11 Date:
October 12, 2011
Amendment 12 Date:
April 03, 2012
Amendment 13 Date:
May 21, 2012
Amendment 14 Date:
July 30, 2012
Amendment 15 Date:
March 27, 2013
Amendment 16 Date:
July 3, 2013
-Amendment 17 Date:
March 5, 2014
Amendment 18 Date:
September 26, 2016
Amendment 19 Date:
November 28, 2017
Amendment 20 Date:
January 17, 2018
Note: This document was approved electronically; the electronic approval signatures can be found at the end 
of the document.
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
2
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior written 
authorization of Millennium Pharmaceuticals is expressly prohibited.
Rationale for Amendment 20
This document describes the changes to the protocol incorporating Amendment 20.  The 
primary purpose of this amendment is to provide consistency within the protocol that no 
dietary restrictions will be imposed on study subjects.
Purposes for Amendment 20
1. Remove dietary restrictions related to CYP inhibitors and inducers consistently within 
the protocol.
2. Revise the list of CYP inhibitors and inducers regarding concomitant medications.
3. Update the FDA guidance link.
For specific examples of changes in text and where the changes are located, see
Section 21.4.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
3
2.   
PROTOCOL APPROVAL PAGE
Study Title:
A Phase I, Open Label, Dose Escalation Study of Oral 
Administration of Single Agent INK128 in Subjects with 
Advanced Malignancies Followed by an Expansion in 
Subjects with Measurable Disease
Protocol Number:
INK128-001
Investigational Product
MLN0128 (also known as TAK-228 and INK128)
Sponsor:
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street, Cambridge, MA  USA  02139
Original Protocol Date:
November 3, 2009
Amendment 1 Date:
December 3, 2009
Amendment 2 Date:
January 28, 2010
Amendment 3 Date:
March 31, 2010
Amendment 4 Date:
July 20, 2010 (not implemented)
Amendment 5 Date:
August 12, 2010
Amendment 6 Date:
September 14, 2010
Amendment 7 Date:
October 27, 2010
Amendment 8 Date:
December 21, 2010
Amendment 9 Date:
March 25, 2011
Amendment 10 Date:
June 28, 2011
Amendment 11 Date:
October 12, 2011
Amendment 12 Date:
April 03, 2012 
Amendment 13 Date:
May 21, 2012 
Amendment 14 Date:
July 30, 2012
Amendment 15 Date:
March 27, 2013
Amendment 16 Date:
July 3, 2013
Amendment 17 Date:
March 5, 2014
Amendment 18 Date:
September 26, 2016
Amendment 19 Date:
November 28, 2017
Amendment 20 Date:
January 17, 2018
This protocol amendment has been approved by Millennium Pharmaceuticals, Inc.  The 
following persons are authorized on behalf of Millennium Pharmaceuticals, Inc. to approve 
this protocol amendment.  Electronic signatures appear at the end of this document.
PPD
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
2139
139
2011
11
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2012 
21, 2012
21, 201
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Date:
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MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
4
3.
SYNOPSIS
Study Title:  A Phase I, Open Label, Dose Escalation Study of Oral Administration of Single Agent 
INK128 in Subjects with Advanced Malignancies Followed by an Expansion in Subjects with 
Measurable Disease
Protocol Number:  INK128-001
Study Sites: Multiple centers in the United States (US) and Spain
Study Period (months):  Approximately 32 months
Phase of Development:  Phase 1
Study Objectives
Primary
! To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of oral
administration of MLN0128 (also known as TAK-228 and INK128) given daily or via
alternate dosing schedules in subjects with advanced malignancies
! To evaluate the safety and tolerability of orally administered single-agent MLN0128, given
daily or via alternate dosing schedules, in both the dose escalation and the expansion phases
of the study
Secondary
! To evaluate the plasma pharmacokinetics (PK) of single-agent MLN0128 following oral
administration daily and according to alternate dosing schedules, in subjects with advanced
malignancies
! To evaluate the pharmacodynamic (PD) effect of MLN0128 activity in surrogate tissue (skin)
and tumor as measured by ribosomal protein S6 (S6), eukaryotic initiation factor 4E-binding
protein 1 (4EBP1), and serine/threonine protein kinase B (AKT) as well as in peripheral
blood cells as measured by 4EBP1
! To evaluate preliminary anti-tumor activity of MLN0128
Exploratory
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MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
5
Overview of Study Design:  This is a phase 1, open-label study that consists of a dose escalation 
phase in subjects with advanced malignancies, followed by an expansion phase of safety and efficacy 
in up to 80 additional response-evaluable subjects with measurable disease in 2 dosing schedules in 2 
tumor-specific cohorts.
Up to 4 different dosing schedules will be explored in the dose escalation phase:  once daily (QD), 
once weekly (QW), once daily for 3 days on, 4 days off repeated each week (QD3d QW), and once 
daily for 5 days on, 2 days off repeated each week (QD5d QW).  Enrollment will start with the once 
daily schedule.  Once the MTD for this schedule is identified, enrollment will begin in parallel in the 
alternate dosing schedules.  Once the MTD has been identified for each of the 4 dosing schedules 
evaluated, an additional 6 subjects may be enrolled in 1 or more of the dosing schedule(s) to gain 
further PK and safety data to determine the recommended dose(s) and schedule(s) prior to the 
expansion phase of the study.
Based on biochemical data, available PK, and tolerability data for each MLN0128 dosing schedule, 
along with potential early signs of anti-tumor activity from subjects treated during the dose 
escalation phase, 1 or more dosing schedules will be evaluated for safety and efficacy, in parallel, in 
the expansion phase.  A total of up to 80 response-evaluable subjects will comprise 2 tumor-specific 
cohorts:  an RCC cohort and a cohort of selected tumor types (endometrial and bladder cancers).
Number of subjects planned:  Dose escalation phase – approximately 90 subjects; Expansion phase 
– approximately 80 response-evaluable subjects
Diagnosis and All Criteria for Inclusion and Exclusion
Individuals eligible to participate in either the dose escalation phase and/or the expansion phase of 
the study must meet all of the following Inclusion Criteria:
1.
Age ≥ 18 years, including males and females;
2.
Subjects must have locally advanced or metastatic solid tumors with the exception of
primary brain tumor, and have failed standard-of-care therapy.  Subjects with locally 
advanced or metastatic solid tumors who have a history of brain metastasis are eligible for 
the study as long as they meet all the following criteria:  their brain metastases have been 
treated, they have no evidence of progression or hemorrhage after treatment, they have been 
off dexamethasone for 4 weeks prior to first study drug administration, and they have no 
ongoing requirement for dexamethasone or anti-epileptic drugs;
3.
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1;
4.
Subjects must have adequate organ function, including the following:
a.
Bone marrow reserve consistent with:  absolute neutrophil count (ANC) 
≥1.5 109/L; platelet count ≥ 100 109/L; hemoglobin ≥ 9 g/dL;
b.
Hepatic:  total bilirubin ≤ 1.5 upper limit of normal (ULN), transaminases 
(aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT 
and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) 
≤2.5 ULN (≤ 5 ULN if liver metastases are present);
c.
Renal: creatinine clearance ≥50 mL/min based either on Cockroft-Gault estimate or 
based on urine collection (12 or 24 hour);
d.
Metabolic:  fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides 
≤300 mg/dL;
5.
Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
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standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition 
scan (MUGA) within 4 weeks prior to first study drug administration (ie, if the institutional 
normal is 50%, subject’s LVEF may be as low as 45% to be eligible for the study);
6.
For women of child-bearing potential, negative serum pregnancy test within 14 days prior to 
the first study drug administration and use of physician-approved method of birth control 
from 30 days prior to the first study drug administration to 90 days following the last study 
drug administration;
7.
Male subjects must be surgically sterile or must agree to use physician-approved 
contraception during the study and for 90 days following the last study drug administration;
8.
Willingness to provide paraffin blocks or a minimum of 10 unstained slides of available 
archival tumor tissues (paraffin blocks are preferred);
9.
Ability to swallow oral medications;
10. Ability to understand and willingness to sign informed consent form prior to initiation of any 
study procedures;
Subjects who have tumor tissue that is accessible for biopsy based on the investigator’s judgment 
will be strongly encouraged to consent for tumor biopsy. 
Additionally, for individuals eligible to participate in the expansion phase of the study:
11. Subjects must have evidence of measurable disease per Response Evaluation Criteria in 
Solid Tumors (RECIST) version 1.1(1) by radiographic techniques (computerized 
tomography [CT] or magnetic resonance imaging [MRI]);
12. Subjects must have a pathologic diagnosis of advanced or recurrent endometrial 
adenocarcinoma, and must have failed at least 1 prior line of standard chemotherapy; or
13. Subjects must have a pathologic diagnosis of advanced/metastatic urothelial cancer 
(carcinoma of the bladder, ureter, and/or renal pelvis) and must have failed at least 1 line of 
prior therapy in the metastatic/unresectable setting; or
14. Subjects must have a pathologic diagnosis of advanced renal cell carcinoma (RCC) and must 
have failed at least 1 prior line of anti-VEGF therapy (including but not limited to sunitinib, 
and/or sorafenib, and/or bevacizumab and/or pazopanib, and/or axitinib) and must not have 
received prior therapy with a TORC1 inhibitor (such as temsirolimus or everolimus); or
15. Subjects must have a pathologic diagnosis of advanced renal cell carcinoma (RCC) and must 
have progressed on previous treatment with a TORC1 inhibitor (such as temsirolimus or 
everolimus).
Individuals who meet any of the following Exclusion Criteria will not be eligible to participate in 
either the dose escalation phase or the expansion phase of the study:
1.
Diagnosis of primary brain tumor;
2.
Untreated brain metastasis or history of leptomeningeal disease or spinal cord compression;
3.
Failed to recover from the reversible effects of prior anticancer therapies with the exception 
of alopecia, and after-effects associated with prior tyrosine kinase inhibitor therapy, such as 
hair depigmentation, hypothyroidism, and/or splinter hemorrhage;
4.
Have received prior cancer or other investigational therapy within 2 weeks prior to the first 
administration of study drug.  For prior therapies with a half-life longer than 3 days, the 
interval must equal 28 days prior to the first administration of study drug, and the subject 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
7
must have documented disease progression;
5.
Have received systemic corticosteroid (inhalers are allowed) within 1 week prior to the first 
administration of study drug (dose escalation phase only);
6.
Have initiated treatment with bisphosphonates less than 30 days prior to the first 
administration of MLN0128.  Concurrent bisphosphonate use is only allowed if the 
bisphosphonate was initiated at least 30 days prior to the first administration of MLN0128;
7.
Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for 
an unknown reason that may alter the absorption of MLN0128;
8.
Poorly controlled diabetes mellitus defined as HbA1c > 7%; subjects with a history of 
transient glucose intolerance due to corticosteroid administration are allowed in this study if 
all other inclusion/exclusion criteria are met;
9.
Other clinically significant comorbidities, such as uncontrolled pulmonary disease, active 
CNS disease, active infection, or any other condition that could compromise subject’s 
participation in the study;
10. Known human immunodeficiency virus (HIV) infection;
11. Pregnancy (positive serum or urine pregnancy test) or breast feeding;
12. Any history of unstable angina, myocardial infarction, New York Heart Association 
(NYHA) Class III or IV heart failure (See Table 21-3), and/or pulmonary hypertension;
13. Significant active cardiovascular disease including:
Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mmHg, diastolic 
blood pressure > 95 mmHg)
Grade 3 or higher valvular disease
Grade 3 or higher atrial fibrillation
Grade 3 or higher bradycardia
Endocarditis
Pulmonary embolism
Recent cerebrovascular accident/transient ischemic attack within 6 months prior to 
enrollment
14. A requirement for positive inotropic support (excluding digoxin) or active/serious 
uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation) within 1 year prior to 
screening;
15. A pacemaker or implantable cardiac defibrillator;
16. Baseline prolongation of the rate-corrected QT interval (QTc) (eg, repeated demonstration of 
QTc interval > 480 milliseconds; See Section 8.6.7.3);
17. History of congenital long QT syndrome, ventricular fibrillation, ventricular tachycardia, or 
torsades de pointes;
18. Diagnosed or treated for another malignancy within 2 years before the first dose or 
previously diagnosed with another malignancy and have any evidence of residual disease.  
Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if 
they have undergone complete resection;
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
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19. Additionally, for individuals eligible to participate in the expansion phase of the study, 
subjects will be excluded if they have received prior AKT, PI3K, dual PI3K/mTOR complex 
(TORC1/2), or TORC1/2 inhibitors.
Other considerations for exclusion: Subjects taking moderate/strong CYP1A2 inhibitors, moderate 
CYP1A2 and/or strong and moderate CYP3A4 inducers should be considered with caution. 
Alternative treatments that are less likely to affect MLN0128 metabolism, if available, should be 
considered. If a subject requires treatment with 1 or more moderate/strong CYP1A2 inhibitor, a 
moderate/strong CYP1A2 and/or a strong CYP3A4 inducer, the medical monitor should be 
consulted. Examples of clinically relevant moderate/strong CYP1A2 inhibitors and inducers, as well 
as strong CYP3A4 inducers, are presented in Table 21.2.
Investigational Product(s), Dose, Route, and Regimen
MLN0128 (also known as TAK-228 and INK128) is supplied in tamper-resistant, high-density 
polyethylene bottles as capsules containing 1-, 3-, or 5-mg dose strengths, which the pharmacist will 
use to make up the appropriate dose for each dose cohort.  On clinic days only, subjects will be 
instructed not to take their study drug at home, and the site will administer MLN0128 to the subject 
from the bulk pharmacy supplies.  The subject should take all the capsules orally for a given dose 
with a meal once in the morning for the QD, QW, QD3d QW, and QD5d QW dosing schedules.  
On each clinic day, the subject should return the study medication bottle and any unused study drug.  
A full accountability by the site staff and the sponsor’s designated Clinical Research Associate 
(CRA) should be conducted before these supplies are destroyed.
Cycles occur in 28-day increments.
The starting dose for the QD dosing schedule is 2 mg QD.  Dose escalation for the QD dosing 
schedule will be according to a modified Fibonacci schema.  For example, the starting dose of 2 mg 
may be escalated in successive cohorts to 4 mg, 7 mg, 10 mg, 14 mg, 18 mg, etc.  The investigators 
and sponsor, after their safety review, may elect to study a dose level that is intermediate to the 
current dose level and the next lower dose level previously studied, eg 6 mg as an intermediate dose 
between 4 mg and 7 mg.  The level of dose escalation and a decision to go to an intermediate dose 
level will be determined after discussion between the participating investigators and Millennium’s 
medical monitor before dose escalation, but will not exceed the planned dose according to a 
modified Fibonacci schema.
After the MTD has been determined for the once daily dosing schedule (MTDqd), study of the 
additional dosing schedules will begin.  Enrollment will be initiated in parallel and independent 
arms:  Arm A with once weekly (QW) dosing starting at a dose not to exceed twice the MTDqd; 
Arm B with MLN0128 administered once daily for 3 days on, 4 days off each week (QD3d QW) 
starting at the MTDqd; and Arm C with MLN0128 administered once daily for 5 days on, 2 days off 
each week (QD5d QW) starting at a dose not to exceed the total weekly dose of the MTDqd
(eg, ≤42 mg).  Subjects will be randomly assigned to 1 of the 3 alternate dosing arms in the event,
that 2 or more arms are open for enrollment at the same time.  Subjects may not participate in more 
than 1 dosing arm.
Dose escalation for each of the arms will be according to a modified Fibonacci schema.  The extent 
of dose escalation will be determined after discussion between the participating investigators and 
Millennium’s medical monitor prior to dose escalation, but will not exceed the planned dose 
according to a modified Fibonacci schema.
Duration of Treatment:  In the absence of unacceptable MLN0128 treatment-related toxicity or 
disease progression, subjects may receive MLN0128 treatment for up to 1 year at the discretion of 
the investigator and beyond 1 year with the agreement of the investigator and the sponsor.
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MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
9
Reference Therapy, Dose, Route, and Regimen:  None
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
10
Criteria for Evaluation
Safety:  Safety will be assessed by periodic physical examinations, 12-lead electrocardiograms 
(ECGs), clinical laboratory assessments, in-home monitoring of glucose levels with a glucometer,
and monitoring of adverse events (AEs).  Adverse events will be graded using National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  Site 
teleconferences between the sponsor and all participating sites will be held approximately every 1 to 
2 weeks during the dose escalation phase to discuss any suspected AEs/DLTs that have occurred 
with each cohort.  Participating investigators and the sponsor’s medical monitor will review 
toxicities from the current cohort during the site teleconferences before escalating to the next dose 
level, expanding the cohort at the current dose level or exploring an intermediate dose level.
Pharmacokinetics:  The PK profile will be assessed by determining the plasma levels of MLN0128 
at intervals throughout the study.  Blood samples for PK profile will be collected in subjects enrolled 
in the dose escalation phase of the study at the following time points:
!
Cycle 1, Day 1 (C1D1):  predose, 0.5 hour (± 15 min), 1 hour (± 15 min), 2 hours 
(± 30 min), 4 hours (± 30 min), 8 hours (± 30 min) post-C1D1 dose;
!
Cycle 1, Day 2 (C1D2 = 24 ± 2 hours post-C1D1 dose):  predose;
!
Cycle 2, Day 1 (C2D1):  predose, 0.5 hour (± 15 min), 1 hour (± 15 min), 2 hours 
(± 30 min), 4 hours (± 30 min), 8 hours (± 30 min) post-C2D1 dose;
!
Cycle 2, Day 2 (C2D2 = 24 ± 2 hours post-C2D1 dose):  predose
During the expansion phase, PK samples will be obtained according to the schedule provided in 
Table 3-5.
Pharmacodynamics:  Throughout the study, pharmacodynamic assessment will be made by 
assessing various biomarker levels in samplings of peripheral blood cells (PBCs) (dose escalation 
phase only), skin and tumor biopsies pre- and posttreatment whenever possible.  During dose 
escalation, the pharmacodynamic effect of MLN0128 activity in surrogate tissues (skin and tumor 
tissue) as measured by 4EBP1, AKT, and S6, as well as in peripheral blood cells via 4EBP1 will be 
evaluated. 
 
Blood samples for PBCs will be collected in all subjects at the following time points during the dose 
escalation phase of the study:
!
Cycle 1, Day 1 (C1D1):  predose, 2 hours (± 30 min), 8 hours (± 30 min) post-C1D1 dose, and
!
Cycle 1, Day 2 (C1D2 = 24 ± 2 hours post-C1D1 dose):  predose, and
!
Cycle 2, Day 1 (C2D1):  predose, 2 hours (±30 min), 8 hours (±30 min) post-C2D1 dose, and
!
Cycle 2, Day 2 (C2D2 = 24 ± 2 hours post-C2D1 dose):  pre-dose, and
!
Termination visit
The previously mentioned biomarkers are downstream effectors of mTOR and have been used for 
determining the sensitivity of proliferative diseases to treatment with mTOR inhibitors.  The changes 
in biomarkers levels will be determined via flow cytometry and/or immunohistochemical analysis.  
The absolute and percent change from baseline will be calculated for each subsequent measurement.  
Summary statistics will be computed for each collection time point.
CCI
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
11
Predictive Markers of MLN0128 Activity:  Candidate somatic genetic markers that may predict 
MLN0128 activity will be evaluated in archival tumor tissues.  These include phosphoinositide 3-
kinase alpha catalytic subunit (PI3KCA), PTEN, and rat sarcoma (K/H/N) [Ras (K/H/N)] in archival 
paraffin tumor tissue with MLN0128 activity.
 
 
 
 
 
 
Efficacy:  Radiographic and/or physical assessments of the malignancy, and evaluations of relevant 
tumor markers (eg, cancer antigen 125 [CA125], prostate-specific antigen [PSA], cancer antigen 
19-9 [CA19-9], cancer antigen 27.29 [CA27.29], cancer antigen 15.3 [CA15.3], and 
carcinoembryonic antigen [CEA]) will be made at screening/baseline (within 28 days prior to the 
first study drug administration) and after every 2 cycles of treatment (or at intervals of up to every 
4 cycles for long-term patients [ie, study participation ≥3 years], as clinically indicated based on the 
investigator’s judgment).  Objective response (complete response [CR] and partial response [PR]) as 
determined by the subject’s best tumor response, duration of response, and time to progression will 
be assessed using RECIST version 1.1.  A confirmatory CT/MRI scan should be performed at 
approximately 4 weeks from the previous scan for all subjects with an objective response of ≥ PR.  
The duration of stable disease will be evaluated for subjects with the best response of stable disease.
Statistical Methods
Safety Analyses:  Safety data analysis will be conducted on all subjects receiving at least 1 dose of 
MLN0128.  Analyses will consist of data summaries for clinical and laboratory parameters, and for 
AEs.  The safety data from the dose escalation phase will be summarized by dose cohort and 
schedule, and by tumor histology cohort for the expansion phase.  For each study phase, the number 
and percentage of subjects experiencing 1 or more AEs will be summarized by the relationship to 
study drug and severity based on CTCAE v4.0.  Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.  Laboratory parameters will be 
summarized using descriptive statistics, by postdosing shifts relative to baseline, and data listings of 
clinically significant abnormalities.  Vital signs and ECG data will be summarized by changes from 
baseline values using descriptive statistics.
Efficacy and Pharmacodynamic Analyses:  Efficacy analyses will be conducted for the response-
evaluable subjects enrolled in the expansion cohorts.  The results of these analyses will be 
summarized for the renal cohorts.  If there is a sufficient number of subjects with a specific tumor 
type, in the multi-tumor type cohort (ie, endometrial and bladder), then efficacy endpoints will also 
be summarized by tumor type.  The number and percentage of subjects experiencing objective 
response (CR and PR) will be summarized.  The duration of objective response will be summarized 
descriptively using the Kaplan-Meier method.  For subjects with best response of stable disease, the 
duration of stable disease will be defined as the number of days from the date of first dose to the date 
of progressive disease.  Summary statistics will be provided for the duration of MLN0128 therapy 
versus the duration of the last systemic anticancer therapy received on subjects whose last systemic 
anticancer therapy prior to entering the study was not an investigational agent.  Summary statistics 
will be computed for baseline biomarkers.  The absolute and percent change from baseline will be 
calculated for each subsequent measurement.  Summary statistics will be computed for each 
collection time point.
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MLN0128
Clinical Study Protocol INK128-001 Amendment 20, EudraCT: 2009-017284-42
12
Pharmacokinetic Analyses:  Pharmacokinetic parameters, including area under the plasma 
concentration-time curve (AUC), maximum plasma concentration (Cmax), minimum plasma 
concentration (Cmin), time of maximum plasma concentration (Tmax), and plasma half-life (t1/2) will be 
determined.  Comparisons across dose levels will be made to assess proportionality. In addition, 
comparison between single-dose and multiple-dose PK parameters will be made for assessment of 
steady-state drug accumulation.
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Schedule of Events
Schedule of Events for the Escalation Phase
Table 3-1   
Schedule of Events – Escalation Phase, Cycle 1
Assessments
Screening/Baseline
Treatment
Termination 
Visit (within 
30 days of 
last dose)
Within 
28 days
Within 14 
days
Day 1
(before dose)
Day 1
Day 2
Day 8
(2 days)
Day 15
(2 days)
Day 22
(2 days)
Informed Consent/PIC and 
HIPAA/DPA
X
Medical History
X
Vital signs, Height1, Weight 
and ECOG PS
X1
X14
X
X
X
X
Physical Examination2
X2
X14
X2
X2
X2
X2
12-lead ECG3
X3
X3,14
X3
X3
X3
X3
X3
X3
ECHO/MUGA
X
Hematology4
X
X14
X
X
X
X
Chemistry5
X
X14
X
X
X
X
X
Coagulation (PT/INR, PTT)
X
X
X
Fasting Serum Glucose6
X
X
X
X6
X
X
X
X
Glycosylated hemoglobin 
(HbA1c)
X
X
Fasting Lipid Profile7
X
X
Urinalysis19
X
X14
X
X
X
X
X
Serum or Urine Pregnancy 
Test8
X
X14
PK Timing9
X
X
X9
X
X
PBCs Timing10
X
X
X
X
X
X
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Table 3-1   
Schedule of Events – Escalation Phase, Cycle 1
Assessments
Screening/Baseline
Treatment
Termination 
Visit (within 
30 days of 
last dose)
Within 
28 days
Within 14 
days
Day 1
(before dose)
Day 1
Day 2
Day 8
(2 days)
Day 15
(2 days)
Day 22
(2 days)
Skin Biopsy for 
pharmacodynamic 
assessments11
X
X
X
X
Fresh Tumor Tissue 
Biopsy11
X
X
X
Collection of Previous 
Tumor Tissues12
X
MLN0128 Treatment20
X
X20
X
X
X
Radiographic Tumor 
Evaluation and Tumor 
Markers13
X13
X15
In-Home Daily Fasting 
Glucose Monitoring18
X18
X18
X18
X18
AE Monitoring16
X
X
X
X
X
X
Concomitant Medications17
X
X
X
X
X
X
X
X
X
Abbreviations: AE = adverse event; CXDY = Cycle X Day Y; CT = computed tomography; DPA = data protection act; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG PS= Eastern Cooperative Oncology Group Performance Status; HbA1c  = glycosylated hemoglobin; HIPAA = Health Insurance 
Portability and Accountability Act; INR = international normalized ratio; PBC = peripheral blood cell; PT = prothrombin time; PTT = partial prothrombin 
time; MRI = magnetic resonance imaging; MUGA = multiple gated acquisition scan; PIC = patient informed consent; PK = pharmacokinetic.
1.
Measurement of height will be taken at screening (baseline) only.
2.
Complete physical examination at screening, at Cycle 1, Day 1 (C1D1), C1D8, C1D15, and during the Termination visit.  A symptom-directed physical 
examination will be done on C1D22.
3.
A 12-Lead ECG will be done at screening/baseline, predose, and at 2 hours (± 30 min) and 4 hours (± 30 min) postdose on C1D1; predose on C1D2 
(approximately 24 ± 2 hours after the C1D1 dose, and at 2 hours (± 30 min) postdose on C1D8 and C1D15, and predose on C1D22.  A 12-lead ECG will 
also be obtained at the Termination visit.  All scheduled ECGs should be performed after the subject has rested quietly for at least 5 minutes in a supine 
position.  When the timing of ECG assessments coincides with a blood collection, the ECG should be obtained prior to the nominal time of the blood
collection.  In some cases, it may be appropriate to repeat an abnormal ECG to rule out improper lead placement as contributing to the ECG abnormality.  
See Section 8.12.1 for details.
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4.
Complete blood count (CBC) with white blood cell count (WBC) with differential, hemoglobin (Hgb), hematocrit (Hct), and platelet count.  Results of 
hematology safety labs must be available and reviewed by the investigator prior to MLN0128 dosing.
5.
Full chemistry includes Chem 7 (sodium, potassium, chloride, bicarbonate, blood urea nitrogen [BUN], creatinine, glucose), liver function tests (LFTs; ALT, 
AST, alkaline phosphatase, total bilirubin, direct bilirubin), LDH, total protein, albumin, calcium, phosphate, and magnesium.  Results of Chem 7 and LFTs 
safety labs must be available and reviewed by the investigator prior to MLN0128 dosing.  Electrolyte levels should be corrected as needed prior to 
MLN0128 dosing.  Electrolyte levels should be corrected as needed prior to MLN0128 dosing.
6.
Fasting glucose will be measured predose and at 0.5 hour (± 15 min), 1 hour (± 15 min), and 2 hours (± 30 min) after dosing on C1D1, predose on C1D2 
when the predose PK and PBC samples are drawn (dose escalation phase only), and predose and 2 hours (± 30 min) after dosing on C1D8, predose only on 
C1D15 and C1D22, and at the Termination Visit.  Subjects are required to fast overnight (nothing except water and/or medications after midnight or for a 
minimum of 8 hours) for all of these measurements.
7.
Total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein (LDL-C), and triglycerides.
8.
Only for female subjects with child-bearing potential.  Serum pregnancy test will be done at screening/baseline.  Either serum or urine pregnancy test will be 
done on C1D1.
9.
Plasma PK samples will be obtained for subjects in the dose escalation phase only at predose, 0.5 hour (± 15 min), 1 hour (± 15 min), 2 hours (± 30 min), 
4 hours (± 30 min), 8 hours (± 30 min), and 24 ± 2 hours postdose on C1D1 (PK draw on Day 2 will be obtained prior to dosing of MLN0128).  
Additionally, PK will be taken on all subjects in Cycle 1, any day of Days 8-15 when MLN0128 is administered (3 hours ± 1 hour postdose) when skin 
biopsy is taken.
10. PBCs will be collected for subjects in the dose escalation phase only at predose, at 2 hours (± 30 min), 8 hours (± 30 min), and 24 hours (±2 hours) postdose 
on C1D1, and Cycle 1, any day of Days 8-15 when MLN0128 is administered (3 hours ± 1 hour postdose) when skin biopsy and PK samples are taken, and 
at the Termination Visit.
11. Skin biopsies (3 mm core) should be obtained for all subjects within 2 weeks prior to the first dose (can be done on C1D1 prior to dosing) and Cycle 1, any 
day of Days 8–15 when MLN0128 is administered at 3 hours ± 1 hour post dose.  Fresh tumor tissue biopsies will be taken from subjects who have 
accessible tumor tissues based on the investigator’s judgment and who have signed the consent for tumor biopsy.  Fresh tumor tissue collections should 
coincide with the collection of skin biopsy, PBC, and PK samples at 3 hours ± 1 hour postdose.
12. Every effort should be made for all subjects who have available archival tumor tissues to collect either paraffin blocks or a minimum of 10 unstained slides 
of archival tumor tissue for assessment of predictive/prognostic markers.  Archival tumor tissues can be collected after the subject begins study drug 
treatment, if extra time is needed to locate the specimens. 
13. Baseline CT (with contrast)/MRI of chest, abdomen, pelvis, and relevant tumor markers (eg, CA125, PSA, CA19 9, CA27.29, CA15.3, and CEA) must be 
obtained within 4 weeks prior to the first dose.  The same method (CT with contrast or MRI) must be used throughout the study.  A confirmatory scan should 
be performed at approximately 4 weeks from the previous scan for all subjects with an objective response of ≥ PR.
14. The assessment does not need to be repeated if it was done within 3 days prior to the first dose.
15. Tumor assessments will only be done on subjects who have not previously demonstrated disease progression in the study unless completed within the 
previous 4 weeks.
16. Adverse events will be collected after administration of the first dose of study drug through 30 days following the last dose of study drug.
17. Concomitant medications will be collected from 30 days prior to the first dose until termination.
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18. Subjects will be given a glucometer on C1D2 to monitor daily fasting glucose levels at home and will be instructed to notify the investigator when the 
fasting glucose is abnormal (ie, ≥150 mg/dL).  Based on investigator judgment, and based upon the subject achieving a minimum of 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, subjects will continue to notify the investigator of fasting blood glucose levels that exceed 150 mg/dL.  At any time during the study, if blood 
glucose levels are not well-controlled, or if the subject requires either oral hypoglycemic agents or insulin to control blood glucose levels, then in-home 
testing of fasting blood glucose levels will be performed daily with the provided glucometer.
19. Urinalysis will include macroscopic assessment of the amount of protein, glucose, white blood cells, and blood if they are present (levels should be recorded 
if available) and microscopic analysis if abnormality is noted.  Microscopic urinalysis will also be performed along with a 12-hour urine collection and spot 
urine electrolytes, protein and creatinine, and serum chemistry at any time when serum creatinine is > 1.5 × baseline value.
20. Subjects will be dosed daily until the MTDqd is determined.  Once the MTDqd is determined, subjects will be randomly assigned to a dose cohort for 1 of 3 
alternate schedules and dosed either once weekly (QW), once daily for 3 days on, 4 days off each week (QD3d QW), or once daily for 5 days on, 2 days off 
each week (QD5d QW), in Arms A, B, and C, respectively.  Subjects in Arm A (QW), will not be dosed on C1D2.  Electrolyte levels should be corrected 
as needed prior to MLN0128 dosing.
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Table 3-2   
Schedule of Events – Escalation Phase, Cycle 2 and Beyond
Assessments
Treatment
Termination 
Visit (within 
30 days of 
last dose)
Cycle 2
Cycles 3 and 4
Cycle 5 
and 
onward
Day 1
Day 2
Day 8
Day 15
Day 22
Day 1
Day 15
(2 days)
Day 22
(7 days) 
– Cycle 4 
only
Day 1
predose
postdose
Vital signs, weight and 
ECOG PS
X
X
X
X
X
X
X
X
Physical Exam1
X1
X1
X1
X1
X1
X1
X1
X1
12-lead ECG2
X2
X2
X2
X2
X
Hematology3
X
X
X
X
X
X
X
X
Chemistry4
X
X
X
X
X
X
X
X
Coagulation (PT/INR, 
PTT)
X
X
X
X
Fasting Serum Glucose5
X
X
X
X
X
X
X
Glycosylated 
hemoglobin (HbA1c)14
X15
X15
X
Fasting Lipid Profile6
X
X
X
X
Urinalysis7
X
X
X
X
X
X
X
X
PK Timing8
X
X
X8
PBCs Timing9
X
X
X9
X
MLN0128 treatment10
X
X
X
X
X
X
X
X
Radiographic tumor 
evaluation and tumor 
markers11
X
X
X
X12
In-home daily fasting 
glucose monitoring13
X13
X13
X13
X13
X13
X13
X13
X13
X13
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Table 3-2   
Schedule of Events – Escalation Phase, Cycle 2 and Beyond
AE Monitoring15
X
X
X
X
X
X
X
X
X
X
Concomitant 
Medications16
X
X
X
X
X
X
X
X
X
X
Abbreviations: AE = adverse event; CXDY = Cycle X Day Y; CT = computed tomography; DPA = data protection act; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG PS= Eastern Cooperative Oncology Group Performance Status; HbA1c  = glycosylated hemoglobin; HIPAA = Health Insurance 
Portability and Accountability Act; INR = international normalized ratio; PBC = peripheral blood cell; PT = prothrombin time; PTT = partial prothrombin time; 
MRI = magnetic resonance imaging; MUGA = multiple gated acquisition scan; PIC = patient informed consent; PK = pharmacokinetic.
1. Complete physical examination (PE) will be performed at Day 1 of every cycle and at the Termination visit.  Symptom-directed PE will be performed at Days 8, 
15, and 22 of Cycle 2 and Day 15 of Cycles 3 and 4.
2. A 12-lead ECG will be obtained at predose and 2 hours (± 30 min) postdose at C2D1 and at 2 hours (± 30 min) postdose on C2D8 and C2D15.  A 12-lead ECG 
will also be obtained at the Termination visit.  All scheduled ECGs should be performed after the subject has rested quietly for at least 5 minutes in a supine 
position.  When the timing of ECG assessments coincides with a blood collection, the ECG should be obtained prior to the nominal time of the blood collection.  
In some cases, it may be appropriate to repeat an abnormal ECG to rule out improper lead placement as contributing to the ECG abnormality.
3. CBC with WBC with differential, Hgb, Hct, and platelet count.  Results of hematology safety labs must be available and reviewed by the investigator prior to 
MLN0128 dosing.
4. Full chemistry includes Chem 7 (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose), LFTs (ALT, AST, alkaline phosphatase, total bilirubin, 
direct bilirubin), LDH, total protein, albumin, calcium, phosphate, and magnesium.  Results of Chem 7 and LFTs safety labs must be available and reviewed by 
the investigator prior to MLN0128 dosing.  Electrolyte levels should be corrected as needed prior to MLN0128 dosing.
5. Fasting serum glucose will be done predose on Days 1 and 15 in Cycles 2-4, on Day 1 of every cycle starting from Cycle 5, and at the Termination visit.  
Subjects are required to fast overnight (nothing except water and/or medications) after midnight or for a minimum of 8 hours for all of these measurements.
6. Total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides.
7. Urinalysis will include macroscopic assessment of the amount of protein, glucose, white blood cells, and blood if present (levels should be recorded if available) 
and microscopic analysis if abnormality is noted.  Microscopic urinalysis will be performed along with 12-hr urine collection, spot urine electrolytes, protein and 
creatinine, and serum chemistry at any time when serum creatinine is > 1.5 × baseline value.
8. Plasma PK samples will be obtained for subjects in the dose escalation phase only at predose, 0.5 hour (± 15 min), 1 hour (± 15 min), 2 hours (± 30 min), 4 hours 
(± 30 min), 8 hours (± 30 min) and 24 ± 2 hours postdose on C2D1.
9. PBCs will be collected for subjects in the dose escalation phase only at predose, at 2 (± 30 min), 8 hours (± 30 min) and 24 + 2 hours postdose on C2D1, and 
during the Termination visit.
10.Subjects will be dosed daily until the MTDqd is determined.  Once the MTDqd is determined, subjects will be randomly assigned to 1 of 3 alternate dosing 
schedules and dosed either once weekly (QW), once daily for 3 days on, 4 days off each week (QD3d QW), or once daily for 5 days on, 2 days of each week 
(QD5d QW), in Arms A, B, or C, respectively.  Subjects in Arm A (QW) will not be dosed on C2D2.  Electrolyte levels should be corrected as needed prior to 
MLN0128 dosing.
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Table 3-2   
Schedule of Events – Escalation Phase, Cycle 2 and Beyond
11.CT (with contrast)/MRI of chest, abdomen, pelvis, and relevant tumor markers (eg, CA125, PSA, CA19-9, CA27.29, CA15.3, and CEA) will be obtained every 
2 cycles (7 days).  For long-term patients, defined as study participation ≥3 years, a CT (with contrast)/MRI of chest, abdomen, pelvis, and relevant tumor 
markers (eg, CA125, PSA, CA19-9, CA27.29, CA15.3, and CEA) will be obtained at intervals of up to every 4 cycles (± 7 days), as clinically indicated. A 
confirmatory scan should be performed at approximately 4 weeks from the previous scan for all subjects with an objective response of ≥PR.  The same method 
(CT with contrast or MRI) must be used throughout the study.
12.Tumor assessments will only be done on subjects who have not previously demonstrated disease progression in the study unless completed within the previous 
4 weeks.
13.Subjects will be given a glucometer on C1D1 to monitor daily fasting glucose levels at home and will be instructed to notify the investigator when the fasting 
glucose is abnormal (ie, ≥150 mg/dL).  Based on investigator judgment, and based upon the subject achieving a minimum of 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, 
subjects will continue to notify the investigator of fasting blood glucose levels that exceed 150 mg/dL.  At any time during the study, if blood glucose levels are 
not well-controlled, or if the subject requires either oral hypoglycemic agents or insulin to control blood glucose levels, then in-home testing of fasting blood 
glucose levels will be performed daily with the provided glucometer.
14.Beginning with Cycle 4, HbA1c sampling should occur on Day 1 and every 3 months thereafter.
15.Adverse events will be collected after administration of the first dose of study drug through 30 days after the last dose of study drug.
16.Concomitant medications will be collected from 30 days before the first dose of study drug until the termination.
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Schedule of Events for the Expansion Phase
Table 3-3   
Schedule of Events – Expansion Phase, Cycle 1
Assessments
Screening/Baseline
Treatment
Termination 
Visit (within 30 
days of last dose)
Within 
28 days
Within 14 
days
Day 1
(before dose)
Day 1
Day 8
(2 days)
Day 15
(2 days)
Day 22
(2 days)
Informed Consent/PIC and 
HIPAA/DPA
X
Medical history
X
Vital signs, height1, weight, and 
ECOG PS
X1
X12
X
X
X
X
Physical examination2
X2
X2,12
X2
X2
X2
X2
12-lead ECG3
X
X3
X3
X3
X3
X3
X
ECHO/MUGA
X
Hematology4
X
X12
X
X
X
X
Chemistry5
X
X12
X
X
X
X
X
Coagulation (PT/INR, PTT)
X
X
X
Fasting Serum Glucose6
X
X
X
X
X
X
X
Glycosylated hemoglobin (HbA1c)
X
X
Fasting Lipid Profile7
X
X
Urinalysis17
X
X12
X
X
X
X
X
Serum or Urine Pregnancy Test8
X
X12
PK Timing9
See Table 3-5, Expansion Phase Sparse PK Sampling Scheme
Collection of Previous Tumor 
Tissues10
X
MLN0128 Treatment18
X18
X18
X18
X18
Circulating tumor DNA19
X
X
Radiographic Tumor Evaluation 
X11
X13
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Table 3-3   
Schedule of Events – Expansion Phase, Cycle 1
and Tumor Markers11
In-Home Daily Fasting Glucose 
Monitoring16
X16
X16
X16
X16
AE Monitoring14
X
X
X
X
X
Concomitant Medications15
X
X
X
X
X
X
X
X
Abbreviations: AE = adverse event; CXDY = Cycle X Day Y; CT = computed tomography; DPA = data protection act; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG PS= Eastern Cooperative Oncology Group Performance Status; HbA1c  = glycosylated hemoglobin; HIPAA = Health Insurance 
Portability and Accountability Act; INR = international normalized ratio; PT = prothrombin time; PTT = partial prothrombin time; MRI = magnetic 
resonance imaging; MUGA = multiple gated acquisition scan; PIC = patient informed consent; PK = pharmacokinetic.
1.
The height measurement will be taken at screening (baseline) only.
2.
Complete physical examination at screening, at Cycle 1, Day 1 (C1D1), C1D8, C1D15, and during the Termination visit.  Symptom-directed physical 
examination will be done on C1D22.
3.
A 12-Lead ECG will be done at screening/baseline, predose and at 2 hours (± 30 min) and 4 hours (± 30 min) postdose on C1D1; and at 2 hours (± 30 
min) postdose on C1D8 and C1D15, and predose on C1D22.  A 12-lead ECG will also be obtained at the Termination visit.  All scheduled ECGs should 
be performed after the subject has rested quietly for at least 5 minutes in a supine position.  When the timing of ECG assessments coincides with a blood 
collection, the ECG should be obtained prior to the nominal time of the blood collection.  In some cases, it may be appropriate to repeat an abnormal 
ECG to rule out improper lead placement as contributing to the ECG abnormality.
4.
Complete blood count (CBC) with white blood cell count (WBC) with differential, hemoglobin (Hgb), hematocrit (Hct), and platelet count.  Results of 
hematology safety labs must be available and reviewed by the investigator prior to MLN0128 dosing.
5.
Full chemistry includes Chem 7 (sodium, potassium, chloride, bicarbonate, blood urea nitrogen [BUN], creatinine, glucose), liver function tests (LFTs; 
ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin), LDH, total protein, albumin, calcium, phosphate, and magnesium.  Results of Chem 7 
and LFTs safety labs must be available and reviewed by the investigator prior to MLN0128 dosing.  Electrolyte levels should be corrected as needed 
prior to MLN0128 dosing.  Electrolyte levels should be corrected as needed prior to MLN0128 dosing.
6.
Fasting glucose will be measured predose and at 0.5 hour (± 15 min), 1 hour (± 15 min) and 2 hours (± 30 min) after dosing on C1D1; and predose and 
2 hours (± 30 min) after dosing on C1D8; predose only on C1D15 and C1D22; and at the Termination Visit.  Subjects are required to fast overnight 
(nothing except water and/or medications after midnight or for a minimum of 8 hours) for all of these measurements.
7.
Total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein (LDL-C), and triglycerides.
8.
Only for female subjects with child-bearing potential.  Serum pregnancy test will be done at screening/baseline.  Either serum or urine pregnancy test 
will be done on C1D1.
9.
See Table 3-5 for specific PK sampling times during the expansion phase.
10. Every effort should be made for all subjects who have available archival tumor tissues to collect either paraffin blocks or a minimum of 10 unstained 
slides of archival tumor tissue for assessment of predictive/prognostic markers.  Archival tumor tissues can be collected after the subject begins study 
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Table 3-3   
Schedule of Events – Expansion Phase, Cycle 1
drug treatment, if extra time is needed to locate the specimens.  
11. Baseline CT (with contrast)/MRI of chest, abdomen, pelvis, and relevant tumor markers (eg, CA125, PSA, CA19 9, CA27.29, CA15.3, and CEA) must 
be obtained within 4 weeks prior to the first dose.  The same method (CT with contrast or MRI) must be used throughout the study.  A confirmatory 
scan should be performed at approximately 4 weeks from the previous scan for all subjects with an objective response of ≥ PR.
12. The assessment does not need to be repeated if it was done within 3 days prior to the first dose.
13. Tumor assessments will only be done on subjects who have not previously demonstrated disease progression in the study unless completed within the 
previous 4 weeks.
14. Adverse events will be collected after administration of the first dose of study drug through 30 days following the last dose of study drug.
15. Concomitant medications will be collected from 30 days prior to the first dose until the Termination visit.
16. Subjects will be given a glucometer on C1D1 to monitor daily fasting glucose levels at home and will be instructed to notify the investigator when the 
fasting glucose is abnormal (ie, ≥150 mg/dL).  Based on investigator judgment and based upon the subject achieving a minimum of 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, subjects will continue to notify the investigator of fasting blood glucose levels that exceed 150 mg/dL.  At any time during the 
study, if blood glucose levels are not well-controlled, or if the subject requires either oral hypoglycemic agents or insulin to control blood glucose 
levels, then in-home testing of fasting blood glucose levels will be performed daily with the provided glucometer.
17. Urinalysis will include macroscopic assessment of the amount of protein, glucose, white blood cells, and blood if they are present (levels should be 
recorded if available) and microscopic analysis if abnormality is noted.  Microscopic urinalysis will also be performed along with a 12-hour urine 
collection and spot urine electrolytes, protein and creatinine, and serum chemistry at any time when serum creatinine is > 1.5 baseline value.
18. Timing of MLN0128 administration will depend on dosing schedule(s) selected for the expansion phase.  Electrolyte levels should be corrected as 
needed prior to MLN0128 dosing.
19. Circulating tumor DNA also at C5D1 and end of treatment.
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Table 3-4   
Schedule of Events – Expansion Phase, Cycle 2 and Beyond
Assessments
Treatment
Termination 
Visit (within 30 
days of last 
dose)
Cycle 2
Cycles 3 and 4
Cycle 5 
and 
onward
Day 1
Day 8 
(2 
days)
Day 15
(2 
days)
Day 22 
(2 
days)
Day 1
Day 15
(2 days)
Day 22
(7 days) 
– Cycle 4 
only
Day 1
Pred
ose
postd
ose
Vital signs, weight, and ECOG PS
X
X
X
X
X
X
X
X
Physical Exam1
X1
X1
X1
X1
X1
X1
X1
X1
12-lead ECG2
X2
X2
X2
X2
X2
Hematology3
X
X
X
X
X
X
X
X
Chemistry4
X
X
X
X
X
X
X
X
Coagulation (PT/INR, PTT)
X
X
X
X
Fasting Serum Glucose5
X
X
X
X
X
X
Glycosylated hemoglobin 
(HbA1c)13
X13
X13
X
Fasting Lipid Profile6
X
X
X
X
Urinalysis7
X
X
X
X
X
X
X
X
PK Timing8
See Table 3-5, Expansion Phase Sparse PK Sampling Scheme
MLN0128 treatnent9
X
X
X
X
X
X
X
X
Radiographic tumor evaluation and 
tumor markers10
X
X
X
X11
In-home daily fasting glucose 
monitoring12
X
X
X
X
X
X
X
X
AE Monitoring14
X
X
X
X
X
X
X
X
X
X
Concomitant Medications15
X
X
X
X
X
X
X
X
X
X
Circulating tumor DNA16
X
X
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Abbreviations: AE = adverse event; CXDY = Cycle X Day Y; CT = computed tomography; DPA = data protection act; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG PS= Eastern Cooperative Oncology Group Performance Status; HbA1c  = glycosylated hemoglobin; HIPAA = Health Insurance 
Portability and Accountability Act; INR = international normalized ratio; PT = prothrombin time; PTT = partial prothrombin time; MRI = magnetic 
resonance imaging; MUGA = multiple gated acquisition scan; PIC = patient informed consent; PK = pharmacokinetic.
1.
Complete physical examination (PE) will be performed at Day 1 of every cycle and at the Termination visit.  Symptom-directed PE will be performed at 
Days 8, 15, and 22 of Cycle 2 and Day 15 of Cycles 3 and 4.
2. A 12-lead ECG will be obtained at predose and 2 hours (± 30 min) postdose at C2D1 and at 2 hours (± 30 min) postdose on C2D8 and C2D15. A 12-
lead ECG will also be obtained at the Termination visit.  All scheduled ECGs should be performed after the subject has rested quietly for at least 
5 minutes in a supine position.  When the timing of ECG assessments coincides with a blood collection, the ECG should be obtained prior to the nominal 
time of the blood collection.  In some cases, it may be appropriate to repeat an abnormal ECG to rule out improper lead placement as contributing to the 
ECG abnormality.
3. CBC with WBC with differential, Hgb, Hct, and platelet count.  Results of hematology safety labs must be available and reviewed by the investigator 
prior to MLN0128 dosing.
4. Full chemistry includes Chem 7 (sodium, potassium, chloride, bicarbonate, BUN, creatinine, glucose), LFTs (ALT, AST, alkaline phosphatase, total 
bilirubin, direct bilirubin), LDH, total protein, albumin, calcium, phosphate, and magnesium.  Results of Chem 7 and LFTs safety labs must be available 
and reviewed by the investigator prior to MLN0128 dosing.  Electrolyte levels should be corrected as needed prior to MLN0128 dosing.
5. Fasting serum glucose will be done predose on Days 1 and 15 in Cycles 2 to 4, on Day 1 of every cycle starting from Cycle 5, and at the Termination 
visit.  Subjects are required to fast overnight (nothing except water and/or medications) after midnight or for a minimum of 8 hours for all of these 
measurements.
6. Total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein (LDL-C), and triglycerides.
7. Urinalysis will include macroscopic assessment of the amount of protein, glucose, white blood cells, and blood if present (levels should be recorded if 
available) and microscopic analysis if abnormality is noted.  Microscopic urinalysis will be performed along with 12-hr urine collection, spot urine 
electrolytes, protein and creatinine, and serum chemistry at any time when serum creatinine is > 1.5 baseline value.
8. See Table 3-5 for specific PK sampling times during the expansion phase.
9. Timing of MLN0128 administration will depend on dosing schedule(s) selected for the expansion phase.  Electrolyte levels should be corrected as 
needed prior to MLN0128 dosing.
10.CT (with contrast)/MRI of chest, abdomen, pelvis, and relevant tumor markers (eg, CA125, PSA, CA19-9, CA27.29, CA15.3, and CEA) will be obtained 
every 2 cycles (7 days).  For long-term patients, defined as study participation ≥3 years, a CT (with contrast)/MRI of chest, abdomen, pelvis, and 
relevant tumor markers (eg, CA125, PSA, CA19-9, CA27.29, CA15.3, and CEA) will be obtained at intervals of up to every 4 cycles (± 7 days), as 
clinically indicated. A confirmatory scan should be performed at approximately 4 weeks from the previous scan for all subjects with an objective 
response of ≥ PR.  The same method (CT with contrast or MRI) must be used throughout the study.
11.Tumor assessments will only be done on subjects who have not previously demonstrated disease progression in the study unless completed within the 
previous 4 weeks.
12.Subjects will be given a glucometer on C1D1 to monitor daily fasting glucose levels at home and will be instructed to notify the investigator when the 
fasting glucose is abnormal (ie, ≥150 mg/dL).  Based on investigator judgment, and based upon the subject achieving a minimum of 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 
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reduced monitoring, subjects will continue to notify the investigator of fasting blood glucose levels that exceed 150 mg/dL.  At any time during the 
study, if blood glucose levels are not well-controlled, or if the subject requires either oral hypoglycemic agents or insulin to control blood glucose levels, 
then in-home testing of fasting blood glucose levels will be performed daily with the provided glucometer.
13.Beginning with Cycle 4, HbA1c sampling should occur on Day 1 and every 3 months thereafter.
14.Adverse events will be collected after administration of the first dose of study drug through 30 days following the last dose of study drug.
15.Concomitant medications will be collected from 30 days before first dose until the Termination visit.
16.Circulating tumor DNA at C5D1 and end of treatment.
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Pharmacokinetic Sampling Scheme in the Expansion Phase
Table 3-5   
Expansion Phase Sparse Pharmacokinetic Sampling Scheme for Population Pharmacokinetic Analysis
Expansion Treatment 
Schedules
Study Cycle
Study Day
Sampling Time (window)
Plasma PK Sample

QD

QDx3d QW

QDx5d QW

QW
1
1
Pre-dose (within 30 min of dosing)
X
1
1
2 h ± 30 min
X
1
1
4 h ± 30 min
X
1
1
6 h ± 30 min
X
1
8, 15, or 22
Pre-dose (within 30 min of dosing)
X
2 h ± 1 h
4a
16a
Any time during clinic visit
Xa
Total number of planned PK samples
6 (or 7a)
Abbreviations:  min = minutes; PK = pharmacokinetics; QD = once daily; QDx3d QW = once daily for 3 days on, 4 days off, repeated each week; 
QDx5d QW = once daily for 5 days on, 2 days off, repeated each week; QW = once weekly
a For the QW schedule only, a PK sample will be obtained based on observed tolerance and investigator discretion, on Cycle 4, Day 16, approximately 24 hours 
after administration of the Cycle 4, Day 15 weekly dose of MLN0128 at home.  The Cycle 4 clinic visit will be delayed 1 day from Day 15 to Day 16 to allow 
for collection of this PK sample and to complete the planned Cycle 4, Day 15 safety assessments.  Subjects will be instructed to note the time of at-home 
MLN0128 dosing and this time will be recorded in the PK sampling log.
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4.   
TABLE OF CONTENTS
1. CLINICAL STUDY PROTOCOL....................................................................................1
2. PROTOCOL APPROVAL PAGE ....................................................................................3
3. SYNOPSIS.......................................................................................................................4
Schedule of Events for the Escalation Phase...................................................................13
Schedule of Events for the Expansion Phase...................................................................20
4. TABLE OF CONTENTS ...............................................................................................27
LIST OF TABLES.............................................................................................................29
LIST OF FIGURES............................................................................................................30
5. LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS.......................................31
6. INTRODUCTION..........................................................................................................35
6.1 Nonclinical Studies...................................................................................................35
6.2 Clinical Experience With MLN0128.........................................................................39
6.2.1 Clinical Safety ...................................................................................................40
6.2.2 Clinical Pharmacokinetics..................................................................................41
6.3 Study Rationale ........................................................................................................41
6.4 Summary of Overall Risks and Benefits ...................................................................44
7. STUDY OBJECTIVES ..................................................................................................46
8. INVESTIGATIONAL PLAN.........................................................................................48
8.1 Overall Study Design and Plan .................................................................................48
8.2 Dose Escalation Phase..............................................................................................48
8.2.1 Dose-Limiting Toxicity......................................................................................49
8.2.2 Dose Escalation Plan to Determine the Maximum Tolerated Dose .....................50
8.3 Expansion Phase.......................................................................................................52
8.4 Intrasubject Dose Escalation.....................................................................................53
8.5 Dose Modification or Treatment Delay for MLN0128-related Toxicity ....................53
8.6 Management of Clinical Events................................................................................53
8.6.1 Management of Hyperglycemia .........................................................................53
8.6.2 Management of Noninfectious Pneumonitis .......................................................55
8.6.3 Management of Hyperlipidemia.........................................................................56
8.6.4 Management of Oral Mucositis ..........................................................................57
8.6.5 Management of Rash .........................................................................................58
8.6.6 Management of Nausea and/or Vomiting ...........................................................58
8.6.7 Management of Cardiac Events..........................................................................59
8.6.8 Management of Other Nonhematologic Toxicities .............................................61
8.7 Discussion of Study Design, Including Choice of Control Group..............................61
8.8 Selection of Study Population...................................................................................61
8.8.1 Inclusion Criteria ...............................................................................................61
8.8.2 Exclusion Criteria ..............................................................................................64
8.8.3 Removal of Subjects From Treatment or Assessment.........................................66
8.8.4 Subject Identification and Replacement of Subjects ...........................................67
8.9 Treatments................................................................................................................68
8.9.1 Treatments Administered...................................................................................68
8.9.2 Identity of Investigational Product .....................................................................68
8.9.3 Storage and Labeling .........................................................................................68
8.9.4 Directions for Administration.............................................................................69
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8.9.5 Product Complaints............................................................................................70
8.9.6 Method of Assigning Subjects to Treatment Groups...........................................70
8.9.7 Selection of Doses Used in the Study.................................................................71
8.9.8 Blinding.............................................................................................................72
8.9.9 Prior and Concomitant Medications ...................................................................72
8.9.10 Treatment Compliance.....................................................................................73
8.10 Investigational Product Accountability ...................................................................73
8.10.1 Return and Disposition of Clinical Supplies .....................................................73
8.11 Dietary or Other Protocol Restrictions ....................................................................74
8.12 Efficacy and Safety Variables.................................................................................74
8.12.1 Safety Variables...............................................................................................74
8.12.2 Efficacy Variables............................................................................................74
8.12.3 Additional Variables ........................................................................................75
9. ADVERSE EVENTS .....................................................................................................76
9.1 Definitions................................................................................................................76
9.1.1 Pretreatment Event Definition............................................................................76
9.1.2 Adverse Event Definition...................................................................................76
9.1.3 Serious Adverse Event Definition ......................................................................76
9.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................77
9.3 Monitoring of Adverse Events and Period of Observation.........................................78
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........79
10. APPROPRIATENESS OF MEASUREMENTS ...........................................................80
10.1 Pharmacokinetics....................................................................................................80
10.2 Biomarker Assessments..........................................................................................80
10.2.1 Pharmacodynamic Assessments.......................................................................80
10.2.2 Assessments of Predictive Markers of MLN0128 Activity ...............................80
11. STUDY PROCEDURES..............................................................................................81
12. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE................82
12.1 Analysis Endpoints.................................................................................................82
12.1.1 Primary Endpoints ...........................................................................................82
12.1.2 Secondary Endpoints........................................................................................82
12.1.3 Exploratory Endpoints .....................................................................................83
12.1.4 Safety and Tolerability Endpoints ....................................................................84
12.2 Analysis Populations ..............................................................................................84
12.2.1 Safety Analysis ................................................................................................84
12.2.2 Efficacy Analysis.............................................................................................85
12.3 Statistical Methods .................................................................................................85
12.3.1 Safety Analysis ................................................................................................85
12.3.2 Efficacy Analysis.............................................................................................86
12.4 Sample Size Determination.....................................................................................89
12.4.1 Dose Escalation Phase......................................................................................89
12.4.2 Expansion Phase ..............................................................................................89
12.5 Interim Analysis and Early Stopping Guidelines.....................................................89
12.6 Changes in the Conduct of the Study or Planned Analyses......................................90
13. ETHICS .......................................................................................................................91
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13.1 Institutional Review Board or Ethics Committee.....................................................91
13.2 Ethical Conduct of Study........................................................................................91
13.3 Subject Information and Informed Consent.............................................................91
14. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE......................93
15. CASE REPORT FORMS AND SOURCE DOCUMENTS...........................................94
16. STUDY MONITORING AND AUDITING .................................................................96
17. RETENTION OF RECORDS.......................................................................................97
18. DISCLOSURE OF DATA............................................................................................98
19. REFERENCES.............................................................................................................99
20. PROTOCOL ACCEPTANCE PAGE .........................................................................102
21. APPENDICES ...........................................................................................................104
21.1 ECOG Performance Status ...................................................................................104
21.2 List of Relevant Cytochrome P450 Inhibitors and Inducers...................................105
21.3 New York Heart Association Classification of Cardiac Disease ............................106
21.4 Amendment 20 Detailed Summary of Changes.....................................................107
LIST OF TABLES
Table 3-1   
Schedule of Events – Escalation Phase, Cycle 1 ..........................................13
Table 3-2   
Schedule of Events – Escalation Phase, Cycle 2 and Beyond.......................17
Table 3-3   
Schedule of Events – Expansion Phase, Cycle 1..........................................20
Table 3-4   
Schedule of Events – Expansion Phase, Cycle 2 and Beyond.......................23
Table 3-5   
Expansion Phase Sparse Pharmacokinetic Sampling Scheme for Population 
Pharmacokinetic Analysis ...........................................................................26
Table 8-1   
Definition of Dose-Limiting Toxicity..........................................................49
Table 8-2   
Maximum Tolerated Dose Determination and Cohort Expansion ................51
Table 8-3   
Management of Hyperglycemia...................................................................54
Table 8-4   
Management of Non-infectious Pneumonitis...............................................56
Table 8-5   
Management of Hyperlipidemia ..................................................................56
Table 8-6   
Management of Oral Mucositis ...................................................................57
Table 8-7   
Management of Rash...................................................................................58
Table 8-8   
Management of Nausea and/or Vomiting ....................................................58
Table 8-9   
Management of Left Ventricular Dysfunction .............................................59
Table 8-10   
Management of QTc Prolongation...............................................................60
Table 8-11   
Management of Other Nonhematologic Toxicities (including 
asthenia/weakness)......................................................................................61
Table 12-1   
Date of Progression or Censoring for Duration of Response........................88
Table 21-1   
ECOG Performance Status........................................................................104
Table 21-2
List of Relevant Cytochrome P450 Inhibitors and Inducers .......................105
Table 21-3   
New York Heart Association Classification of Cardiac Disease.................106
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LIST OF FIGURES
Figure 8-1   
Expansion Stage Cohort Enrollment............................................................52
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5.   
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
AE
Adverse Event
AKT
Serine/Threonine Protein Kinase (also PKB; Serine/Threonine Protein Kinase B)
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AST
Aspartate Aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-24
Area under the plasma concentration-time curve from 0 to 24 hr
AUC0-last
Area under the plasma concentration-time curve from time zero to time of last 
measurable concentration
AUC0-∞
Area under the plasma concentration-time curve from time zero to infinity
BRAF
V-raf murine Sarcoma Viral Oncogene Homolog B1
BUN
Blood Urea Nitrogen
Cmax
Maximum Plasma Concentration
Cmax,ss
Maximum steady-state plasma concentration
Cmin
Minimum Plasma Concentration
CA15.3
Cancer Antigen 15.3
CA19-9
Cancer Antigen 19-9
CA27.29
Cancer Antigen 27.29
CA125
Cancer Antigen 125
CBC
Complete Blood Count
CEA
Carcinoembryonic Antigen
CFR
Code of Federal Regulations
Cleaved Caspase 
3
Cleaved Cysteine-aspartic Acid Protease 3
CNS
Central Nervous System
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CT
Computerized Tomography  
CTCAE
Common Terminology Criteria for Adverse Events
CSR
Clinical Study Report
DLT
Dose Limiting Toxicity
DPA
Data Protection Act
4EBP1
Eukaryotic Initiation Factor 4E-binding Protein 1
EC
Ethics Committee
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ECG(s)
Electrocardiogram(s)
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal Growth Factor Receptor
ER
Estrogen Receptor
ERBB2
Epidermal Growth Factor Receptor 2
ERK
Extracellular Signal-regulated Kinase 
FBG
Fasting Blood Glucose
FDA
Food and Drug Administration
FBXW7
F-box and WD repeat domain containing 7
FOXO
Forkhead Box O
FSG
Fasting Serum Glucose
GCP
Good Clinical Practice
GI
Gastrointestinal
GOLPH3
Golgi Phosphoprotein 3
HbA1c
Hemoglobin A1c (Glycosylated Hemoglobin)
HDL-C
High Density Lipoprotein Cholesterol
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HNSTD
Highest Non-Severely Toxic Dose
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IP(s)
Investigational Product(s)
INR
International Normalized Ratio
IRB
Institutional Review Board
IV
Intravenous, Intravenously
LDL-C
Low Density Lipoprotein 
LFT
Liver function test
LKB1
Liver Kinase B1
LVEF
Left Ventricular Ejection Fraction
MCL-1
Myeloid Leukemia Sequence 1
MedDRA
Medical Dictionary for Regulatory Activities 
Millennium
Millennium Pharmaceuticals, Inc.
MLN0128
Also known as TAK-228
MRI
Magnetic Resonance Imaging
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MTD
Maximum Tolerated Dose
mTOR
Mechanistic (formerly Mammalian) Target of Rapamycin 
MUGA
Multiple Gated Acquisition Scan
Myc (N/C)
C-Myc, N-Myc oncogene
NCI
National Cancer Institute
NDRG1
N-Myc Downstream Regulated 1
NF1
Neurofibromin 1
NHL
Non-Hodgkin Lymphoma
NYHA
New York Heart Association
P53(TP53)
Protein 53 (tumor protein 53)
P85(PIK3R1)
Regulatory subunit p85 (Phosphoinositide 3-kinase, regulatory subunit 1)
PBC(s)
Peripheral Blood Cell(s)
PCR
Polymerase Chain Reaction
PD
Pharmacodynamic(s) 
PE
Physical Examination
PI
Principal Investigator
PIC
Patient Informed Consent
PI3K(s)
Phosphoinositol-3-Kinase(s)
PIK3CA
Phosphoinositide 3-kinase Alpha Catalytic Subunit
PK
Pharmacokinetic(s)
PO
by mouth (oral)
PR
Partial Response
PRAS40
Proline Rich AKT Substrate of 40 kDa
PSA
Prostate-specific Antigen
PT
Prothrombin Time
PTEN
Phosphatase and Tensin Homolog
PTT
Partial Thromboplastin Time
QD
Once a day
QDx3 QW
Once a day 3 on 4 days off repeated each week
QDx5 QW
Once a day 5 days on 2 days off repeated each week
QT
Interval on ECG between the start of the Q wave and end of the T wave
QTc
QT interval corrected for heart rate
QW
Once weekly
Rapalog
Rapamycin Analog
RECIST
Response Evaluation Criteria in Solid Tumors
S6
Ribosomal Protein S6
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S6K
Ribosomal S6 kinase
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
STD10
Severely Toxic Dose to 10% of rats
t1/2
Plasma Half-life
Tmax
Time of maximum plasma concentration
TORC
Target of Rapamycin Complex
TORC1
Target of Rapamycin Complex 1
TORC2
Target of Rapamycin Complex 2
TORC1/2
Target of Rapamycin Complex 1 and 2
TSC1/2
Tuberous sclerosis complex 1/2
ULN
Upper Limit of Normal
UPSC
Uterine Papillary Serous Carcinoma
US
United States
VHL
Von Hippel-Lindau Tumor Suppressor
WBC
White blood cell
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6.   
INTRODUCTION
MLN0128 (also known as TAK-228 and INK128) is a potent and highly selective, 
adenosine triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase termed 
the mechanistic (formerly, mammalian) target of rapamycin (mTOR).  MLN0128 is 
mechanistically distinct from the allosteric inhibitors of mTOR (rapamycin and its 
derivatives, referred to as rapalogs).  The rapalogs inhibit mTOR complex 1 only; this is 
distinct from MLN0128 that inhibits both mTOR complex 1 (TORC1) and mTOR complex 
2 (TORC2).  MLN0128 is formulated as capsules intended for the treatment of solid and 
hematologic malignancies.
A comprehensive review of MLN0128 is contained in the Investigator’s Brochure (IB) 
supplied by Millennium Pharmaceuticals, Inc. (Millennium).  The investigator should 
review this document before initiating this study.
6.1   Nonclinical Studies
Nonclinical studies have been conducted to demonstrate the mechanism of action, efficacy, 
and safety of MLN0128 in biological models to characterize pharmacodynamics, define the 
pharmacokinetic (PK) properties, characterize the toxicity profile, and support a safe starting 
dose in humans for MLN0128 drug product.
The pharmacology studies conducted with MLN0128 identified it as an orally active, potent, 
and selective inhibitor of the serine/threonine protein kinase mTOR in both cellular 
signaling complexes, TORC1 and TORC2.  In a biochemical assay, MLN0128 inhibited 
mTOR with a concentration inhibiting enzyme activity by 50% (IC50) of 1.1 nM.  When 
tested against the closely structural-related phosphoinositol-3-kinases (PI3Ks), the 
MLN0128 IC50 values were increased more than 100-fold over mTOR potency, establishing 
a large selectivity window.  In cellular models, MLN0128 displayed inhibition of TORC1/2 
signaling pathways with IC50s less than 10 nM.  In human tumor mouse xenograft models of 
a wide range of tissue types and varying genetic backgrounds, such as glioblastoma (U87), 
non-small cell lung cancer (A549), breast cancer (ZR-75-1), renal cell cancer (786-O), and 
endometrial cancer (AN3-CA), MLN0128 inhibited pharmacodynamic (PD) markers of 
TORC1/2 pathways that correlate with strong tumor growth inhibition in a specific and 
dose-dependent manner.  Treatment with MLN0128 significantly ameliorated tumor growth 
in mice at well-tolerated doses.
Secondary pharmacology studies using commercial, in vitro receptor binding assays 
revealed MLN0128 had affinity for binding 2 adenosine receptors at concentrations 
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(~10 μM) well above expected therapeutic drug concentrations.  Similarly, MLN0128 
displayed low potential (IC50 = 175 µM) to affect the human ether-a-go-go related (hERG) 
potassium channel, and displayed no effect on electrocardiograms obtained from conscious 
telemeterized monkeys.  Based on this profile, the anticipated risk for clinically deleterious 
cardiovascular effects is considered low.
MLN0128 displayed consistent and predictable pharmacokinetic parameters across mouse, 
rat, dog, and cynomolgus monkey.  It was rapidly absorbed after oral delivery (time of first 
maximum plasma concentration [Tmax] ranged from 0.25 hr-6.0 hr), showed high oral 
bioavailability (30%-91%) and dose-proportional plasma exposures.  Plasma to brain 
concentration ratios of 5- to 10-fold in the mouse indicated a moderate propensity for 
MLN0128 to cross the blood-brain barrier. MLN0128 was modestly bound (70.5%) to 
human plasma proteins.  Allometric scaling of the animal data to human predicts a low 
clearance (CL ~ 2.1 mL/min/kg), a small volume of distribution (Vss ~ 1.2 L/kg), and a 
plasma half-life (t1/2) amenable to once-daily administration (t1/2 ~ 15-30 hr).
Multiple phase I/II metabolic pathways, including hydroxylation and glucuronidation, have 
been identified for MLN0128.  The metabolites generated in human microsomal incubations 
were also observed in rats and monkeys, the species studied in Good Laboratory Practice 
(GLP) toxicology studies.  The dog (either in vitro or in vivo) did not produce any phase I 
metabolites formed in human microsomal incubations.
The human cytochrome P450 (CYP) isoforms CYP3A4, CYP2C9, and CYP2C19 contribute 
to MLN0128 metabolism.  MLN0128 displayed low potential (IC50 ≥ 30 µM) as a direct 
inhibitor of the major human CYP isoforms (CYP1A2, CYP3A4, CYP2C8, CYP2C9, 
CYP2C19, and CYP2D6).  Recently completed in vitro metabolism experiments in human 
hepatocytes using 14C-labeled MLN0128 suggest that MLN0128 is metabolized primarily 
via CYP1A2 (approximately 31%-40%), with a minor contribution from CYP3A4 
(approximately 11%-22%).  These data suggest that MLN0128 is also metabolized by direct 
glucuronidation (approximately 22%) and an unidentified non-CYP, non-uridine 
diphosphate glucuronosyltransferase pathway (approximately 18%).  The new data differ 
from the previous in vitro CYP phenotyping data obtained using recombinant CYP enzymes, 
which suggested the involvement of CYP2C9 (approximately 35%), CYP2C19 
(approximately 28%), and CYP3A4 (approximately 28%) in MLN0128 metabolism.  
MLN0128 does not inhibit or induce any of the major CYP enzymes.  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 21.2) should only be administered with caution and at the discretion of the 
investigator during the study.
The MLN0128 toxicology program consisted of oral single-dose studies in rats, dogs, and 
monkeys, repeat-dose studies in rats (non-GLP 4-day, non-GLP 14-day, and GLP 28-day 
with 14 days recovery) and monkeys (non-GLP 14-day and GLP 28-day with 14 days 
recovery), a GLP cardiac safety pharmacology study in telemeterized monkeys, and a GLP 
Ames assay.  MLN0128 freebase drug substance (Form A) was used in all these studies and 
will be used in phase 1 clinical studies.
In dogs and monkeys, clinical signs were observed following single intravenous and oral 
doses of MLN0128.  Dogs received an intravenous (IV) dose of 1 mg/kg (20 mg/m2) or an 
oral (PO) dose of 3 mg/kg (60 mg/m2); all animals were euthanized in extremis at 3-days 
postdose with signs of gastrointestinal distress, decreased activity, decreased body 
temperature, and decreased food intake.  Post-mortem gross examinations defined all tissues 
within normal limits.  In the monkey, IV and PO doses were administered at 1 mg/kg 
(12 mg/m2) and 3 mg/kg (36 mg/m2), respectively; all animals displayed clinical signs of 
emesis, decreased activity, and decreased food intake.  Clinical signs persisted up to 7-days 
postdose.  Supportive care consisting of heat lamps, subcutaneous fluids, and supplemental 
food offerings (fruits and vegetables) appeared to aid in the resolution of clinical signs.  
Animals recovered by 10 days postdose.  The overdoses and associated plasma exposures 
exceeded those at the subsequently defined Highest Non-Severely Toxic Dose (HNSTD) of 
0.15 mg/kg/day (1.8 mg/m2/day) in monkeys by 7 to 33-fold.
The toxicity profiles in rats from the 14-day and 28-day studies were consistent.  In the 
28 day repeat-dose with 14-day recovery rat study, dose-related increases in toxicity were 
observed; no effects at 0.3 mg/kg/day (1.8 mg/m2/day), no significant adverse effects at 
1.0 mg/kg/day (6.0 mg/m2/day), and mild to moderate effects at 3 mg/kg/day 
(18 mg/m2/day).
The effects seen at the 3.0-mg/kg/day dose were 26% body weight decreases as compared to 
controls.  Clinically significant changes observed in clinical chemistry parameters with 
increases in aspartate aminotransferase, glucose, and insulin; decreases in leukocytes, 
lymphocytes, and eosinophils; and histopathological changes in the bone marrow 
(hypocellularity), thymus (lymphoid necrosis), testes (degeneration/atrophy), epididymides 
(oligospermia), ovaries (abnormal estrous cycle), and lungs (alveolar histiocytosis).  A 
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functional observational battery (FOB) test (conducted on study Days 1, 2, and 27) observed 
a mild change in gait only in the high-dose males on Day 27.  The MLN0128 plasma 
exposures (maximum plasma concentration [Cmax] and area under the concentration-time 
curve from time 0 to time of last measurable concentration [AUC0-last]) increased dose-
proportionally between 0.3 to 3.0 mg/kg/day with no difference between male and female 
rats and the toxicokinetic parameters were similar between Day 1 and Day 28.
Following a 14-day recovery period, all test-article related findings were resolved to normal 
levels, demonstrating reversibility of MLN0128 induced toxicities in the rat.  Based on the 
data from the 28-day, repeat-dose, rat study, the dose of 3 mg/kg/day (18 mg/m2/day) was 
considered the rodent STD10 (severely toxic dose to 10% of rats).
In the 28-day, repeat-dose, GLP, cynomolgus monkey study, MLN0128 toxicities were dose 
related and were either absent or tended toward normal at the end of the 14-day recovery 
period.  The high dose (0.3 mg/kg/day [3.6 mg/m2/day]) resulted in severe toxicities that led 
to the moribund sacrifice of 2 monkeys, discontinuation of dosing, and the end of study 
assessments on Day 19.  MLN0128-related effects observed at the high dose included 
clinical signs of 10% body weight decreases as compared to baseline, decreased appetite, 
abnormal posture, decreased activity, and decreased body temperature.  Clinical chemistry 
changes were increases in aspartate aminotransferase, creatinine kinase (MM isoform), 
cholesterol, triglycerides, and insulin; and decreases in sodium, potassium, and phosphorus.  
Hematology parameter alterations were decreases in lymphocytes and increases in 
neutrophils and monocytes.  Milder effects were observed at 0.15 mg/kg/day 
(1.8 mg/m2/day).  The low dose (0.05 mg/kg/day [0.6 mg/m2/day]) produced only some 
instances of test-article related organ weight changes; weight decreases in thymus 
(statistically significant) and in spleen, and weight increases in adrenals.
Histopathological changes at the 0.15-mg/kg/day and 0.3-mg/kg/day doses were seen in the 
thymus, spleen, lymph nodes, gut-associated lymphoid tissue, bone marrow, adrenal glands, 
salivary glands, gastrointestinal tract, skin, and epididymides.  In the recovery animals, 
findings were limited to the thymus (minimal to mild lymphoid depletion).  Specific 
MLN0128-related microscopic findings in the lymphoid organs, including gut-associated 
lymphoid tissue, were multicentric lymphoid depletion and splenic red pulp depletion.  At 
the high dose, the spleen had moderate to severe depletion of red blood cells and 
hematopoietic cells.  In bone marrow, minimal to moderate mixed cell depletion was seen.  
In adrenals, minimal to moderate bilateral cortical hypertrophy/hyperplasia was evident.  In 
the pancreas, there was minimal to severe acinar cell secretory depletion.  Similar findings 
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were seen in the parotid and mandibular salivary glands at the high dose.  In the 
gastrointestinal tract, there were findings in the cardiac and pyloric stomach of minimal to 
mild erosion/ulceration, edema, hemorrhage, and acute inflammation; in the ileum of 1 high-
dose male, minimal hemorrhage; and in 1 high-dose female, mild mucosal atrophy.  In the 
jejunum, colon, and rectum, there were findings of minimal dilatation of mucosal glands; 
and in the rectum, minimal to mild erosion/ulceration.  At the high dose (0.3 mg/kg/day), 
some monkeys exhibited mild to moderate erosion/ulceration and minimal to moderate 
epidermal hyperplasia of the skin on the face, neck, and forelimbs; the effect was considered 
possibly related to test article, debilitation, or self-trauma.  In the epididymides of all 
controls and treated males there were severe bilateral oligospermia considered indicative of 
sexual immaturity.
In the recovery monkeys, test article-related findings of minimal to mild lymphoid depletion 
were limited to thymus in females at 0.15 mg/kg/day and in both sexes at 0.30 mg/kg/day.  
This lymphoid depletion was of lesser severity than that noted at the terminal necropsy 
indicating partial resolution over the recovery period.
Electrocardiography conducted on all animals at baseline, Day 1, and Day 27 demonstrated 
no test article effects.  This was consistent with the lack of significant findings in the 
GLP-compliant, cardiovascular, safety pharmacology study conducted in conscious 
monkeys.
MLN0128 plasma exposures (Cmax and AUC0-last) increased in a dose-proportional manner 
between 0.05 to 0.30 mg/kg/day with no difference observed between male and female 
monkeys.  Steady-state plasma exposures (Day 19 or Day 28 AUC0-last for high or mid/low 
doses, respectively) were 0.8-fold to 2.7-fold higher than those obtained on Day 1 consistent 
with t1/2s of 5 to 16 hours that suggest this level of accumulation.
On the basis of the data from the 28-day, GLP, repeat-dose, monkey study, a dose of 
0.05 mg/kg/day was well tolerated, minimal to moderate toxicities were observed at 
0.15 mg/kg/day, and a dose of 0.3 mg/kg/day produced dose-limiting, severe toxicity.  Thus, 
the HNSTD in monkeys was considered to be 0.15 mg/kg/day (1.8 mg/m2/day).
6.2   Clinical Experience With MLN0128
A detailed review of the safety and PK profile observed with MLN0128 can be found in the 
MLN0128 Investigator’s Brochure (IB).
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6.2.1   Clinical Safety
The safety and tolerability of single-agent MLN0128 administration is being studied in this 
first-in-human (FIH), phase 1, dose-finding study in subjects with advanced solid 
malignancies and a second phase 1 study (Study INK128-002) in subjects with multiple 
myeloma and non-Hodgkin lymphoma, including Waldenström Macroglobulinemia.  A third 
phase 1b trial (Study INK128-003) is evaluating MLN0128 in combination with paclitaxel 
in subjects with advanced solid malignancies.
Repeated in 28-day cycles, the dosing regimens (and dose ranges) studied to date in 
INK128-001 are the following:  once daily (QD; 2-7 mg), once weekly (QW; 10-40 mg), 
once daily for 3 consecutive days per week (QD3d QW; 6-20 mg), and once daily for 5 
consecutive days per week (QD5d QW; 7-13 mg).  As of 09 December 2012, dose-limiting 
toxicities have included hyperglycemia, asthenia, fatigue, mucositis, and rash.  SAEs 
attributed to MLN0128 have included hyperglycemia, asthenia, mucosal inflammation, 
stomatitis, esophagitis, nausea, anemia, renal failure, cardiac arrest, and ventricular 
fibrillation.
There have been 5 deaths during the study attributable to (1 subject each) pleural effusion, 
small intestinal obstruction, cancer pain, disease progression, and cardiac arrest.  The only 
death considered related to study drug was due to cardiac arrest in a subject receiving 6 mg 
QD.
Regardless of causality, adverse events (AEs) with intensity Grade 3 have been reported in 
10% of subjects and include hyperglycemia, asthenia, mucosal inflammation, anemia, 
lymphopenia, hypophosphatemia, and rash.  Inclusive of all grades, the most frequently 
reported AEs (those with 20% incidence) include hyperglycemia, asthenia, fatigue, 
mucosal inflammation, decreased appetite, nausea, vomiting, diarrhea, rash, and pruritus.
As of 09 December 2012, there have been 2 dosing regimens studied in INK128-002.  In 
repeated 28-day cycles, they are QD (2-7 mg) and QD3d QW (9-12 mg).  DLTs have 
included asthenia, fatigue, mucosal inflammation, rash, urticaria, and thrombocytopenia.  
None of the13 SAEs reported was attributed to MLN0128.  Two subjects have died during 
the study of events not related to MLN0128:  1 death was due to subdural bleeding and the 
other death was due to an unspecified cause.  Regardless of causality, AEs with intensity 
Grade 3 reported in at least 2 subjects include fatigue, mucosal inflammation, neutropenia, 
thrombocytopenia, hypocalcemia, hypophosphatemia, and pneumonia.  Inclusive of all 
grades, the most frequently reported AEs (those with 20% incidence) include 
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hyperglycemia, fatigue, stomatitis, decreased appetite, nausea, vomiting, diarrhea, anemia, 
and thrombocytopenia.
As of 09 December 2012, the MLN0128 dosing regimens (and dose ranges) studied in 
INK128-003 are QD3d QW (6-10 mg), QD5d QW (7 mg), and QW (30 and 40 mg).  
MLN0128 is administered in combination with paclitaxel (80 mg/m2) administered on 
Days 1, 8, and 15 of each 28-day cycle.  The dose escalation phase of this study has 
completed and the administration of MLN0128 plus paclitaxel with or without trastuzumab 
is being evaluated in the expansion phase.  Observed DLTs include fatigue, mucosal 
inflammation, rash, nausea, diarrhea, leukopenia, neutropenia, and thrombocytopenia.  SAEs 
observed with the MLN0128 + paclitaxel are dehydration, diarrhea, vomiting, and mucositis.  
There have been 7 deaths during the study including 4 due to disease progression, and 
1 death each due to myocardial infarction, enlarging tumor mass causing tracheal 
compression, and pneumonia.  None of these deaths were attributed to MLN0128 or 
paclitaxel.  Regardless of causality, AEs with intensity Grade 3 reported in at least 
2 subjects are hyperglycemia, fatigue, diarrhea, dehydration, neutropenia, and 
hypophosphatemia.  Inclusive of all grades, the most frequently reported AEs (those with 
20% incidence) include hyperglycemia, asthenia, fatigue, mucosal inflammation, anorexia, 
rash, nausea, vomiting, diarrhea, dehydration, hypokalemia, hypophosphatemia, anemia, 
neutropenia, urinary tract infection, and constipation.
Details on these studies are provided in the MLN0128 IB.
6.2.2   Clinical Pharmacokinetics
MLN0128 displays high oral bioavailability and predicable PK with minimal levels of 
steady state accumulation.  It is rapidly absorbed with Tmax occurring between 1 to 4 hours 
following oral administration.  The mean elimination half-life of MLN0128 ranged from 
approximately 7 to 11 hours across 4 dose levels.  The mean accumulation index of 
MLN0128 following multiple doses ranged from 0.7-fold to 1.7-fold.  The mean steady-state 
plasma concentrations (Cmax,ss) ranged from 52 to 232 nM.  Comparisons of plasma 
exposures (Cmax and area under the plasma concentration-time curve from 0 to 24 hr 
[AUC0-24]) following oral doses of MLN0128 suggest dose-linear plasma pharmacokinetics.
6.3   Study Rationale
The mTOR is a kinase that regulates cell growth, translational control, angiogenesis, and 
cell survival by integrating nutrient and hormonal signals.  mTOR plays a key role in several 
pathways that are frequently dysregulated in human cancer.(2)  The mTOR activity in the 
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intracellular signaling complexes (TORC1 and TORC2) is an important therapeutic target 
because (i) it is a key intracellular point of convergence for a number of cellular signaling 
pathways; (ii) it appears to be a stable target that does not mutate; (iii) inhibiting mTOR may 
inhibit abnormal cell proliferation, tumor angiogenesis, and abnormal cellular metabolism.  
Thus, mTOR inhibitors may be effective as single agents and may enhance the efficacy of 
other cancer treatments.
mTOR operates in 2 distinct multi-protein complexes, TORC1 and TORC2.  TORC1, 
stimulated by growth factors and amino acids, regulates cell growth by controlling the 
activity of the ribosomal protein S6 (S6) kinases and eukaryotic initiation factor 4 binding 
proteins (4EBPs).(3)  Rapamycin (Rapamune®) is a TORC1 inhibitor that has been approved 
for prophylaxis of organ rejection in subjects receiving renal transplants.  Although 
rapamycin has been shown to possess some antitumor activity, its poor aqueous solubility 
and chemical stability has precluded its utilization at doses necessary for anticancer 
treatment.  This led to the development of new rapalogs.  Those currently in clinical 
development as anticancer agents include temsirolimus (cell cycle inhibitor-779 or 
CCI-779), everolimus (RAD-001), and deforolimus (AP23573).  These agents have 
demonstrated antiproliferative activity against a range of malignancies in preclinical studies 
and clinical evaluations have revealed some encouraging data in selected disease 
populations.  In 2007, temsirolimus (Torisel®) was approved by the United States (US) Food 
and Drug Administration (FDA) for treatment of advanced renal cell cancer and, in March 
2009, everolimus (Afinitor®) was approved for treatment of advanced renal cancer after 
failure of treatment with sunitinib or sorafenib.(4, 5)  Despite some encouraging clinical data, 
the rapalogs have limitations and efficacy may be confined to distinct subject subtypes or 
diseases.  There are several scientific hypotheses that may explain the limited success of 
rapalogs.  Inhibition of TORC1 (without inhibition of TORC2) leads to activation of 
serine/threonine protein kinase B (AKT) due to a feedback mechanism, and this 
upregulation of AKT may actually accelerate tumor progression, thus limiting the clinical 
efficacy of rapalogs.(6)
Additionally, TORC2 phosphorylates AKT which is required for full activity of AKT.  
Activated AKT is involved in cancer cell survival, proliferation, growth, metabolism, 
angiogenesis, and metastasis.  Inhibition of AKT activity through TORC2 inhibition has 
been explored for anticancer therapeutics and preclinical investigations have shown 
inhibition of TORC2 blocks cancer growth.(7)  TORC2 inhibition can also reverse the 
activation of AKT induced by TORC1 inhibition.  Therefore, mTOR inhibitors that target 
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both mTOR complexes such as MLN0128 may achieve greater clinical efficacy than 
rapalogs.(8)
To date, INK128-001 has evaluated in QD, QW, QD3d QW, and QD5d QW dosing 
schedules in subjects with advanced malignancies.
The PI3K/mTOR pathway is central to a number of vital cellular functions, such as cell 
growth, translational control, angiogenesis, and survival.  Dysregulation of this pathway has 
been implicated in many types of human cancers.(2)  In the expansion phase, patients with 
the following tumor types will be enrolled based on the recognized importance of the 
PI3K/mTOR pathway in each:  renal, endometrial, and bladder.  The significance of the 
PI3K/mTOR pathway in each of these tumor types is presented in the following.
Renal Cancer:  mTOR controls cell growth, proliferation, and survival and plays a critical 
role in the pathogenesis of renal cell carcinoma (RCC).(9)  mTOR frequently shows 
alterations in the mTOR signaling pathway, either increasing mTOR activity or, depending 
on mTOR activation for their oncogenic potential, mTOR controls production of HIF-1, an 
important protein in RCC, where its unregulated activity is causally related to disease 
pathogenesis.(10)  The HIF transcription factors drive the expression of hypoxic stress 
response genes, which include angiogenic growth factors, such as VEGF, PDGF-, TGF-, 
and Ang-1.  PTEN is frequently lost in RCC, which stimulates mTOR activity through 
enhancement of the PI3K/AKT pathway.  Loss of PTEN is correlated with survival and 
indicates a poorer prognosis.(11)  Two partial TORC1 inhibitors, temsirolimus and 
everolimus, have already been approved for the treatment of RCC.  MLN0128 is a potent 
inhibitor of TORC1 and TORC2.  It shows strong inhibition of RCC cells regardless of their 
genetic backgrounds.  MLN0128 also displays potent anti-tumor efficacy in various 
preclinical RCC tumor models.(12)
Endometrial Cancer:  The PI3K pathway is frequently hyper-activated in endometrial cancer 
through various PI3K/AKT activating mutations (such as phosphatase and tensin homolog 
[PTEN] and phosphoinositide-3-kinase alpha catalytic subunit [PIK3CA]).(13)  The finding 
of PTEN mutations in 40% to 60% of endometrial cancers and PIK3CA mutations in 23%, 
suggests this pathway is important in the pathogenesis of this disease.(14)  Loss of PTEN 
leads to constitutive activation of AKT, which in turn leads to up-regulation of mTOR.  The 
PIK3CA mutations are nonsynonymous missense mutations that confer constitutive kinase 
activity rendering the PI3K/mTOR pathway hyperactivated.  MLN0128 potently inhibits 
proliferation of endometrial cells with PTEN and PI3Kα mutations in vitro.  It displays 
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single agent anti-tumor activity in preclinical tumor models and enhances the efficacy of 
standard-of-care chemotherapeutic agents such as paclitaxel and docetaxel.(15, 16)
Bladder Cancer:  PI3K/mTOR pathway activation is involved in bladder cancer 
tumorigenesis and development.  This pathway can be activated by multiple components.  
PI3K-α mutation is detected in about 25% of bladder cancers.(17)  Over 10% of bladder 
cancers show mutations in PTEN and TSC1 genes.(17)  The expression of pAkt, p4EBP1, and 
pS6 is significantly higher in high-grade and advanced-stage bladder cancers and is 
associated with poorer prognosis.(18, 19)  Rapalogs have been shown to inhibit bladder cancer 
cell proliferation and induce apoptosis in vitro, and inhibit bladder tumor growth in mouse 
models.(20, 21)  MLN0128, which more potently inhibits pAKT and p4EBP1 than rapalogs, 
could be exploited as a potential therapeutic strategy in bladder cancer.
6.4   Summary of Overall Risks and Benefits
Currently, 206 subjects have participated in phase 1 studies including 145 subjects in single-
agent studies INK128-001 and INK128-002 (N = 106 and N = 39, respectively); and 
61 subjects in the paclitaxel combination study INK128-003.  Toxicities have been mostly 
Grades 1 and 2, reversible, and manageable with supportive care and/or interruption or dose 
reduction of study drug.  Commonly reported study drug-related AEs have included 
hyperglycemia, asthenia, fatigue, mucosal inflammation, decreased appetite, rash, nausea, 
vomiting, and diarrhea.  This emerging safety profile is consistent with those of other 
TORC1/2 and PI3K pathway inhibitors.
As of 2012, there are no FDA-approved TORC1/2 inhibitors.  Rapamycin and rapalogs are 
TORC1 inhibitors with well-described toxicity profiles.  Common toxicities include the 
following:  immunosuppression with the potential to increase the risk of both nonserious and 
serious infections, and/or malignancies; mucositis, stomatitis, and mouth sores with a 
frequency from 41% to 78%; anorexia (approximately 30%), pneumonitis including 
interstitial lung disease (5%-36%); diarrhea (25%-56%); skin toxicity (48%-66%) which 
manifests typically as maculopapular or acneform rash, skin dryness, eczema, skin 
discoloration, and nail dystrophy; hyperlipidemia (hypercholesteremia and/or 
hypertriglyceridemia) with incidences from 8% to 44%; hyperglycemia (8%-22%); 
thrombocytopenia (10%-33%); anemia (27%-94%); leucopenia (27%-38%); hypokalemia 
(11%-21%); hypophosphatemia (15%-49%); hypertension (4%-7% in renal cancer subjects); 
elevated serum creatinine (37%-57%); elevated liver function tests (about 20%); arthralgia 
(25%-30%); asthenia (about 30%); peripheral edema (24%-35%).(22, 23, 24, 25)  Serious 
infections have included sepsis, opportunistic infections, and even death.  An increase in the 
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development of lymphomas is also a possibility because of the immunosuppression.  
Additionally, hypersensitivity reactions (18%), and fatal bowel perforation (1%) have been 
reported.  Rapidly progressive, and sometimes fatal, acute renal failure not clearly related to 
renal cancer disease progression, abnormal wound healing, and increased risk of developing 
intracerebral bleeding (including fatal outcomes) in subjects with central nervous system 
(CNS) malignancies and/or receiving anticoagulation therapy have been reported in subjects 
receiving temsirolimus.  Because of potential hazard to the developing fetus, women of 
childbearing potential are advised to avoid becoming pregnant while receiving Rapamycin 
or rapalogs.(23, 24, 25)
The toxicities of rapamycin or rapalogs are typically reversible and infrequently serious.  
MLN0128 targets both TORC1 and TORC2, and thus may prove to have a different 
risk/benefit profile from the rapalogs.  There is no human information available on 
inhibition of TORC2 alone.  The safety profile of MLN0128 continues to be explored in 
advanced malignancies, including non-Hodgkin lymphoma (NHL), and hematologic 
malignancies.
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7.   
STUDY OBJECTIVES
The primary objectives of the study are:
!
To determine the MTD and DLT of oral administration of MLN0128 given daily or 
via alternate dosing schedules in subjects with advanced malignancies
!
To evaluate the safety and tolerability of orally administrated single-agent 
MLN0128, given daily or via alternate dosing schedules, in both the dose escalation 
and the expansion phases of the study
The secondary objectives of the study are:
!
To evaluate the plasma PK of single-agent MLN0128 following oral administration 
daily and according to alternate dosing schedules, in subjects with advanced 
malignancies
!
To evaluate the pharmacodynamic effect of MLN0128 activity in surrogate tissue 
(skin) and tumor as measured by S6, eukaryotic initiation factor 4E-binding protein 1 
(4EBP1), and AKT, as well as in peripheral blood cells as measured by 4EBP1
!
To evaluate preliminary anti-tumor activity of MLN0128
The exploratory objectives of the study are:
CCI
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CCI
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8.   
INVESTIGATIONAL PLAN
8.1   Overall Study Design and Plan
This is a phase 1, open-label study that consists of a dose escalation phase in subjects with 
advanced malignancies, followed by an expansion phase of safety and efficacy in up to 
80 additional response-evaluable subjects with measurable disease.  Up to 4 different dosing 
schedules will be explored in the dose escalation phase:  QD, once weekly (QW), 
QDx3d QW, and QDx5d QW.  Enrollment will start with the once daily schedule.  Once the 
MTD for this schedule is identified, enrollment will begin in parallel in the alternate dosing 
schedules.  Once the MTD has been identified for each of the 4 dosing schedules evaluated, 
an additional 6 subjects may be enrolled in 1 or more of the dosing schedules to gain further 
PK and safety data prior to the expansion phase of the study.
Based on biochemical data, available PK, and tolerability data for each MLN0128 dosing 
schedule, along with potential early signs of anti-tumor activity from subjects treated during 
the dose escalation phase, 1 or more dosing schedules will be selected to be evaluated in the 
expansion phase.  In the expansion phase, the safety and efficacy of 1 or more MLN0128 
treatment schedules will be evaluated in parallel in a renal tumor-specific cohort, as well as 
in cohorts of selected tumor types (endometrial and bladder cancers) for a total of 
80 response-evaluable subjects.
8.2   Dose Escalation Phase
Up to 4 different dosing schedules will be explored in the dose escalation phase:  QD, QW, 
QD3d QW, and QD5d QW.  The MTD for the QD schedule of MLN0128 in subjects 
with advanced solid malignancies was determined to be 6 mg (MTDqd = 6 mg) on the basis 
of the initial evaluation of 6 subjects in this cohort.
After the MTD was determined for the once-daily dosing schedule (MTDqd = 6 mg), study 
of the additional dosing schedules began with implementation of Amendment 7.  Enrollment 
was initiated in 2 parallel and independent arms:  Arm A with once-weekly dosing starting 
at a dose not to exceed that of twice the MTDqd; and Arm B with MLN0128 administered 
QD3d QW starting at the MTDqd.  Amendment 10 added a further dosing schedule as 
noted, QD5d QW.  Subjects are randomly assigned to an alternate dosing arm when all 
arms are open for enrollment at the same time.  Subjects may not participate in more than 1 
dosing arm.
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In the absence of unacceptable MLN0128 treatment-related toxicity or disease progression, 
subjects may receive MLN0128 treatment for up to 1 year at the discretion of the 
investigator and beyond 1 year with the agreement of the investigator and the sponsor.
8.2.1   Dose-Limiting Toxicity
Dose-limiting toxicities (DLTs) are defined according to the adverse event profile observed 
during the first 28 days of drug administration in the dose escalation phase of the study and 
as described in Table 8-1.  Adverse events will be graded according to the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0.  A copy 
of this grading scale will be provided to the study sites upon request or can be accessed at 
http://ctep.cancer.gov/forms/CTCAEv4.pdf.  All AEs should be considered possibly related 
to the study drug unless such relationship can be definitively excluded.
Dose-limiting toxicity is defined as any of the following MLN0128-related toxicities that 
occur within the first 28 days of the administration of MLN0128 (Table 8-1).
Table 8-1   
Definition of Dose-Limiting Toxicity

Grade ≥ 3 non hematologic toxicity, except for
o
Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all subjects 
should receive optimal antiemetic and/or antidiarrheal prophylaxis and/or treatment);
o
Grade 3 hyperglycemia lasting ≤ 14 days (all subjects should receive optimal antiglycemic 
treatment, including insulin);
o
Grade 3 rash lasting ≤ 3 days (all subjects should receive topical steroid treatment, oral 
antihistamines, and pulse oral steroids, if necessary).

Grade 4 neutropenia lasting > 7 days in the absence of growth factor support.

Grade 4 neutropenia of any duration accompanied with fever ≥ 38.5°C and/or systemic infection.

Any other Grade ≥ 4 hematologic toxicity.

Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 due to drug-
related toxicity.

Any clinically significant occurrence which the investigators and sponsor agree would place 
subjects at undue safety risk.
Subjects who experience an AE that meets the definition for a DLT during or after 
completing Cycle 1 should have their study drug treatment interrupted.  If the event resolves 
to Grade 1 or baseline values within 28 days of interrupting planned therapy, and in the 
opinion of the investigator and the sponsor’s medical monitor, the benefits of continuing 
treatment outweigh the risks posed by the toxicity, subjects may continue study treatment 
with MLN0128 at a 25% dose reduction (or next lower dose level) with approval of the 
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sponsor’s medical monitor.  See Section 8.6 for management of MLN0128 dose for specific 
clinical events.
8.2.2   Dose Escalation Plan to Determine the Maximum Tolerated Dose
Cohorts of 3 to 6 subjects with advanced malignancies will be enrolled at each MLN0128 
dose and dosing schedule being evaluated.  Subjects at each dose will be treated and 
observed for DLT through the end of the first cycle.  Each subject will participate in only 1 
cohort dose level and 1 dosing schedule arm.
The initial dose escalation started with the once-daily dosing schedule in subjects with 
advanced solid malignancies, and the MTDqd has been determined to be 6 mg QD.  Upon 
implementation of Amendment 7, enrollment was initiated and is ongoing to evaluate 
2 alternate dosing schedules:  Arm A with QW dosing starting at a dose not to exceed that of 
twice the MTDqd and Arm B with MLN0128 administered QD3d QW starting at the 
MTDqd.  Amendment 10 added a further dosing arm, Arm C, where study drug is 
administered QD5d QW starting at a dose not to exceed the total weekly dose of the 
MTDqd (≤ 42 mg/week).  Initial dose cohorts for each of the alternate dosing schedules 
(Arms A, B) prior to Amendment 10 enrolled a single subject.  If Grade ≥ 2 AE, regardless 
of relatedness to MLN0128, is observed in any single subject cohort, an additional 2 to 
5 subjects will be assigned to that cohort and subsequent dose cohorts in that arm will 
include 3 to 6 subjects as previously described.  Upon implementation of Amendment 10, 
Arm C will enroll 3 subjects, with an additional 3 subjects enrolled should a DLT be 
observed per standard 3 + 3 phase 1 cohort design.  Subjects will be randomly assigned to 
each of the 3 alternate dosing arms should 2 or more arms be open for enrollment at the 
same time.
Dose escalation will only proceed if no DLT is observed in a cohort of at least 3 subjects.  If 
a DLT is observed in only 1 subject in a cohort of 3 subjects, an additional 3 subjects may 
be enrolled up to a total of 6 subjects at this dose level.  Dose escalation will then only 
proceed if no more than 1 subject in the cohort of 6 subjects has experienced a DLT during 
the first cycle of treatment.  If a DLT is observed in 2 or more subjects in a cohort of 3 or 
6 subjects, an additional 3 subjects will be enrolled for a total of 6 subjects at the previous 
lower dose level, if only 3 subjects were treated at that lower dose level.
A summary of the dose escalation decision rules for MTD determination is provided in 
Table 8-2.
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Table 8-2   
Maximum Tolerated Dose Determination and Cohort Expansion
Number of Subjects with 
DLTa
Dose Escalation Decision Rule
0 of 3
Enter 3 subjects at the next dose level.
1 of 3
Enter up to 3 more subjects at this dose level.

If none of the 3 additional subjects has a DLT, proceed to the next 
dose level.

If 1 or more of the 3 additional subjects has a DLT, then dose 
escalation will be stopped, and the MTD has been exceeded.  Up to 
3 additional subjects may be entered at a lower dose level if only 
3 subjects were treated previously at that dose or a new cohort of 
3 subjects at an intermediate dose level may be evaluated.
2
Stop dose escalation.  MTD may have been exceeded.

Up to 3 additional subjects will be entered at a lower dose level if 
only 3 subjects were treated previously at that dose or a new cohort 
of 3 subjects at an intermediate dose level or a lower level may be 
evaluated.
1 of 6 at the highest 
evaluated dose level
This is usually the MTD.
Abbreviations:  DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
a Number of subjects per cohort with a DLT during Cycle 1 (Days 1 - 28).
The MTD determination for each of the 4 dosing schedules evaluated will be based on initial 
cohorts of 6 evaluable subjects each as described in Table 8-2.  Once the MTD has been 
identified for each of the 4 dosing schedules, an additional 6 subjects may be enrolled at the 
MTD of each dosing schedule to gain more PK and safety data before the expansion phase 
of the study.  The safety and tolerability data from all subjects enrolled at a given dose and 
schedule will be evaluated to determine the recommended dose(s) and schedule(s), based on 
the totality of safety data, for further study in the expansion phase.
All participating sites are required to send in DLT notification forms within 24 hours of 
learning of the event (details will be provided in the Study Reference Manual).  All DLT(s) 
will immediately be communicated to all participating sites via emails and/or conference 
calls.  Additionally, site teleconferences between the sponsor and all participating sites will 
be held approximately every 1 to 2 weeks during the dose escalation phase to discuss any 
suspected AEs/DLTs that have occurred in each cohort.  Participating investigators and the 
sponsor’s medical monitor will review study toxicities from the current cohort during the 
site teleconferences before escalating to the next dose level, de-escalating to an intermediate 
dose level, or adding additional subjects at the current dose level.
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8.3   Expansion Phase
After the MTD has been determined for each of the dosing schedules in the dose escalation 
phase, based on the evaluation of biochemical, PK, and tolerability data, and potentially 
early signs of antitumor activity, 1 or more of these schedules (initially 2) will be advanced 
in the expansion phase for study in 2 cohorts, a renal cancer cohort and a cohort of selected 
tumor types (endometrial and bladder cancers).  As shown in Figure 8-1, approximately 15 
to 25 response-evaluable subjects per treatment schedule will be enrolled into each cohort.
Figure 8-1   
Expansion Stage Cohort Enrollment
Subjects who receive at least 1 dose of MLN0128, have measureable disease at baseline, and undergo at least 
1 postbaseline disease assessment are considered response-evaluable.
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8.4   Intrasubject Dose Escalation
Once the MTD is determined for each dosing schedule (QD, QW, QD3d QW, and 
QD5d QW) of single-agent MLN0128, intrasubject dose escalation within a given dosing 
schedule may be allowed (at the investigator’s discretion and with the sponsor’s approval) in 
subjects actively receiving single-agent MLN0128 at a dose lower than the MTD and for a 
minimum of 8 weeks in the absence of disease progression or unacceptable treatment-related 
toxicity.  Subjects may not switch from 1 dosing schedule to another or participate in more 
than 1 dosing schedule arm at any time.
8.5   Dose Modification or Treatment Delay for MLN0128-related Toxicity
MLN0128 dosing should be withheld for ≥ Grade 3 MLN0128-related toxicities.  If the 
event resolves to Grade 1 or baseline values within 28 days of interrupting therapy, the 
subject may resume study treatment at a 25% dose reduction or, for subjects in the dose 
escalation phase, at the next lower dose level with the sponsor’s approval.  If dose 
modification is required for subjects receiving 4 mg QD, then the dosing frequency should 
be decreased to 5 days per week, instead of decreasing the daily dose administered.  If 
MLN0128 dosing is delayed for > 28 consecutive days for MLN0128-related toxicity 
despite supportive treatment per standard clinical practice or more than 2 dose reductions of 
MLN0128 is required in a subject, stop MLN0128 therapy, discontinue the subject from the 
study, and complete the follow-up visit within 30 days of the last administration of 
MLN0128.
See Section 8.6 for management of MLN0128 dosing for specific clinical events.
The sponsor’s medical monitor should be contacted prior to any dose modification in 
MLN0128 for any subject in the study.
8.6   Management of Clinical Events
8.6.1   Management of Hyperglycemia
In addition to obtaining fasting serum glucose (FSG) levels at the clinic visits as outlined in 
the Schedule of Events, all subjects will be given a glucometer to monitor their daily 
predose fasting blood glucose (FBG) levels at home.  Subjects will be instructed to notify 
the study staff immediately with any abnormal readings (ie, ≥ 150 mg/dL) for further 
instructions on the management of their hyperglycemia.  Hyperglycemia observed during 
home glucose monitoring should be confirmed in the clinic.  Investigators will be 
responsible for reviewing the home glucose monitoring logs for hyperglycemia.  If no 
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irregularities in the fasting blood glucose 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.  Subjects will continue to notify the 
investigator of fasting blood glucose levels that exceed 150 mg/dL and, if blood glucose 
levels are not well-controlled, or if the subject requires either oral hypoglycemic agents or 
insulin to control blood glucose levels, then the frequency of in-home testing of fasting 
blood glucose levels will be reinstated to daily.
Guidance for MLN0128 dose management in the event of hyperglycemia is provided in 
Table 8-3.
Table 8-3   
Management of Hyperglycemia
Grade
Description
Treatment
MLN0128 Dose Modification
1
Fasting blood sugar
> ULN–160 mg/dL
Continue close monitoring of 
blood sugars.
Initiate oral hypoglycemic 
agent.
None.
2
Fasting blood sugar
> 160–250 mg/dL
Initiate oral hypoglycemic 
agent and/or insulin if not well 
controlled on oral agent.
None.
≥3
Fasting blood sugar
> 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 25%a;
> 2 weeks:  stop MLN0128 and 
discontinue subject from the study.
Prevention/Prophylaxis

Follow fasting serum glucose levels during clinic visits.

Monitor home glucometer test results.

Check HbA1c levels every 3 months during therapy.

Life-style modifications, as appropriate (balanced diet, limit alcohol consumption, increase 
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.

Fasting blood glucose levels ≥150 mg/dL by glucometer should be followed by closer monitoring 
of serum glucose and possible intervention.
Abbreviations:  dL = deciliters; mg = milligrams; ULN = upper limit of normal.
a If dose modification is required for subjects receiving 4 mg QD, then the frequency of dosing should be 
decreased to 5 days/week, rather than decreasing the daily dose administered.
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In the event that any FSG reading performed at the site indicates hyperglycemia (> upper 
limit of normal [ULN] or ≥ 110 mg/dL), the study staff should first ascertain that the subject 
was fasting at the time of the blood draw (ie, nothing by mouth for at least 8 hours prior to 
blood being obtained), had continued to take their concomitant antiglycemic medications 
should the subject have underlying diabetes mellitus, and repeat the FSG as needed.  If the 
repeat FSG continues to demonstrate hyperglycemia, investigators should initiate steps 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 from MLN0128 trials, most episodes of hyperglycemia 
observed have been Grade 1 or 2 that have responded quickly to oral metformin.  
Hyperglycemia has not been dose-limiting since instituting a standard regimen for early 
treatment of hyperglycemia.  All subjects developing hyperglycemia on the study should 
have their glucose closely monitored by study staff.  The investigator may choose either to 
continue close monitoring of subjects who develop Grade 1 hyperglycemia 
(FSG > ULN ≤160 mg/dL) or, alternatively, consider initiating treatment with an oral 
hypoglycemic agent, such as metformin.  All subjects with Grade ≥ 2 hyperglycemia 
(FSG > 160 mg/dL) must be treated aggressively with oral hypoglycemic agents and/or 
insulin as clinically indicated while continuing on MLN0128.  The investigator should 
consult an endocrinologist if needed to aid in optimizing the subject’s hyperglycemia 
treatment plan.
It is recommended that subjects be treated initially with a fast acting, insulin sensitizer, such 
as metformin at 500 mg PO QD, and titrate up to a maximum of 1000 mg PO BID as 
needed.  Concurrent addition to metformin of DPP-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 
subjects.  The dose of oral hypoglycemic agents should be adjusted in subjects with renal 
insufficiency.
8.6.2   Management of Noninfectious Pneumonitis
Guidance for MLN0128 dose management in the event of noninfectious pneumonitis is 
shown in Table 8-4.  Noninfectious pneumonitis has not been observed with MLN0128 as of 
December 2012.
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Table 8-4   
Management of Non-infectious Pneumonitis
Grade
Description
Treatment
MLN0128 Dose Modification
1
Asymptomatic:
Radiographic findings only
Rule out infection and 
closely monitor.
None.
2
Symptomatic:
Not interfering with ADLs
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1.
Interrupt MLN0128 treatment:
When symptoms ≤ Grade 1, re-
initiate MLN0128 treatment with a 
25% dose reductiona.
Discontinue MLN0128 treatment 
if failure to recover within 4 
weeks.
3
Symptomatic:
Interfering with ADLs;
Requires administration of 
O2
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1.
Interrupt MLN0128 treatment until 
symptoms resolve to ≤ Grade 1.
Consider re-initiating MLN0128 
treatment with a 25% dose 
reductiona.
If toxicity recurs at Grade 3, 
discontinue MLN0128 treatment.
4
Life-threatening:
Ventilatory support 
indicated
Rule out infection and 
consider treatment with 
corticosteroids.
Discontinue MLN0128 treatment.
Abbreviations:  ADL = activities of daily living ; O2 = oxygen gas.
a If dose modification is required for subjects receiving 4 mg QD, then the frequency of dosing should be 
decreased to 5 days/week, rather than decreasing the daily dose administered.
8.6.3   Management of Hyperlipidemia
Guidance for MLN0128 dose management in the event of hyperlipidemia is shown in Table 
8-5.
Table 8-5   
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.
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Table 8-5   
Management of Hyperlipidemia
Grade
Description
Treatment
MLN0128 Dose Modification
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 25% dose 
reductiona.
4
Cholesterol:
> 500 mg/dL
Triglycerides:
> 1000 mg/dL
Same as for Grade 2.
Discontinue treatment.
Prevention/Prophylaxis

Life-style modifications, as appropriate (balanced diet, limit consumption of alcoholic beverages, 
increase physical activity).
Abbreviations:  dL = deciliters; mg = milligrams; ULN = upper limit of normal.
a If dose modification is required for subjects receiving 4 mg QD, then the frequency of dosing should be 
decreased to 5 days/week, rather than decreasing the daily dose administered.
8.6.4   Management of Oral Mucositis
Guidance for MLN0128 dose management in the event of oral mucositis is provided in 
Table 8-6.
Table 8-6   
Management of Oral Mucositis
Grade
Description
Treatment
MLN0128 Dose Modification
1
Asymptomatic or mild 
symptoms
Non-alcoholic 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 intra-lesional 
corticosteroids.
Hold dose until recovery to ≤ Grade 1, 
then restart with a 25% dose 
reductiona.
4
Life-threatening 
consequences
Same as for Grade 2.
Consider intra-lesional 
corticosteroids.
Discontinue treatment.
Prevention/Prophylaxis

Consider initiation of a non- alcoholic mouth wash or 0.9% salt water rinses 4-6 times daily with 
start of therapy before signs of mucositis develop.
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
Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis as they may worsen mouth ulcers.
a If dose modification is required for subjects receiving 4 mg QD, then the frequency of dosing should be 
decreased to 5 days/week, rather than decreasing the daily dose administered.
8.6.5   Management of Rash
Guidance for MLN0128 dose adjustment for the event of rash is provided in Table 8-7.
Table 8-7   
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 anti-histamines.
None.
3
Macules/papules covering 
30% body surface area 
with or without symptoms
Consider treatment with 
topical steroid 
cream/ointment, oral 
anti-histamines, and/or 
pulsed steroids.
Hold until Grade 2;
Resume MLN0128 based on timing of 
recovery:
≤ 2 weeks: reduce dose by 25%a;
> 2 weeks: stop MLN0128 and 
discontinue subject from the study.
a If dose modification is required for subjects receiving 4 mg QD, then the frequency of dosing should be 
decreased to 5 days/week, rather than decreasing the daily dose administered.
8.6.6   Management of Nausea and/or Vomiting
Guidance for MLN0128 dose adjustment for the event of nausea and/or vomiting is provided 
in Table 8-8.
Table 8-8   
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, anti-nausea, and anti-diarrheal medications are encouraged and may be used 
before each dose of MLN0128 as needed throughout the study.
Abbreviations:  IV = intravenous; IVF = intravenous fluids; TPN = total parenteral nutrition
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8.6.7   Management of Cardiac Events
8.6.7.1   Management of Cardiac Instability
For subjects showing signs of cardiac instability after MLN0128 dosing, additional 
monitoring onsite before clinic discharge should be considered.
8.6.7.2   Management of Left Ventricular Dysfunction
Guidance for MLN0128 dose adjustment for the event of left ventricular dysfunction is 
provided in Table 8-9.
Table 8-9   
Management of Left Ventricular Dysfunction
Grade
Description
MLN0128 Dose Modification
1
Asymptomatic decline in
LVEF > 15% from baseline values OR;
LVEF > 10%-15% from baseline values and is 
below institution’s LLN
No change; continue MLN0128 at same dose 
and schedule.
2
Symptomatic cardiac dysfunction/congestive 
heart failure
Discontinue treatment.
Abbreviations:  LLN = lower limit of normal; LVEF = left ventricular ejection fraction.
8.6.7.3   Management of QTc Prolongation
Guidance for MLN0128 dose adjustment for the event of QTc prolongation is provided in 
Table 8-10.
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Table 8-10   Management of QTc Prolongation
Grade
Description
Treatment
MLN0128 Dose Modification
2
480 msec 
QTc 
501 msec
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication, etc.)
None; continue MLN0128 at the same 
dose and schedule.
3
QTc 501 
msec
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication)a;
Consider a formal consult by a 
cardiologist;
Notify the sponsor’s medical monitor;
Additional ECGs may be performed at 
intervals that the treating physician 
deems clinically appropriate until 
repeated QTc measurements fall or are 
below the threshold interval that 
triggered the repeat measurement.
MLN0128 should be interrupted.
The decision whether to reinitiate 
MLN0128 treatment with or without 
dose reduction and additional 
monitoring in those subjects who had 
asymptomatic prolonged QTc 501 
msec (Grade 3) that has reverted to an 
acceptable interval, have previously 
tolerated MLN0128, and appear to 
have benefitted from MLN0128 
treatment with either disease control or 
response, will be agreed to by the 
investigator and the medical monitor 
on a case-by-case basis.
Abbreviations:  ECG = electrocardiogram; IV = intravenous; msec = milliseconds; QTc = QT interval 
corrected for heart rate
a A list of medications known to prolong QTc can be found at www.torsades.org and www.QTdrugs.org.
8.6.7.3.1   
Acquisition of 12-Lead Electrocardiograms
All scheduled ECGs should be performed after the subject has rested quietly for at least 5 
minutes in a supine position.  When the timing of ECG assessments coincides with a blood 
collection, the ECG should be obtained prior to the nominal time of the blood collection.  In 
some cases, it may be appropriate to repeat an abnormal ECG to rule out improper lead 
placement as contributing to the ECG abnormality.
8.6.7.3.2   
Review of 12-Lead Electrocardiograms
To ensure safety, a qualified individual at the site will review any clinically significant ECG 
abnormalities, including confirmation that the machine-estimates of the QTc are accurate 
using the appropriate QT correction formula.  In the event, that a QTc value confirmed by 
the qualified reader is > 480 msec, an evaluation should be conducted to correct other 
possible causes (eg, electrolyte disturbance, concomitant medication, etc; See Table 8-10).  
A list of medications known to prolong QTc can be found at torsades.org and QTdrugs.org.  
If done prior to protocol enrollment and if a repeat ECG meets eligibility requirements, the 
subject may enroll in the study upon review and agreement by the medical monitor.
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8.6.8   Management of Other Nonhematologic Toxicities
Guidance for MLN0128 dose management in the event of nonhematologic toxicities is 
shown in Table 8-11.
Table 8-11   Management of Other Nonhematologic Toxicities
(including asthenia/weakness)
Grade
Description
Treatment
MLN0128 Dose Modification
1
Mild:  Asymptomatic or mild 
symptoms; clinical or diagnostic 
observations only; intervention not 
indicated
If tolerable, no adjustment required.
2
Moderate:  minimal, local, or 
non-invasive intervention 
indicated
Initiate appropriate 
medical therapy and 
monitor.
If tolerable, no adjustment required.
If toxicity becomes intolerable, 
interrupt MLN0128 dosing until 
recovery to ≤ Grade 1.  Reinitiate 
at same dose level.
If toxicity recurs at Grade 2, 
interrupt MLN0128 dosing until 
recovery to ≤ Grade 1.  Reinitiate 
with a 25% dose reductiona.
3
Severe or medically significant but 
not immediately life-threatening; 
hospitalization or prolongation of 
hospitalization indicated
Interrupt MLN0128 treatment until 
symptoms resolve to ≤ Grade 1.
Re-initiate MLN0128 treatment 
with a 25% dose reductiona.
If toxicity recurs at Grade 3, 
discontinue MLN0128 treatment.
4
Life-threatening consequences –
urgent intervention required
Discontinue MLN0128 treatment.
a If dose modification is required for subjects receiving 4 mg QD, then the frequency of dosing should be 
decreased to 5 days/week, rather than decreasing the daily dose administered.
8.7   Discussion of Study Design, Including Choice of Control Group
The proposed study design is consistent with other first-in-human oncology trials that assess 
safety and tolerability.  Neither a placebo nor an active control is included in this study.
8.8   Selection of Study Population
8.8.1   Inclusion Criteria
Individuals eligible to participate in either the dose escalation phase and/or the expansion 
phase of the study must meet all the following Inclusion Criteria:
1. Age ≥ 18 years, including males and females;
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2. Subjects must have locally advanced or metastatic solid tumors with the exception of
primary brain tumor, and have failed standard of care therapy.  Subjects with locally 
advanced or metastatic solid tumors who have a history of brain metastasis are 
eligible for the study as long as they meet all the following criteria:  their brain 
metastases have been treated, they have no evidence of progression or hemorrhage 
after treatment, they have been off dexamethasone for 4 weeks prior to first study 
drug administration, and they have no ongoing requirement for dexamethasone or 
anti-epileptic drugs;
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1;
4. Subjects must have adequate organ function, including the following:
a.
Bone marrow reserve consistent with absolute neutrophil count (ANC) 
≥1.5 109/L; platelet count ≥ 100 109/L hemoglobin ≥ 9 g/dL;
b. Hepatic:  total bilirubin ≤ 1.5 upper limit of normal (ULN), transaminases 
(aspartate aminotransferase/serum glutamic oxaloacetic 
transaminase-AST/SGOT and alanine aminotransferase/serum glutamic 
pyruvic transaminase-ALT/SGPT) ≤ 2.5 ULN (≤ 5 ULN if liver 
metastases are present);
c.
Renal:  creatinine clearance ≥50 mL/min based either on Cockroft-Gault 
estimate or based on urine collection (12 or 24 hour);
d. Metabolic:  fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides 
≤300 mg/dL;
5. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of 
institutional standard of normal as measured by echocardiogram (ECHO) or multiple 
gated acquisition scan (MUGA) within 4 weeks prior to first study drug 
administration (ie, if the institutional normal is 50%, subject’s LVEF may be as low 
as 45% to be eligible for the study);
6. For women of child-bearing potential, negative serum pregnancy test within 14 days 
prior to the first study drug administration and use of physician-approved method of 
birth control from 30 days prior to the first study drug administration to 90 days 
following the last study drug administration;
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7. Male subjects must be surgically sterile or must agree to use physician-approved 
contraception during the study and for 90 days following the last study drug 
administration;
8. Willingness to provide paraffin blocks or a minimum of 10 unstained slides of 
available archival tumor tissues (paraffin blocks are preferred);
9. Ability to swallow oral medications;
10. Ability to understand and willingness to sign informed consent form prior to 
initiation of any study procedures;
Subjects who have tumor tissue that is accessible for biopsy based on the investigator’s 
judgment will be strongly encouraged to consent for tumor biopsy.
Additionally, for individuals eligible to participate in the expansion phase of the study:
11. Subjects must have evidence of measurable disease per Response Evaluation Criteria 
in Solid Tumors (RECIST) version 1.1(1) by radiographic techniques (computerized 
tomography [CT] or magnetic resonance imaging [MRI]);
12. Subjects must have a pathologic diagnosis of advanced or recurrent endometrial 
adenocarcinoma and must have failed at least 1 prior line of standard chemotherapy; 
or
13. Subjects must have a pathologic diagnosis of advanced/metastatic urothelial cancer 
(carcinoma of the bladder, ureter, and/or renal pelvis) and must have failed at least 
1 line of prior therapy in the metastatic/unresectable setting; or
14. Subjects must have a pathologic diagnosis of advanced renal cell carcinoma (RCC) 
and must have failed at least 1 prior line of anti-VEGF therapy (including but not 
limited to sunitinib, and/or sorafenib, and/or bevacizumab and/or pazopanib, and/or 
axitinib) and must not have received prior therapy with a TORC1 inhibitor (such as 
temsirolimus or everolimus); or
15. Subjects must have a pathologic diagnosis of advanced renal cell carcinoma (RCC) 
and must have progressed on treatment with a TORC1 inhibitor (such as 
temsirolimus or everolimus).  
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8.8.2   Exclusion Criteria
Individuals who meet any of the following Exclusion Criteria will not be eligible to 
participate in either the dose escalation phase or the expansion phase of the study:
1. Diagnosis of primary brain tumor;
2. Untreated brain metastasis or history of leptomeningeal disease or spinal cord 
compression;
3. Failed to recover from the reversible effects of prior anticancer therapies, with the 
exception of, alopecia, and after-effects associated with prior tyrosine kinase 
inhibitor therapy, such as hair depigmentation, hypothyroidism, and/or splinter 
hemorrhage;
4. Have received prior cancer or other investigational therapy within 2 weeks prior to 
the first administration of study drug.  For prior therapies with a half-life longer than 
3 days, the interval must equal 28 days prior to the first administration of study drug, 
and the subject must have documented disease progression;
5. Have received systemic corticosteroid (inhalers are allowed) within 1 week prior to 
the first administration of study drug (dose escalation phase only);
6. Have initiated treatment with bisphosphonates less than 30 days prior to the first 
administration of MLN0128.  Concurrent bisphosphonate use is only allowed if the 
bisphosphonate was initiated at least 30 days prior to the first administration of 
MLN0128;
7. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI 
disease, or for an unknown reason that may alter the absorption of MLN0128;
8. Poorly controlled diabetes mellitus defined as HbA1c > 7%; subjects with a history 
of transient glucose intolerance due to corticosteroid administration are allowed in 
this study if all other inclusion/exclusion criteria are met;
9. Other clinically significant comorbidities, such as uncontrolled pulmonary disease, 
active CNS disease, active infection, or any other condition that could compromise 
subject’s participation in the study;
10. Known human immunodeficiency virus (HIV) infection;
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11. Pregnancy (positive serum or urine pregnancy test) or breast feeding;
12. Any history of unstable angina, myocardial infarction, New York Heart Association 
(NYHA) Class III or IV heart failure (See Table 21-3), and/or pulmonary 
hypertension;
13. Significant active cardiovascular disease including:

Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mm Hg, 
diastolic blood pressure > 95 mm Hg);

Grade 3 or higher valvular disease;

Grade 3 or higher atrial fibrillation;

Grade 3 or higher bradycardia;

Endocarditis;

Pulmonary embolism;

Recent cerebrovascular accident/transient ischemic attack within 6 months 
prior to enrollment.
14. A requirement for positive inotropic support (excluding digoxin) or active/serious 
uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation) within 1 year 
prior to screening;
15. A pacemaker or implantable cardiac defibrillator;
16. Baseline prolongation of the rate-corrected QT interval (QTc) (eg, repeated 
demonstration of QTc interval > 480 milliseconds) (See Section 8.6.7.3.2);
17. History of congenital long QT syndrome, ventricular fibrillation, ventricular 
tachycardia, or torsades de pointes;
18. Diagnosed or treated for another malignancy within 2 years before the first dose or 
previously diagnosed with another malignancy and have any evidence of residual 
disease.  Patients with nonmelanoma skin cancer or carcinoma in situ of any type are 
not excluded if they have undergone complete resection;
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19. Additionally, for individuals eligible to participate in the expansion phase of the 
study, subjects will be excluded if they have received prior AKT, PI3K, dual 
PI3K/mTOR complex (TORC1/2), or TORC1/2 inhibitors.
Other considerations for exclusion: Subjects taking moderate/strong CYP1A2 inhibitors, 
moderate CYP1A2 and/or strong and moderate CYP3A4 inducers should be considered with 
caution. Alternative treatments that are less likely to affect MLN0128 metabolism, if 
available, should be considered. If a subject requires treatment with 1 or more 
moderate/strong CYP1A2 inhibitor, a moderate/strong CYP1A2 and/or a strong CYP3A4 
inducer, the medical monitor should be consulted. Examples of clinically relevant 
moderate/strong CYP1A2 inhibitors and inducers, as well as strong CYP3A4 inducers, are 
presented in Table 21.2.
8.8.3   
Removal of Subjects From Treatment or Assessment
Subjects may withdraw their consent to participate in this study at any time without 
prejudice.  The investigator must withdraw from the study any subject who requests to be 
withdrawn.  A subject’s participation in the study may be discontinued at any time at the 
discretion of the investigator and in accordance with his/her clinical judgment.  When 
possible, the tests and evaluations listed for the Termination visit should be carried out.
Millennium must be notified of all subject withdrawals as soon as possible.  Also, 
Millennium reserves the right to discontinue the study at any time for either clinical or 
administrative reasons and to discontinue participation by an individual investigator or site 
for poor enrollment or noncompliance.
Reasons for which the investigator or Millennium may withdraw a subject from the study 
include, but are not limited to, the following:

Subject experiences disease progression;

Subject experiences unacceptable toxicity, ie,

Subject develops an AE which meets the DLT definition but the AE does not 
resolve to Grade ≤ 1 within 28 days despite optimal treatment per standard 
clinical practice;

Subject requires more than 2 dose reductions;
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
Subject experiences toxicity that is determined by the Investigator to be no 
longer safe for the subject to continue therapy;

Subject requests to withdraw from the study treatment;

Subject requires or has taken medication prohibited by the protocol;

Subject is unwilling or unable to comply with the study requirements;

Subject was erroneously admitted into the study or does not meet entry criteria;

Subject is lost to follow-up;

Subject becomes pregnant.
Subjects will return for a Termination visit within 30 days after the last administration of the 
study drug.  If a subject fails to return for scheduled visits, a documented effort must be 
made to determine the reason.  If the subject cannot be reached by telephone after 
2 attempts, a certified letter should be sent to the subject (or the subject’s legally authorized 
representative, if appropriate) requesting contact with the investigator.  This information 
should be recorded in the study records.
Prior to enrollment into the study, the investigator or designee must explain to each subject, 
that the subject’s protected health information obtained during the study may be shared with 
the study sponsor, regulatory agencies, and Institutional Review Board (IRB)/Ethics 
Committee (EC) in order to analyze and evaluate study results.  It is the investigator’s (or 
designee’s) responsibility to obtain written permission to use protected health information 
per country-specific regulations, such as Health Insurance Portability and Accountability 
Act (HIPAA) in the US, and Organic Law 15/1999 of 13 December 1999 on the Protection 
of Personal Data in Spain, from each subject, or if appropriate, the subject’s legally
authorized representative.  If permission to use protected health information is withdrawn, it 
is the investigator’s responsibility to obtain a written request, to ensure that no further data 
will be collected from the subject and the subject will be removed from the study.
8.8.4   Subject Identification and Replacement of Subjects
Each subject will be assigned a unique subject identifier.  This unique identifier will be on 
all Case Report Form (CRF) pages.  During dose escalation, subjects who discontinue 
treatment before completing ≥ 75% (21 of 28 for QD dosing schedule; 9 of 12 for QD3d 
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QW, and 15 of 20 for QD5d QW dosing schedules; or 3 of 4 for QW dosing schedule) of 
planned MLN0128 doses during Cycle 1 for reasons other than study drug-related toxicity 
will be replaced.  During expansion, subjects who receive less than 75% of MLN0128 doses 
during Cycles 1 and 2 will not be replaced if they discontinue due to either disease 
progression or unacceptable toxicity.
8.9   Treatments
8.9.1   Treatments Administered
Subjects will receive MLN0128 as monotherapy in this study.  In the absence of 
unacceptable MLN0128 treatment-related toxicity or disease progression, subjects may 
receive MLN0128 treatment for up to 1 year at the discretion of the investigator and beyond 
1 year with the agreement of the investigator and the sponsor.  Millennium and its designee 
will provide the study site with a supply of MLN0128 sufficient for the completion of the 
study.
8.9.2   Identity of Investigational Product
MLN0128 is a small molecule being developed as a potent, selective inhibitor of TORC1/2 
for the treatment of subjects with advanced malignancies, including NHL, and hematologic 
malignancies.
8.9.2.1   Product Characteristics
MLN0128 will be supplied in tamper-resistant bottles as capsules containing 1 of 3 dose 
strengths.

MLN0128 capsules, 1 mg;

MLN0128 capsules, 3 mg; and/or

MLN0128 capsules, 5 mg;
Each 1-, 3-, and 5-mg capsule for oral administration contains 1, 3, and 5 of MLN0128, 
respectively, and the following inactive ingredients:  microcrystalline cellulose (solid 
filler/diluents), magnesium stearate (lubricant), and hard gelatin capsule.
8.9.3   Storage and Labeling
At a minimum, each bottle label shipped to the sites will provide the following information:  
batch number/lot number, study identification, required storage conditions, directions for 
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use, and region-specific caution statements (including “New Drug – Limited by United 
States federal law to investigational use” language).
MLN0128 accountability records will be maintained by the pharmacy or designated drug 
preparation area at the study site.  Upon receipt of MLN0128 supplies, the pharmacist or 
designated drug handler will inventory MLN0128 (separately for each strength) and 
complete the designated section of the shipping form.  The shipping/inventory form must be 
sent to Millennium or its designee, as instructed.
MLN0128 should be stored at controlled room temperature 15C to 30C (59F to 86F).  
All study supplies must be kept in a restricted access area.
A complete dispensing log must be maintained for all MLN0128 dispensed and all capsules 
of MLN0128 must be accounted for.
8.9.4   Directions for Administration
MLN0128 will be administered orally once in the morning with a meal at approximately the 
same time of day.  Subjects should be encouraged to drink at least 18 to 24 ounces (oz) of 
liquids a day to stay well-hydrated.  Cycles are repeated every 28 days.

QD dosing schedule:  once daily in the morning on Days 1 through 28 of each cycle;

QW dosing schedule:  once in the morning on Days 1, 8, 15, and 22 of each cycle;

QD3d QW dosing schedule:  once in the morning on Days 1, 2, 3, 8, 9, 10, 15, 16, 
17, 22, 23, and 24 of each cycle;

QD5d QW dosing schedule:  once in the morning on Days 1, 2, 3, 4, 5, 8, 9, 10, 11, 
12, 15, 16, 17, 18, 19, 22, 23, 24, 25, and 26 of each cycle.
On each clinic day, the site will administer MLN0128 to the subject (the subject should be 
counseled not to take their MLN0128 dose at home on the day of the clinic visit).  In cases 
where a subject misses dosing at his/her dosing time, the subject may still take the dose 
within 12 hours of the regular dosing time with a meal (subjects should not take 
2 consecutive daily doses within 12 hours of each other).  Subjects who vomit shortly after 
receiving MLN0128 will not receive a replacement dose.  If confirmed that the study drug 
has been vomited, the dose should be noted as having been missed.  Additional details will 
be provided in the Pharmacy Manual.
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Subjects should not have anything by mouth (eat or drink) except water and/or medications 
after midnight or a minimum of 8 hours prior to their clinic visits when blood draws for 
fasting glucose or fasting lipid profile will be required.  The investigator may consider 
hydrating subjects as clinically indicated with 500 mL IV Normal Saline (NS) solution pre-
and/or post- MLN0128 dosing on clinic days to minimize risk of dehydration, especially in 
fasting subjects, and subsequent prerenal azotemia.
MLN0128 capsules should not be opened or crushed.  MLN0128 capsules should be 
swallowed with water without chewing or sucking the capsule.  If the subject chews or sucks 
the capsules by error, the subject should drink a large glass of water (~8 oz).  Direct contact 
with the powder in MLN0128 capsules with skin or mucous membranes should be avoided.  
If such contact occurs, the subject should wash thoroughly with water.
Prophylactic use of anti-emetic, anti-nausea, and anti-diarrheal medications are encouraged 
and may be used prior to each MLN0128 dosing as needed throughout the study.
8.9.5   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 Millennium 
or designee and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a 
sponsor’s Quality representative.
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed and submitted as described in Section 9.2.
8.9.6   Method of Assigning Subjects to Treatment Groups
The enrollment and treatment assignment will be centrally managed by Millennium and its 
designee.  When a treatment cohort is open for enrollment, sites will fax a Subject 
Registration Form along with subject eligibility supporting documents for each potential 
subject to Millennium and its designee.  Millennium and its designee will assign a subject 
number and treatment cohort for each subject that is accepted into the study.  In the event,
that more than 1 dosing arm is open for enrollment during the dose escalation or expansion 
phases, then subjects will be assigned to a dose schedule in an alternating basis.  Subjects 
may not participate in more than 1 dosing arm.
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Sites cannot enroll or start dosing the subject without receiving the assigned subject number 
and treatment cohort from Millennium or its designee.
8.9.7   Selection of Doses Used in the Study
The starting dose for the daily dosing schedule is 2 mg once daily.
The STD10 has been defined as 3 mg/kg/day (18 mg/m2/day) and the HNSTD in monkeys as 
0.15 mg/kg/day (1.8 mg/m2/day).  Using the FDA endorsed paradigm for selecting the 
maximum starting dose in humans, 1-tenth the rodent STD10 (ie, 1.8 mg/m2/day) was 
compared to the HNSTD in monkeys.(26)  Since 1/10th the STD10 in the rat was not severely 
toxic to the monkey, 1/10th the STD10 in rats can be used as the maximum human starting 
dose.  A maximum human starting dose of 1.8 mg/m2/day for an average sized subject of 
1.7 m2 is calculated as 3 mg/day.  Recognizing that prior human experience does not exist 
with MLN0128 and allometric scaling predicts a potential for drug accumulation in humans 
at steady state, Millennium proposes the human starting dose be 2 mg/day (1.2 mg/m2/day).  
Based on preclinical data, it is estimated that a dose of 2 mg/day in humans could achieve 
systemic exposures sufficient for biological inhibition of target.  Thus, this starting dose 
should offer an opportunity for potential therapeutic benefit while minimizing subject’s risk.
The starting doses of the additional dosing schedules to be evaluated will be based on the 
MTD of the QD dosing schedule (MTDqd).  Arm A, with once-weekly dosing, will start at a 
dose not to exceed that of twice the MTDqd.  Arm B, with MLN0128 being administered 
QD3d QW, will start at the MTDqd; Arm C, with MLN0128 QD5d QW, will start at a 
dose not to exceed the total weekly dose of the MTDqd (ie, ≤ 42 mg/week).  Dose escalation 
for the dosing schedules will be according to a modified Fibonacci schema.  For example, 
the starting dose of 2 mg may be escalated in successive cohorts to 4 mg, 7 mg, 10 mg, 14 
mg, 18 mg, or an intermediate dose between 2 planned doses may be evaluated.  The level 
of dose escalation will be determined after review of available safety data and discussion 
between the participating Investigators and Millennium’s medical monitor prior to the dose 
escalation, but the dose selected will not exceed the planned dose according to a modified 
Fibonacci schema.
8.9.7.1   Selection of Timing of Dose for Each Subject
It is anticipated that MLN0128 will possess a plasma half-life commensurate with once daily 
administration in humans.  Preclinical models of efficacy, safety, and PK have largely relied 
on once-daily dosing.  Investigation of different dosing schedules in preclinical efficacy 
models has demonstrated commensurate tumor growth inhibition with administration of 
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MLN0128 either once daily, twice daily, or intermittently (eg, once every other day or 
weekly).
8.9.8   Blinding
This is an open-label study with no placebo or comparators.
8.9.9   Prior and Concomitant Medications
All prescription and over-the-counter medications, including influenza vaccines, taken by a 
subject within 30 days before the first study drug administration will be recorded on the 
designated CRF.
The following medications/therapies are prohibited during the study:

Other investigational agents or mTOR inhibitors

Other anticancer therapies including chemotherapy, immunotherapy, 
radioimmunotherapy, targeted agents, radiation or surgery (subjects can have 
palliative radiation or surgery in the study for pre-existing lesions)

Systemic corticosteroids (either IV or oral steroids, excluding inhalers) during the 
dose escalation phase of the study, unless necessary for treatment of MLN0128 
related AE, ie, rash

Anti-epileptic drugs for subjects with treated brain metastasis

Moderate and strong cytochrome CYP1A2 inhibitors and moderate and strong 
CYP1A2 and CYP3A4 inducers should be administered with caution and at the 
discretion of the investigator.
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications are encouraged 
and may be used prior to first dose of study drug (MLN0128), and as needed throughout the 
study prior to each dosing and as clinically indicated per standard practice.  Initiation of 
hematopoietic growth factors, transfusions of blood, and blood products should not be used 
in the first cycle during the dose escalation phase unless absolutely clinically necessary and 
after discussion with Millennium’s medical monitor.  However, they may be administered 
after Cycle 1 if needed.  Subjects who have been on chronic erythropoietin for ≥ 30 days 
may continue to receive the concomitant medication upon study entry.
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Concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 
30 days prior to the first administration of MLN0128.  Bisphosphonates should be given 
after Cycle 1 to minimize confounding factors which may contribute to potential drug-
related toxicities.
Other medications considered necessary for the subject’s safety and well-being may be 
given at the discretion of the investigator.  Any concomitant medications added or 
discontinued during the study should be recorded on the CRF.
8.9.10   
Treatment Compliance
The importance of treatment compliance should be emphasized to the subject.  Subjects will 
be given study drug and detailed instructions on how to take medications at home.  Subjects 
will be instructed to return all used and unused study drug containers at each study visit.  
Subject compliance with the dosing schedule will be assessed by reconciliation of the used 
and unused study drug at each clinic visit and review of the dosing diaries.  The quantity 
dispensed, returned, used, lost, etc. must be recorded on the dispensing log provided for the 
study.  Compliance will be monitored and documented by site personnel on the appropriate 
form.  The site personnel will question the subject regarding adherence to the dosing 
schedule by reviewing the dosing diaries, recording the number of capsules and strengths 
returned, the date returned, and determining treatment compliance before dispensing new 
medication to the study subject.
8.10   Investigational Product Accountability
The principal investigator (PI) or designee is responsible for maintaining accurate records 
(including dates and quantities) of investigational product (IP) received, subjects to whom IP 
is dispensed (subject-by-subject dose specific accounting), and IP lost or accidentally or 
deliberately destroyed.  The PI or designee must retain all unused or expired study supplies 
until the Millennium-designated Clinical Research Associate (CRA) has confirmed the 
accountability data.
8.10.1   
Return and Disposition of Clinical Supplies
Unused study drug must be kept in a secure location for accountability and reconciliation by 
the Millennium-designated CRA.  The investigator or designee must provide an explanation 
for any destroyed or missing study drug or study materials.
Unused study drug may be destroyed on site, per the site’s standard operating procedures,
but only after Millennium or its designee has granted approval for drug destruction.  The 
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Millennium-designated CRA must account for all study drug in a formal reconciliation 
process before destroying study drug.  All study drug destroyed on site must be documented.  
Documentation must be provided to Millennium or its designee and retained in the PI’s 
study files.  If a site is unable to destroy study drug appropriately, the site can return unused 
study drug to Millennium’s designee upon request.  The return of study drug or study drug 
materials must be accounted for on a Study Drug Return Form provided by Millennium’s 
designee.
All study drug and related materials should be stored, inventoried, reconciled, and destroyed 
or returned according to applicable state and federal regulations and study procedures.
8.11   Dietary or Other Protocol Restrictions
No dietary restrictions will be imposed on study subjects.
8.12   Efficacy and Safety Variables
See the Schedule of Events for timing of evaluations.
8.12.1   
Safety Variables
Safety will be assessed by periodic physical examinations, 12-lead electrocardiograms 
(ECGs; see Sections 8.6.7.3.1 and 8.6.7.3.2), clinical laboratory assessments, in-home 
monitoring of glucose levels via a glucometer, and monitoring of AEs.
Any abnormal clinical laboratory test results determined to be clinically significant by the 
investigator should be repeated (at the investigator’s discretion) until the cause of the 
abnormality is determined, the value returns to baseline or to within normal limits, or the 
investigator determines that the abnormal value is no longer clinically significant.
All clinical laboratory result pages should be initialed and dated by an investigator, along 
with a comment regarding whether or not the result is clinically significant.
The diagnosis, if known, associated with abnormalities in clinical laboratory tests that are 
considered clinically significant by the Investigator will be recorded on the AE CRF.
Adverse events will be graded using NCI CTCAE version 4.0.
8.12.2   
Efficacy Variables
Radiographic and/or physical assessments of the malignancies, and evaluations of relevant 
tumor markers (eg, cancer antigen 125 [CA125], prostate-specific antigen (PSA), cancer 
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antigen 19-9 [CA19-9], CA27.29, CA15.3, and carcinoembryonic antigen [CEA]) will be 
made at screening/baseline (within 28 days before the first study drug administration) and 
after every 2 cycles of treatment (or up to every 4 cycles for long-term patients, defined as 
study participation ≥3 years).  Objective response (complete response [CR] and partial 
response [PR]) as determined by the subject’s best tumor response, duration of response, and 
time to progression.  Response will be assessed using RECIST version 1.1.  A confirmatory 
CT/MRI scan should be performed at approximately 4 weeks from the previous scan for all 
subjects with an objective response of ≥ PR.
8.12.3   
Additional Variables
Additional variables to be examined as a part of this study include PK parameters such as 
Cmax, Cmin, Tmax, AUC, and half-life of the study drug in plasma.  The pharmacodynamic 
effect of MLN0128 activity in surrogate tissue (skin and tumor tissue) via 4EBP1, AKT, and 
S6 as well as 4EBP1 in peripheral blood cells (dose escalation phase only) and correlation of 
somatic mutations (PI3KCA, PTEN, Ras) in archival paraffin tumor tissue with MLN0128 
activity will be evaluated.  
 
 
 
 
 
 
 
 
 
.
Additionally, duration of a subject on MLN0128 versus the duration of the same subject on 
the last systemic anticancer therapy that is not an investigational agent prior to entering the 
study will be explored.
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9.   
ADVERSE EVENTS
9.1   Definitions
9.1.1   Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study 
participation.
9.1.2   Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.
9.1.3   Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient or subject was at risk of 
death at the time of the event.  It does not refer to an event which hypothetically 
might have caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).
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
Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient or 
subject, 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.(27)  Clarification should be 
made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 
or 4), because the terms serious and severe are NOT synonymous.  The general term severe
is often used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a Grade 3 headache).  This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above, and is usually associated with events that pose a threat to a patient’s life or ability to 
function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
9.2   Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient or subject and/or in response to an open 
question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded on the appropriate page of the eCRF (see Section 9.3
for the period of observation).  Any clinically relevant deterioration in laboratory 
assessments or other clinical finding is considered an AE.  When possible, signs and 
symptoms indicating a common underlying pathology should be noted as 1 comprehensive 
event.
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Regardless of causality, SAEs and serious pretreatment events (as defined in Section 9.1) 
must be reported (see Section 9.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below).  This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event.  The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site.  A sample of the SAE Form may be found in the Study Manual.  Follow-
up information on the SAE or serious pretreatment event may be requested by Millennium.  
SAE report information must be consistent with the data provided on the eCRF.
SAE Reporting Contact Information
Cognizant
United States and Canada
Toll-Free Fax:  1-800-963-6290
Email: TakedaOncoCases@cognizant.com
All Other Countries (Rest of World)
Fax #: 1-202-315-3560
Email: TakedaOncoCases@cognizant.com
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the subject was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (eg, surgery was performed earlier or 
later than planned).  For both serious and nonserious AEs, the investigator must determine 
both the intensity of the event and the relationship of the event to study drug administration.  
For serious pretreatment events, the investigator must determine both the intensity of the 
event and the relationship of the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the NCI 
CTCAE, Version 4.0.  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 non-serious and serious, will be monitored throughout the study as follows:

AEs will be reported from administration of the first dose of study drug through 30 
days after the administration of the last dose of study drug and recorded in the CRFs.
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Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first dose of 
study drug, but will not be recorded in the CRF.

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 the administration of the last dose of study drug and recorded in the CRF.  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 clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).
9.4   Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug.  The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 9.2).  
The pregnancy must be followed for the final pregnancy outcome.
If a female partner of a male subject becomes pregnant during the male subject’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 9.2).  Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.
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10.   
APPROPRIATENESS OF MEASUREMENTS
10.1   Pharmacokinetics
The plasma concentrations for MLN0128 will be determined using a liquid chromatography 
tandem mass spectrometry method.  The measured MLN0128 plasma concentrations will be 
used to determine the PK parameters, including AUC, Cmax, Cmin, Tmax, and t1/2.  
Comparisons across dose levels will be made to assess proportionality.  In addition, 
comparison between single dose and multi-dose PK parameters will be made for assessment 
of steady-state drug accumulation.
10.2   Biomarker Assessments
10.2.1   
Pharmacodynamic Assessments
During the dose escalation phase, pharmacodynamic assessment will be made by assessing 
various biomarker levels in samplings of peripheral blood cells (PBCs), skin and tumor 
biopsies pre- and post-treatment whenever possible.  The PD effect of MLN0128 activity in 
surrogate tissue (skin and tumor tissue) via 4EBP1, AKT, and S6 as well as peripheral blood 
cells (dose escalation only) via 4EBP1 will be evaluated.  
 
 
 
The afore mentioned biomarkers are downstream effectors of mTOR and have been used for 
determining the sensitivity of proliferative diseases to treatment with mTOR inhibitors.  The 
changes in biomarkers levels will be determined via flow cytometry and/or 
immunohistochemical analysis.  The absolute and percent change from baseline will be 
calculated for each subsequent measurement.  Summary statistics will be computed for each 
collection time point.
10.2.2   
Assessments of Predictive Markers of MLN0128 Activity
Candidate somatic genetic markers that may predict MLN0128 activity will be evaluated in 
archival tumor tissues.  These include PI3KCA, PTEN, Ras (K/H/N) in archival paraffin 
tumor tissue with MLN0128 activity.
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11.   
STUDY PROCEDURES
See the Schedule of Events for the timing of all study-related procedures.
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12.   
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
This section outlines the statistical analysis strategy and procedures for the study.  Specific 
details of the primary and key secondary analyses will be provided in the Statistical Analysis 
Plan (SAP).  If, after the study has begun, but prior to the final analysis, important changes 
are made to the protocol that affect principal features of the primary or key secondary 
analyses, then the protocol and/or SAP will be amended, as appropriate.  Any other changes 
made to the planned analyses after the protocol and SAP have been finalized, along with an 
explanation as to when and why they occurred, will be listed in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
12.1   Analysis Endpoints
The safety and efficacy endpoints to be evaluated are listed below, followed by descriptions 
of the derivations of selected endpoints.
12.1.1   
Primary Endpoints
12.1.1.1   Dose Escalation Phase
The maximum tolerated dose of MLN0128 when administered orally daily as monotherapy 
in subjects with advanced solid malignancies will be determined.  The MTD is defined as 
the highest dose level of MLN0128 at which no more than 1 out of 6 evaluable subjects 
experience a DLT during the first cycle (28 days) of therapy.  The rate of DLT in each 
cohort will be determined from the occurrence of AEs which meet the criteria in 
Section 8.2.1.  Once the MTD for daily administration of MLN0128 has been determined, 
the MTD for alternate dosing schedules of MLN0128 will be evaluated.
12.1.1.2   Expansion Phase
The objective response rate will be estimated for subject.  The objective response rate is 
based on the subject’s best overall tumor response documented during the course of 
MLN0128 therapy.  Objective response includes CR and PR and will be determined based 
on RECIST (version 1.1).  The duration of objective response will be evaluated for subjects 
who achieve CR or PR.  In addition, the duration of stable disease will be evaluated for 
subjects with the best response of stable disease.
12.1.2   
Secondary Endpoints
The pharmacokinetics of daily and alternate schedule dosing of MLN0128 will be 
determined from selected subjects based on the PK parameters listed below.  Serum samples 
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for PK analysis will be collected at the time points specified in the Schedule of Events and 
in the PK Sampling Scheme in Table 3-5.
!
Maximum plasma concentration (Cmax);
!
Minimum plasma concentration (Cmin);
!
Time of maximum plasma concentration (Tmax);
!
Plasma half-life (t½);
!
Area under the plasma concentration-time curve from time zero to infinity (AUC0-∞), 
zero to last dose (AUC0-last), and %AUC extrapolated;
The PD effect of MLN0128 activity in surrogate tissue (skin and tumor tissue) via 4EBP1, 
AKT, and S6 as well as peripheral blood cells via 4EBP1 will be evaluated.
!
Change from baseline in the levels of 4EBP1and S6 in skin and tumor tissues as well 
as 4EBP1 in peripheral blood cells.
12.1.3   
Exploratory Endpoints
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!
Dose expansion phase
12.1.4   
Safety and Tolerability Endpoints
Safety and tolerability of MLN0128 will be assessed in each study phase based on the 
following:
!
Incidence, duration, and severity of treatment-emergent AEs, including dose-limiting 
toxicity (see Section 8.2.1), SAEs, AEs resulting in dose modification or permanent 
discontinuation of study drug, and deaths within 30 days of the last dose of study 
drug;
!
Changes in laboratory test results including chemistry and hematology;
!
Changes in vital signs including blood pressure, pulse, and temperature;
!
Changes in electrocardiogram results.
12.2   Analysis Populations
12.2.1   
Safety Analysis
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data.  
The ASaT population consists of all enrolled subjects who receive at least 1 dose of 
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MLN0128.  The safety data from the dose escalation phase will be summarized by dose 
cohort and dose schedule; and by tumor histology cohort for the expansion phase.
For purposes of defining the MTD and/or expansion phase recommended dose(s) of 
MLN0128, subjects will be evaluated according to the actual starting dose of MLN0128 
during the first treatment cycle.  For most subjects, this will be the dose cohort to which they 
were assigned.  Subjects who receive at least 75% of the planned doses in Cycle 1 will be 
considered to have sufficient safety data/follow-up to support dose escalation.  Subjects who 
withdraw from study before receiving 75% of the planned doses in the first cycle of 
treatment for reasons unrelated to study drug toxicity will be considered to have inadequate 
data to support dose escalation.  In such cases, replacement subjects may be enrolled to 
receive the same starting dose of MLN0128 as the subjects who withdraw prematurely.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study drug, is required for inclusion in the analysis of a specific safety parameter.  To assess 
change from baseline, a baseline measurement is also required.
12.2.2   
Efficacy Analysis
The response-evaluable population will serve as the primary population for the analysis of 
tumor response and other efficacy-related data for the expansion cohorts.  The response-
evaluable population includes subjects who receive at least 1 dose of MLN0128 dose, have 
measurable disease at baseline, and undergo at least 1 post-baseline disease assessment.
12.3   Statistical Methods
12.3.1   
Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters 
including AEs, DLTs, laboratory values, electrocardiogram results, and vital signs.
The observed DLT rate in each dose cohort and dose schedule will be calculated by the 
crude proportion of subjects who experience DLT during the first cycle of therapy.  Multiple 
concurrent AEs leading to DLT will be considered a single DLT.  The estimate of the DLT 
rate will be accompanied by a 2-sided 95% exact binomial confidence interval.  The 
relationship between the dose and schedule of MLN0128 and probability of DLT will be 
assessed by fitting various regression models such as Emax, logistic and exponential model 
shapes.
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Adverse events will be coded using the latest available version of MedDRA.  Treatment-
emergent AEs are defined as AEs that start on or after the first dose of study drug and within 
30 days of the last administration of study drug.  Adverse events will be summarized by the 
number and percentage of subjects who experienced the event, according to system organ 
class and preferred term.  A subject reporting multiple cases of the same AE will be counted 
once within each system organ class and similarly counted once within each preferred term.  
Unless specified otherwise, the denominator for these calculations will be based on the 
number of subjects in each dose cohort and dose schedule who receive at least 
1 administration of MLN0128, irrespective of the total number of doses or treatment cycles 
administered.  These conventions will be appropriately modified to calculate AE incidence 
rates separately for each cycle that study therapy is administered.  Adverse event incidence 
rates may also be calculated based on other measures of subject exposure (eg, total number 
of treatment cycles administered).  All AEs will also be summarized by NCI-CTCAE 
version 4.0 severity grade and by relationship to each study drug.  Additional summaries 
may also be provided for SAEs, and events resulting in the permanent discontinuation of 
therapy.  All AEs will be included in individual subject listings.
The changes in hematology, chemistry, and other laboratory values will be summarized 
descriptively for each scheduled and unscheduled protocol assessment time point.  Changes 
will be calculated relative to the values collected at baseline and on the first day of each 
cycle of treatment.  The incidence of Grade 3 and 4 hematological toxicities (including 
neutropenia, thrombocytopenia, and anemia) will be provided by treatment cycle and across 
all treatment cycles. The toxicity grades for laboratory tests will be based on NCI-CTCAE 
version 4.0 criteria.  The use of blood transfusions (platelets, red blood cells) and/or growth 
factor support will be reported.  Similar analyses will be done for selected chemistry tests 
(including liver and renal function tests).  Subject listings of all laboratory data collected 
during the study will be presented.  Laboratory values outside normal limits will be 
identified in the subject listings and will include flags for high and low values.
Vital sign results (blood pressure, pulse, respirations, and temperature) will be summarized 
descriptively for each scheduled and unscheduled protocol time point.  Changes will be 
calculated relative to the assessments at baseline and on the first day of each cycle of 
therapy.
12.3.2   
Efficacy Analysis
The efficacy analyses for the expansion cohorts will be conducted based on the response-
evaluable population in Section 12.2.  The results of these analyses will be summarized for 
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the renal cohorts.  If there is a sufficient number of subjects, with a specific tumor type in 
the multi-tumor type cohort (ie, endometrial and bladder), then efficacy endpoints will also 
be summarized by tumor type.
Objective Response Rate
The objective response rate will be estimated for each tumor histology type evaluated in the 
expansion phase.  The estimate of the objective response rate will be calculated based on the 
maximum likelihood estimator (ie, crude proportion of subjects whose best overall response 
is CR or PR).  The estimate of the objective response rate will be accompanied by 2-sided 
95% exact binomial confidence intervals.
Duration of Objective Response
The duration of objective response will be calculated for subjects who achieve CR or PR.  
For such subjects, the duration of objective response is defined as the number of days from 
the start date of PR or CR (whichever response is achieved first) to the first date that 
progressive disease is objectively documented.  Disease progression will be determined by 
the investigator using RECIST (version 1.1).  The duration of objective response will be 
right-censored for subjects who achieve CR or PR and meet 1 of the following conditions:  
1) non-protocol anticancer treatment started before documentation of disease progression, 
2) death or documented disease progression after more than 1 missed disease assessment 
visit, or 3) alive and does not have documentation of disease progression before a data 
analysis cutoff date.  For such subjects, the duration of objective response will be right-
censored according to Table 12-1 below.  These conventions are based on the May 2007 
FDA Guidance for Industry.‘(28)’
The duration of objective response will be summarized descriptively using the Kaplan-Meier 
method.  The 50th percentile of the Kaplan-Meier distribution will be used to estimate the 
median response duration.
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Table 12-1   Date of Progression or Censoring for Duration of Response
Situation 
Date of Progression or Censoring
Outcome
Non-protocol anticancer treatment started 
before death or documentation of disease 
progression or death
Date of last disease assessment prior to start of 
non-protocol anticancer treatment
Censored
Death or progression after more than 1 
missed disease assessment
Date of last disease assessment visit without 
documentation of disease progression that is 
before the first missed visit
Censored
Alive and without documentation of 
disease progression
Date of last disease assessment
Censored
Death or disease progression between 
planned disease assessments
Date of death or first disease assessment 
showing disease progression, whichever occurs 
first
Progressed
Death before first disease assessment
Date of death
Progressed
The duration of stable disease will be evaluated for subjects with a best response of stable 
disease and will be defined as the number of days from the date of first dose to the date of 
progressive disease.
Biomarkers
Descriptive statistics will be primarily used to summarize the biomarker data generated in 
this study.  For continuous variables, the number of subjects with non-missing data, mean, 
either the standard error or standard deviation, median, 25th percentile (first quartile), 75th
percentile (third quartile), minimum, and maximum will be presented.  For discrete data, the 
frequency and percent distribution will be presented.
The effect of MLN0128 on the expression levels of selected biomarkers will be evaluated by 
calculating the difference in each biomarker from baseline, and the repeat post-baseline 
samples obtained during the course of the study.  The Wilcoxon signed rank test will be used 
to identify any statistically significant (p < 0.05) changes in biomarker levels.  Additionally, 
the correlation among the various initial biomarker levels will be assessed by calculating 
Spearman’s correlation coefficient between pairs of biomarkers.
Analysis of covariance (ANCOVA) models will be used to explore the relationship between 
the biomarker parameters and the estimated pharmacokinetic parameters.  Nonparametric 
methods and/or nonlinear models may also be used to further examine the between 
biomarker and pharmacokinetic parameters.
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12.4   Sample Size Determination
12.4.1   
Dose Escalation Phase
Cohorts of 3 to 6 subjects will be enrolled in each MLN0128 dose cohort and dose schedule 
evaluated based on a standard phase 1 sequential dose escalation scheme.  Additional 
subjects, up to a total of 12, may be enrolled in a given cohort and schedule to better 
understand the safety profile and tolerability of a particular dose level/dose schedule 
combination.  Each subject will participate in only 1 dose cohort/dose schedule.  The total 
number of subjects to be enrolled in the dose escalation phase of the study is dependent 
upon the observed safety profile, which will determine the number of subjects per dose 
cohort, as well as the number of dose escalations required to achieve the MTD for each dose 
schedule evaluated.
12.4.2   
Expansion Phase
Based on safety and available PK data of MLN0128 along with possible early signs of anti-
tumor activities from subjects treated during the dose escalation phase, the expansion phase 
of the study will evaluate 1 or more populations (initially 2) with measurable disease: renal 
cell cancer and a cohort of selected tumor types (endometrial and bladder cancers).  Cohorts 
may enroll subjects in parallel in the expansion phase, each with 15 to 25 response-evaluable 
subjects.  The smaller sample size of 15 response-evaluable subjects per disease cohort is 
based on following considerations:  A single agent that results in an objective response rate 
of 1% or less is considered to have insufficient activity to warrant further study.  An 
objective response rate of 20% or greater is considered sufficient to warrant further study of 
the agent.  Fifteen subjects per cohort will provide 83% power to detect a statistically 
significant difference between the uninteresting and interesting objective response rates 
based on the exact 1-sample binomial test and 1-sided significance level of 5%.
12.5   
Interim Analysis and Early Stopping Guidelines
Safety will be monitored throughout the trial.  Dose escalation will proceed according to the 
dose escalation scheme described in Section 8.2.2.  If any significant safety issues arise, the 
sponsor will be notified and if necessary, a decision to modify or terminate the trial (or 1 of 
the cohorts) will be made.
All participating sites are required to provide DLT notification forms within 24 hours of 
learning of the event.  Additionally, site teleconferences between the sponsor and all 
participating sites will be held approximately every 1 to 2 weeks during the dose escalation 
phase to discuss any suspected AEs/DLTs that have occurred at each cohort.  Participating 
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investigators and the sponsor’s Medical Monitor will review toxicities from the current 
cohort during the site teleconferences before initiating enrollment into the next planned dose 
cohort.
12.6   Changes in the Conduct of the Study or Planned Analyses
Only Millennium may modify the protocol.  Any change in study conduct considered 
necessary by the PI will be made only after consultation with Millennium, who will then 
issue a formal protocol amendment to implement the change.  The only exception is when 
an investigator considers that a subject’s safety is compromised without immediate action.  
In these circumstances, immediate approval of the chairman of the IRB/EC must be sought, 
and the investigator should inform Millennium and the full IRB/EC within 2 working days 
after the emergency occurs.
With the exception of minor administrative or typographical changes, the IRB/EC must 
review and approve all protocol amendments.  Protocol amendments that have an impact on 
subject risk or the study objectives, or require revision of the ICF, must receive approval 
from the IRB/EC prior to their implementation.
When a protocol amendment substantially alters the study design or the potential risks or 
burden to subjects, the ICF will be amended and approved by Millennium and the IRB/EC, 
and all active subjects must again provide informed consent.
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13.   
ETHICS
13.1   Institutional Review Board or Ethics Committee
Prior to initiating the study, the Investigator will obtain written confirmation that the IRB or 
EC is properly constituted and compliant with all United States FDA requirements and local 
regulations.  A copy of the confirmation from the IRB/EC will be provided to Millennium or 
its designee.  The PI will provide the IRB/EC with all appropriate material, including the 
protocol, Investigator’s Brochure, the ICF/PIC, and any other written information provided 
to the subjects, including all consent forms translated to a language other than the native 
language of the clinical site.  The study will not be initiated until appropriate IRB/EC 
approval of the protocol, the ICF and all subject recruitment materials are obtained in 
writing by the PI and copies are received at Millennium or its designee.  The approval 
document should refer to the study by protocol title and Millennium, protocol number (if 
possible), identify the documents reviewed, and include the date of the review and approval.  
Appropriate reports on the progress of the study should be made to the IRB/EC or REB and 
Millennium or its designee by the PI in accordance with applicable governmental 
regulations and in agreement with policy established by the IRB/EC and Millennium.
13.2   Ethical Conduct of Study
This study will be conducted in accordance with the Declaration of Helsinki and Good 
Clinical Practice (GCP) according to International Conference on Harmonization (ICH) 
guidelines.  Specifically, this study is based on adequately performed laboratory and animal 
experimentation; the study will be conducted under a protocol reviewed and approved by an 
IRB/EC; the study will be conducted by scientifically and medically qualified persons; the 
benefits of the study are in proportion to the risks; the rights and welfare of the subjects will 
be respected; the physicians conducting the study do not find the hazards to outweigh the 
potential benefits; and each subject, or his/her legally authorized representative will provide 
written, informed consent before any study-related tests or evaluations are performed.
13.3   Subject Information and Informed Consent
A properly written and executed ICF, in compliance with the Declaration of Helsinki, ICH 
GCP and US Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25 
[a, b.], CFR 50.27, and CFR Part 56, Subpart A), HIPAA for the US only, Organic Law 
15/1999 of 13 December 1999 on the DPA in Spain, and other applicable local regulations, 
will be obtained for each subject prior to entering the subject into the study.  The 
Investigator will prepare the ICF/PIC and HIPAA authorization/DPA and provide the 
documents to Millennium or its designee for approval prior to submission to the IRB/EC.  
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Millennium and the IRB/EC must approve the documents before they are implemented.  If a
subject is unable to sign the ICF/PIC and HIPAA authorization/DPA, a legal representative 
may sign for the subject.  The investigator will provide copies of the signed ICF/PIC to each 
subject (or the subject’s legal representative) and will maintain the original in the subject’s 
record file.
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14.   
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Prior to beginning the study, the PI at each site must provide to Millennium or its designee a 
fully executed and signed Form FDA 1572 and a Financial Disclosure Form.  All sub-
investigators must be listed on Form FDA 1572.  Financial Disclosure Forms must also be 
completed for all sub-investigators listed on the Form FDA 1572 who will be directly 
involved in the treatment or evaluation of research subjects in this study.
The study will be administered by and monitored by employees or representatives of 
Millennium.  CRAs will monitor each site on a periodic basis and perform verification of 
source documentation for each subject as well as other required review processes. 
Millennium’s designee will be responsible for the timely reporting of SAEs to appropriate 
regulatory authorities as required.
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15.   
CASE REPORT FORMS AND SOURCE DOCUMENTS
Case report forms will be provided for each subject.  The investigator must review and sign 
the completed CRFs to verify their accuracy.
CRFs must be filled out legibly and completed using a black ballpoint pen.  Unless 
explicitly allowed in the CRF instructions, blank data fields are not acceptable.  If a field is 
blank because the item was not done, the field will be marked “ND.”  If the item is 
unknown, the field will be marked “UNK.”  If the item is not applicable, the field will be 
marked “NA.”  If the item is not available, the field will be marked “NAV.”
If an entry error has been made and the original CRF page is still at the study site, the error 
must be corrected on the CRF page by making a single straight line through the incorrect 
data and writing the correct data, allowing the original text to remain legible.  Each 
correction must be initialed and dated by the person making the change.  If corrections are 
made after review and signature by the Investigator, he or she must confirm and endorse the 
changes.  ERRORS MAY NOT BE ERASED, AND WHITEOUT MAY NOT BE USED 
ON ANY STUDY- RELATED DOCUMENTS.  The study staff will be queried for 
clarification regarding illegible or incomplete entries.  There should be no writing in the 
margins.
Millennium’s policy is that study data on the CRFs must be verifiable to the source data, 
which necessitates access to all original recordings, laboratory reports, and subject records.  
In addition, all source data should be attributable (signed and dated).  The investigator must 
therefore agree to allow direct access to all source data.  Subjects (or their legal 
representatives) must also allow access to their medical records, and subjects will be 
informed of this and will confirm their agreement when giving informed consent.  If an 
investigator or institution refuses to allow access to subject records because of 
confidentiality, arrangements must be made to allow an “interview” style of data 
verification.
A CRA designated by Millennium will compare the original CRFs with the original source 
documents at the study site and evaluate the CRFs for completeness and accuracy before 
returning them to Millennium or its designee for data management and analysis.  If 
necessary, the study site personnel will be contacted for corrections and/or clarifications.  
Errors to CRFs that are identified after the original CRF page has been removed by the CRA 
will be corrected as described in the Study Reference Manual.  The investigator or designee 
must also review and sign all Data Clarification Forms (DCFs) or the corrections to the CRF 
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to verify their accuracy prior to submission to Millennium or its designee.  Data that are 
modified via DCFs must be supported in the source documents.
A copy of the CRF and any accompanying DCFs will be maintained in the investigator’s 
file.  Designated site personnel must complete CRFs as soon as possible after a subject visit, 
and the forms must be available for review at the next scheduled monitoring visit.
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16.   
STUDY MONITORING AND AUDITING
Qualified individuals designated by Millennium will monitor all aspects of the study 
according to GCP and standard operating procedures for compliance with applicable 
government regulations.  The PI agrees to allow these Millennium-designated CRAs direct 
access to the clinical supplies, dispensing, and storage areas and to the clinical files, 
including original medical records, of the study subjects, and, if requested, agrees to assist 
the Millennium-designated CRAs.  The PI and staff are responsible for being present or 
available for consultation during routinely scheduled site visits conducted by Millennium or 
its designees.
Members of Millennium GCP Compliance Department or designees may conduct an audit 
of a clinical site at any time during or after completion of the study.  The PI will be informed 
if an audit is to take place and advised as to the scope of the audit.  Representatives of the 
FDA or other Regulatory Agencies may also conduct an audit of the study.  If informed of 
such an inspection, the PI should notify Millennium immediately.  The PI will ensure that 
the auditors have access to the clinical supplies, study site facilities, original source 
documentation, and all study files.
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17.   
RETENTION OF RECORDS
The PI must retain all study records required by Millennium and by the applicable 
regulations in a secure and safe facility.  The PI must notify Millennium of any change in 
the location, disposition or custody of the study files.  The PI/institution must take measures 
to prevent accidental or premature destruction of essential documents, that is, documents 
that individually and collectively permit evaluation of the conduct of a study and the quality 
of the data produced, including paper copies of study records (eg, subject charts) as well as 
any original source documents that are electronic as required by applicable regulatory 
requirements.
All study records must be retained for at least 2 years after the last approval of a marketing 
application in the U.S. or an ICH region and until (1) there are no pending or contemplated 
marketing applications in the U.S. or an ICH region or (2) at least 2 years have elapsed since 
the formal discontinuation of clinical development of the IP.  No records relating to this 
study should be disposed of without the written approval of Millennium.  It is the 
responsibility of Millennium to inform the PI/institution as to when these documents no 
longer need to be retained.
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18.   
DISCLOSURE OF DATA
Subject medical information obtained by this study is confidential, and disclosure to third 
parties other than those noted below is prohibited.
Upon the subject’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his or her welfare.
Data generated by this study must be available for inspection upon request by 
representatives of the U.S. FDA, national and local health authorities, Millennium, and the 
IRB for each study site, if appropriate.
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19.   
REFERENCES
1.
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.
2.
Chiang GG, Abraham RT. Targeting the mTOR signaling network in cancer. Trends 
in Molecular Medicine 2007;13(10):433-42.
3.
Sabatini DM. mTOR and cancer: insights into a complex relationship. Nature 
Reviews. Cancer 2006;6(9):729-34.
4.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. 
Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. New 
England Journal of Medicine 2007;356(22):2271-81.
5.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of 
everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-
controlled phase III trial. Lancet 2008;372(9637):449-56.
6.
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.
7.
Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, et al. mTOR 
complex 2 is required for the development of prostate cancer induced by Pten loss in 
mice. Cancer Cell 2009;15(2):148-59.
8.
Nardella C, Carracedo A, Alimonti A, Hobbs RM, Clohessy JG, Chen Z, et al. 
Differential requirement of mTOR in postmitotic tissues and tumorigenesis. Science 
Signaling [Electronic Resource] 2009;2(55):ra2.
9.
Robb VA, Karbowniczek M, Klein-Szanto AJ, Henske EP. Activation of the mTOR 
signaling pathway in renal clear cell carcinoma. Journal of Urology 
2007;177(1):346-52.
10.
Kapoor A, Figlin RA. Targeted inhibition of mammalian target of rapamycin for the 
treatment of advanced renal cell carcinoma. Cancer 2009;115(16):3618-30.
11.
Brenner W, Farber G, Herget T, Lehr HA, Hengstler JG, Thuroff JW. Loss of tumor 
suppressor protein PTEN during renal carcinogenesis. International Journal of 
Cancer 2002;99(1):53-7.
12.
Liu Y, Jessen K, Wang S, Kessler L, Li L, Darjania L, et al. INK128, a potent and 
selective TORC1/2 inhibitor, demonstrates anti-tumor activity in preclinical models 
of renal cell carcinoma by a distinct mechanism. Eu J of Cancer Suppl 2010;8(7 
suppl):poster 482.
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13.
Ollikainen M, Gylling A, Puputti M, Nupponen NN, Abdel-Rahman WM, Butzow 
R, et al. Patterns of PIK3CA alterations in familial colorectal and endometrial 
carcinoma. International Journal of Cancer 2007;121(4):915-20.
14.
Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent 
mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Research 
2005;65(23):10669-73.
15.
Jessen K, Stewart J, Darjania L, Li L, Chan K, Martin M, et al. INK128, A TORC1/2 
kinase inhibitor demonstrates oral antitumor activity in preclinical models of 
endometrial and breast cancers and enhances efficacy of taxol [abstract]. In: 
Proceedings of the 102nd Annual Meeting of the American Association for Cancer 
Research; 2011: AACR; p. abstr nr B64.
16.
Hsieh A, Shokat K, Weissman J, Rommel C, et al. Translational control in prostate 
cancer. In: AACR PI3K Meeting; 2011 24-27 Feb; San Francisco, CA.
17.
Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P, Knowles MA. Spectrum 
of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clinical 
Cancer Research 2009;15(19):6008-17.
18.
Park SJ, Lee TJ, Chang IH. Role of the mTOR Pathway in the Progression and 
Recurrence of Bladder Cancer: An Immunohistochemical Tissue Microarray Study. 
Korean J Urol 2011;52(7):466-73.
19.
Sun CH, Chang YH, Pan CC. Activation of the PI3K/Akt/mTOR pathway correlates 
with tumour progression and reduced survival in patients with urothelial carcinoma 
of the urinary bladder. Histopathology 2011;58(7):1054-63.
20.
Mansure JJ, Nassim R, Chevalier S, Rocha J, Scarlata E, Kassouf W. Inhibition of 
mammalian target of rapamycin as a therapeutic strategy in the management of 
bladder cancer. Cancer Biology & Therapy 2009;8(24):2339-47.
21.
Chiong E, Lee IL, Dadbin A, Sabichi AL, Harris L, Urbauer D, et al. Effects of 
mTOR inhibitor everolimus (RAD001) on bladder cancer cells. Clinical Cancer 
Research 2011;17(9):2863-73.
22.
Sankhala K, Mita A, Kelly K, Mahalingam D, Giles F, Mita M. The emerging safety 
profile of mTOR inhibitors, a novel class of anticancer agents. Targeted Oncology 
2009;4(2):135-42.
23.
RAPAMUNE (sirolimus) Oral Solution and Tablets [package insert]. Philadelphia, 
PA: Pfizer; 2010.
24.
AFINITOR (everolimus) tablets for oral administration [package insert]. East 
Hanover, NJ: Novartis; 2011.
25.
TORISEL Kit (temsirolimus) injection, for intravenous infusion only [package 
insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc (Pfizer); 2011.
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26.
U.S. Department of Health and Human Services, Food and Drug Administration 
(FDA), Center for Drug Evaluation and Research (CDER), and Center for Biologics 
Evaluation and Research (CBER). Guidance for Industry:  S9 Nonclinical Evaluation 
for Anticancer Pharmaceuticals.  March 2010.
27.
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.
28.
Unites States Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER). Guidance for Industry:  Clinical Trial 
Endpoints for the Approval of Cancer Drugs and Biologics.  May 2007.
29.
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.
30.
The Criteria Committee of New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, 
Brown & Co; 1994.
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20.   
PROTOCOL ACCEPTANCE PAGE
Study Title:
A Phase I, Open Label, Dose Escalation Study of Oral Administration of 
Single Agent INK128 in Subjects with Advanced Malignancies Followed 
by an Expansion in Subjects with Measurable Disease
Protocol Number:
INK128-001
Investigational Product:
MLN0128 (also known as TAK-228 and INK128)
Sponsor:
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street, Cambridge, MA USA 02139
Medical Monitor:
Fabian Zohren, M.D.
Date of Original Protocol:
November 3, 2009
Date of Amendment 1:
December 3, 2009
Date of Amendment 2:
January 28, 2010
Date of Amendment 3:
March 31, 2010
Date of Amendment 4:
July 20, 2010 (not implemented)
Date of Amendment 5:
August 12, 2010
Date of Amendment 6:
September 14, 2010
Date of Amendment 7:
October 27, 2010 
Date of Amendment 8:
December 21, 2010
Date of Amendment 9:
March 25, 2011
Date of Amendment 10:
June 28, 2011
Date of Amendment 11:
October 12, 2011
Date of Amendment 12:
April 03, 2012
Date of Amendment 13:
May 21, 2012
Date of Amendment 14:
July 30, 2012
Date of Amendment 15:
March 27, 2013
Date of Amendment 16:
July 3, 2013
Date of Amendment 17:
March 5, 2014
Date of Amendment 18:
September 26, 2016
Date of Amendment 19:
November 28, 2017
Date of Amendment 20:
January 17, 2018
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By my signature below, I hereby state that I have read, and agree to abide by, the 
instructions, conditions, and restrictions of the protocol and amendments referenced above.
Investigator Signature
Date
Printed Name of Investigator
Please return a copy of this form to Millennium Pharmaceuticals or its designee.  Contact 
details will be provided to the investigator.  Please retain a copy for your study files.
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21.   
APPENDICES
21.1   ECOG Performance Status
Table 21-1   ECOG 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.(29)
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21.2   List of Relevant Cytochrome P450 Inhibitors and Inducers
Table 21-2
List of Relevant Cytochrome P450 Inhibitors and Inducers
Moderate CYP1A2 Inhibitors
methoxsalen
mexiletine
oral contraceptives
Strong CYP1A2 Inhibitors
fluvoxamine
zafirlukast
ciprofloxacin
enoxacin
Clinically Relevant CYP Inducers (moderate* CYP1A2 and strong CYP3A4)
phenytoin
rifampin
ritonavir
teriflunomide
carbamazepine 
enzalutamide
mitotane
phenytoin
St. John’s wort
Source: 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/u
cm093664.htm#table3-2
* No strong CYP1A2 inducers could be identified in the above source at present 
Note that these lists are not exhaustive. Please refer to the above link for further information and examples of 
other CYP inhibitors/inducers.
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21.3   New York Heart Association Classification of Cardiac Disease
Table 21-3   New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  If 
any physical activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis of 
Diseases of the Heart and Great Vessels.  9th Ed.  Boston, MA:  Little, Brown & Co; 1994:253-256.(30)
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21.4   Amendment 20 Detailed Summary of Changes
The primary section(s) of the protocol affected by the changes in Amendment 20 are 
indicated.  The corresponding text has been revised throughout the protocol.
Change 1: Specify cautionary use of CYP1A2 inhibitors and CYP1A2 and Cyp3A4 
inducers as concomitant medications.
The primary change occurs in Section 8.9.9, Prior and Concomitant Medications.
Revised
text:
Strong cytochrome CYP1A2 inhibitors, moderate CYP1A2 inducers, and strong 
and moderate CYP3A4 inducers should be administered with caution and at the 
discretion of the investigator.Moderate and strong cytochrome CYP1A2 
inhibitors and moderate and strong CYP1A2 and CYP3A4 inducers should 
be administered with caution and at the discretion of the investigator.
Rationale for Change:
This change was made to address the use of moderate cytochrome CYP1A2 inhibitors and 
strong CYP1A2 inducers.
Change 2: Remove dietary restrictions related to CYP inhibitors and inducers consistently 
within the protocol.
The primary change occurs in the synopsis and exclusion criteria to align with Section 8.11,
Dietary or Other Protocol Restrictions.
Deleted 
text: 
Subjects should not consume food or beverages containing the fruit or juice 
from grapefruits or Seville oranges within 7 days before first dose of study 
drug.
Rationale for Change:
This change was made for consistency within the protocol with new data that remove the 
necessity for restrictions concerning CYP2C9 and 2C19.
Change 3: Update FDA guidance link.
The primary change occurs in the footnote to Table 21-2.
Revised
text: 
fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInte
ractionsLabeling/ ucm093664.htm. 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentRes
ources/DrugInteractionsLabeling/ucm093664.htm#table3-2
Rationale for Change:
This change was made to provide the current FDA guidance.
Change 4: Add additional information to footnote.
The primary change occurs in the footnote to Table 21-2.
Added 
Please refer to the above link for further information and examples of 
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text: 
other CYP inhibitors/inducers.
Rationale for Change:
This change was made to specify that additional information is available via the FDA 
guidance link.
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SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase I, Open Label, Dose Escalation Study of Oral Administration of Single Agent 
INK128 in Subjects with Advanced Malignancies Followed by an Expansion in Subjects with 
Measurable Disease
NCT Number: NCT01058707
SAP Approve Date: 17 January 2014
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


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MLN0128
Final
Statistical Analysis Plan, Study INK128-001
EDMS Template Version 2.0
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS...........................................4
1. INTRODUCTION................................................................................................................5
1.1 Study Design...................................................................................................................5
1.2 Study Objectives.............................................................................................................5
2. POPULATIONS FOR ANALYSIS .....................................................................................7
2.1 All Subjects as Treated (ASaT) Population....................................................................7
2.2 Response-Evaluable Population .....................................................................................7
2.3 Pharmacokinetics Population .........................................................................................7
2.4 Pharmacodynamics Population.......................................................................................7
2.5 Dose-Escalation Evaluable Population...........................................................................7
3. HYPOTHESES AND DECISION RULES..........................................................................8
4. INTERIM ANALYSIS.........................................................................................................8
5. STATISTICAL METHODOLOGY.....................................................................................8
5.1 Sample Size Justification................................................................................................9
5.2 Randomization and Stratification ...................................................................................9
5.3 Unblinding......................................................................................................................9
5.4 Data Handling...............................................................................................................10
5.4.1 Methods for Handling Missing Data .....................................................................10
5.4.2 Definition of Baseline Values................................................................................10
5.4.3 Windowing of Visits..............................................................................................10
5.5 Subject Disposition.......................................................................................................10
5.6 Demographics and Baseline Disease Characteristics ...................................................10
5.6.1 Demographics........................................................................................................10
5.6.2 Medical History .....................................................................................................10
5.7 Treatments and Medications.........................................................................................11
5.7.1 Concomitant Medications......................................................................................11
5.7.2 Study Treatments...................................................................................................12
5.8 Efficacy Analyses.........................................................................................................13
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis...................................13
5.9.1 Pharmacokinetic Analyses.....................................................................................13
5.9.2 Pharmacodynamic Analyses..................................................................................15
5.10 Safety Analyses ..........................................................................................................15
5.10.1 Adverse Events ....................................................................................................16
5.10.2 Laboratory Data...................................................................................................18
5.10.3 Vital Signs............................................................................................................19
5.10.4 Electrocardiogram................................................................................................19
5.10.5 ECOG Performance Status ..................................................................................19
6. CHANGES TO PLANNED ANALYSES FROM PROTOCOL.......................................19
7. PROGRAMMING CONSIDERATIONS ..........................................................................20
7.1 Statistical Software.......................................................................................................20
7.2 Rules and Definitions ...................................................................................................20
7.2.1 Study Drug.............................................................................................................20
7.2.2 Study Day 1 ...........................................................................................................20
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7.2.3 Study Day ..............................................................................................................20
7.2.4 Cycle k Day j .........................................................................................................20
7.2.5 Age at Screening....................................................................................................21
7.2.6 Incomplete Adverse Event Start Dates..................................................................21
8. REFERENCES ...................................................................................................................22
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation or 
Term
Definition
AE
adverse event
AUC
area under the curve
Cmax
maximum concentration
Ctrough
Trough concentration
CR
complete response
CRF
case report form
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
FAS
full analysis set
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MTD
maximum tolerated dose
N
number of subjects
NCI
National Cancer Institute
ORR
objective response rate
PD
pharmacodynamic
PK
Pharmacokinetic
PR
partial response
QD
Once daily
QW
Once weekly
RECIST
Response Criteria for Solid Tumors
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SE
standard error
T1/2
half-life
Tmax
time of maximum concentration
TEAEs
treatment emergent adverse events
WHO
World Health Organization
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1.   
INTRODUCTION
In general, the purpose of the statistical analysis plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies.  Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that will 
addresses the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1   
Study Design
This is a phase 1, open-label study that consists of a dose escalation phase in subjects with
advanced malignancies, followed by an expansion phase of safety and efficacy in up to 80 
additional response-evaluable subjects with measurable disease. Up to 4 different dosing
schedules will be explored in the dose escalation phase: QD, once weekly (QW), QDx3d 
QW, and QDx5d QW. Enrollment will start with the once daily schedule. Once the MTD for 
this schedule is identified, enrollment will begin in parallel in the alternate dosing schedules. 
Once the MTD has been identified for each of the 4 dosing schedules evaluated, an 
additional 6 subjects may be enrolled in 1 or more of the dosing schedules to gain further
PK and safety data prior to the expansion phase of the study.
Based on biochemical data, available PK, and tolerability data for each MLN0128 dosing
schedule, along with potential early signs of anti-tumor activity from subjects treated during
the dose escalation phase, 1 or more dosing schedules will be selected to be evaluated in the
expansion phase. In the expansion phase, the safety and efficacy of 1 or more MLN0128
treatment schedules will be evaluated in parallel in a renal tumor-specific cohort, as well as
in cohorts of selected tumor types (endometrial and bladder cancers) for a total of 80 
response-evaluable subjects.
1.2   
Study Objectives
The primary objectives of the study are:

To determine the MTD and DLT of oral administration of MLN0128 given daily or 
via alternate dosing schedules in subjects with advanced malignancies
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
To evaluate the safety and tolerability of orally administrated single-agent 
MLN0128, given daily or via alternate dosing schedules, in both the dose escalation 
and the expansion phases of the study
The secondary objectives of the study are:

To evaluate the plasma PK of single-agent MLN0128 following oral administration
daily and according to alternate dosing schedules, in subjects with advanced
malignancies

To evaluate the pharmacodynamic effect of MLN0128 activity in surrogate tissue
(skin) and tumor as measured by S6, eukaryotic initiation factor 4E-binding protein 
1 (4EBP1), and AKT, as well as in peripheral blood cells as measured by 4EBP1

To evaluate preliminary anti-tumor activity of MLN0128
The exploratory objectives of the study are:
CCI
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2.   
POPULATIONS FOR ANALYSIS
2.1   
All Subjects as Treated (ASaT) Population
The ASaT population consists of all enrolled subjects who receive at least 1 dose of 
MLN0128.  The All Subjects as Treated (ASaT) population will be used for the analysis of 
safety data.  
2.2   
Response-Evaluable Population
The response-evaluable population includes subjects who receive at least 1 dose of 
MLN0128 dose, have measurable disease at baseline, and undergo at least 1 post-baseline 
disease assessment.   Subjects who do not have at least 1 post-baseline disease assessment 
but discontinued study drug due to symptomatic and/or clinical deterioration will be 
included in the response-evaluable population.
2.3   
Pharmacokinetics Population
The PK population consists of all subjects enrolled during the dose escalation phase of the 
study who receive at least one dose of MLN0128 and have sufficient concentration-time 
data to calculate one or more PK parameters.
2.4   
Pharmacodynamics Population
The PD population consists of all subjects enrolled during the dose escalation phase with at 
least one pre and post treatment peripheral blood, tumor biopsy, or skin biopsy sample 
collected.  Analyses of p4EBP1 from peripheral blood samples and p4EBP1, pAKT, pS6,
pNDRG1, and pPRAS40 from skin and tumor biopsies will be performed using the PD 
population.
2.5   
Dose-Escalation Evaluable Population
The dose-escalation evaluable population is defined as subjects who received 75% or more 
of planned doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of 
planned doses because of study drug related AE (considered as a DLT).  Per the protocol 
during the dose escalation phase, subjects who receive at least 75% (21 of 28 for QD dosing 
schedule; 3 of 4 for QW dosing schedule; 9 of 12 for QDx3d QW dosing schedule; 15 of 20 
for QDx5d QW dosing schedule) of the planned doses in Cycle 1 will be considered to have 
sufficient safety data/follow-up to support dose escalation.  Subjects who withdraw from 
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study before receiving 75% of the planned doses in the first cycle of treatment for reasons 
unrelated to study drug toxicity will be considered to have inadequate data to support dose 
escalation.
The dose-escalation evaluable population will be used for the analysis of DLTs.
3.   
HYPOTHESES AND DECISION RULES
Not applicable in a phase 1 study.
4.   
INTERIM ANALYSIS
Not applicable.
5.   
STATISTICAL METHODOLOGY
In general, summary tabulations will be presented that display the number of observations, 
mean, standard deviation (SD), median, minimum, and maximum for continuous variables, 
and the number and percent (of nonmissing) per category for categorical data, unless 
specified otherwise.   Unless noted otherwise data from the dose escalation phase will be 
summarized by schedule and dose level [ordered] and data from the expansion phase will be 
summarized as follows:
1. Disposition/Demographics/Baseline/Characteristics/Prior 
Therapy/AE/ECG/Vitals/ConMeds:
Cohort:  Renal
TORC1 Naïve
TORC1 Failure
5 mg QD
30 mg 
QW
40mg
QW
Total
5 mg QD
30 mg 
QW
40mg
QW
Total
Cohort: Endometrial/Bladder
Endometrial
Bladder
5 mg QD
30 mg 
QW
40mg
QW
Total
5 mg QD
30 mg 
QW
40mg
QW
Total
2. Efficacy:
Cohort:  Renal
TORC1 Naïve
TORC1 Failure
5 mg QD
30 mg 
QW
40mg
QW
Total
QW
5 mg QD
30 mg 
QW
40mg
QW
Total
QW
Cohort: Endometrial/Bladder
Endometrial
Bladder
5 mg QD
30 mg 
QW
40mg
QW
Total
QW
5 mg QD
30 mg 
QW
40mg
QW
Total
QW
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5.1   
Sample Size Justification
Dose Escalation Phase 
Cohorts of 3 to 6 subjects will be enrolled in each MLN0128 dose cohort and dose schedule 
evaluated based on a standard phase 1 sequential dose escalation scheme. Additional 
subjects, up to a total of 12, may be enrolled in a given cohort and schedule to better 
understand the safety profile and tolerability of a particular dose level/dose schedule 
combination. Each subject will participate in only 1 dose cohort/dose schedule. The total 
number of subjects to be enrolled in the dose escalation phase of the study is dependent 
upon the observed safety profile, which will determine the number of subjects per dose 
cohort, as well as the number of dose escalations required to achieve the MTD for each dose 
schedule evaluated.
Expansion Phase
Based on safety and available PK data of MLN0128 along with possible early signs of 
antitumor activities from subjects treated during the dose escalation phase, the expansion 
phase of the study will evaluate 1 or more populations (initially 2) with measurable disease: 
renal cell cancer and a cohort of selected tumor types (endometrial and bladder cancers). 
Cohorts may enroll subjects in parallel in the expansion phase, each with 15 to 25 response-
evaluable subjects. The smaller sample size of 15 response-evaluable subjects per disease 
cohort is based on following considerations: A single agent that results in an objective 
response rate of 1% or less is considered to have insufficient activity to warrant further 
study. An objective response rate of 20% or greater is considered sufficient to warrant 
further study of the agent. Fifteen subjects per cohort will provide 83% power to detect a 
statistically significant difference between the uninteresting and interesting objective 
response rates based on the exact 1-sample binomial test and 1-sided significance level of 
5%.
5.2   
Randomization and Stratification
Not applicable.
5.3   
Unblinding
Not applicable.
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5.4   
Data Handling
5.4.1   
Methods for Handling Missing Data
All available efficacy and safety data will be included in data listings and tabulations.  Data 
that are potentially spurious or erroneous will be examined under the auspices of standard 
data management operating procedures.
5.4.2   
Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of study drug administration.  
5.4.3   
Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected.  These 
visit designators are predefined values that appear as part of the visit tab in the eCRF.  
5.5   
Subject Disposition     
The number of subjects enrolled, in each analysis population, and the reason study drug was
discontinued will be summarized for the dose escalation phase by schedule and dose level 
[ordered] and for the expansion phase as shown in Section 5.
5.6   
Demographics and Baseline Disease Characteristics
5.6.1   
Demographics
The following demographic characteristics will be summarized for the dose escalation phase
(all subjects) and for the expansion phase as shown in Section 5: age, sex, ethnicity, race, 
weight, and baseline ECOG performance status.
5.6.2   
Medical History
5.6.2.1   General Medical History
Non-Cancer Medical History will be in a by-subject listing.
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5.6.2.2   Disease-Specific History
The following disease specific endpoints will be summarized for the dose escalation phase
(all subjects) and for the expansion phase as shown in Section 5:

Type of cancer at diagnosis
o
Breast cancer

ER+ and/or PR+/HER2-

ER+ and/or PR+/HER2+

ER-/PR-/ HER2+

ER-/PR-/ HER2-
[ HER2+ is defined as IHC 3 or FISH positive]
o
Lung cancer: Small Cell and NSCLC

Years since initial diagnosis

Stage of disease at initial diagnosis

Stage of disease at study entry

Years since initial metastatic diagnosis or diagnosis of locally advanced inoperable
cancer
The number and percentage of subjects with prior surgery, prior radiation, and prior 
systemic anticancer therapies will be summarized for the dose escalation phase (all subjects) 
and for the expansion phase as shown in Section 5. The following will be summarized for 
those subjects with prior systemic therapies:

Systemic regimen received (e.g. antibody therapy,  hormonal therapy)

Number of prior systemic treatment regimens

Setting of most recent systemic treatment

Best response to most recent systemic treatment

Reason most recent systemic treatment discontinued

Months on most recent systemic treatment
A scatter plot of the duration of treatment with MLN0128 versus the duration on the most 
recent systemic treatment (in months) will be generated for  each renal expansion cohort 
(TORC1 Naïve and TORC1 Failure, different symbols for schedule and dose level).
5.7   
Treatments and Medications
5.7.1   
Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (March 2013 version). The number and percentage of subjects taking 
concomitant medications will be tabulated by ATC classification and generic name in the 
ASaT population by schedule and dose level [ordered] for the dose escalation phase and for 
the expansion phase as shown in Section 5.
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5.7.2   
Study Treatments
MLN0128 will be administered orally once in the morning with a meal at approximately the 
same time of day.  Cycles are repeated every 28 days. 
QD dosing schedule: once daily in the morning on Days 1 through 28 of each cycle; 
QW dosing schedule: once in the morning on Days 1, 8, 15, and 22 of each cycle; 
QD3d QW dosing schedule: once in the morning on Days 1, 2, 3, 8, 9, 10, 15, 16, 17, 22, 
23, and 24 of each cycle; 
QD5d QW dosing schedule: once in the morning on Days 1, 2, 3, 4, 5, 8, 9, 10, 11,12, 
15, 16, 17, 18, 19, 22, 23, 24, 25, and 26 of each cycle.
5.7.2.1   Extent of Exposure
The overall duration of study drug administration (weeks: date of last dose – date of first 
dose + 1/ 7), total number of cycles administered (distribution and summary statistics), 
cumulative dose, dose per administration, and percentage of planned original dose will be 
summarized by schedule and dose level [ordered] for the dose escalation phase and for the 
expansion phase as shown in Section 5.
The percentage of planned original dose is calculated as the cumulative dose taken (mg)
divided by the total planned dose (mg).  The total planned dose is: 
dose level at study start * doses per week * 4 weeks/cycle * maximum no of cycles.
The number and proportion of subjects with one or more dosage modifications will be 
tabulated along with the reason for dosage modification.  The number and proportion of 
subjects with intra-patient dose escalation will be summarized
The Cycle 1 compliance is used in the determination of the DLT evaluable population and is 
calculated as the cumulative dose taken during Cycle 1 (mg) divided by the expected dose in 
Cycle 1.  The expected dose in cycle 1 is: 
dose level at study start * doses per week * 4 weeks/cycle
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5.8   
Efficacy Analyses
The number and percent of subjects in each response category, the objective response rate 
(CR + PR), clinical benefit rate (CR + PR + SD), best response of SD <6 months, best 
response of SD ≥6 months will be presented by schedule and dose level [ordered] for the 
escalation phase and for the expansion phase as shown in Section 5. In addition, for the 
expansion phase the percentage of subjects with any decrease in the sum of the longest 
diameters from baseline will be summarized. The objective response rate will be based on 
the subject’s best overall tumor response documented during the course of protocol therapy.  
The duration of stable disease will be calculated relative to Study Day 1 for those subjects 
with a best response of stable disease and will be included in a data listing.
The duration of objective response will be calculated for subjects who achieve objective 
response and will be included in a data listing.  For such subject, the duration of objective 
response is defined as the number of days from the start date of CR, or PR (whichever 
response is achieved first) to the first date that progressive disease is objectively 
documented.   Those subjects who did not progress are censored at the date of the last 
response assessment.
Tumor marker data will be included in a data listing.
5.9   
Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis
5.9.1   
Pharmacokinetic Analyses
The pharmacokinetic analyses will be based on PK data collected during the dose escalation
portion of the study.  Sparse PK data collected during the expansion cohort will be in a data 
listing.  The sparse pharmacokinetic sampling in the expansion cohort will be used as part of 
the population PK modeling in a separate report.
5.9.1.1    PK Parameters for MLN0128
Data permitting the following PK parameters may be estimated and reported:
Parameter
Definition
Units
Cmax
Observed maximum concentration
ng/mL
Tmax
First time Cmax is observed
hr
Ctrough
Observed concentration at the end of the dosing interval
ng/mL
AUC8hr
Area under the concentration-time curve, from time 0 to 
8 hr, estimated using the linear-log trapezoidal method
hr*ng/mL
AUC24hr
Area under the concentration-time curve, time 0 to 24 hr 
hr*ng/mL
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Parameter
Definition
Units
sample, estimated using the linear-log trapezoidal 
method
lambdaz
Terminal disposition phase rate constant.  The presence 
of at least three points in the terminal phase, an r2 greater 
than 0.80, and a span equal to or greater than 1.5 are 
required to report lambdaz and the other PK parameters
that are calculating using lambdaz.
1/hr
t1/2
Terminal disposition phase half-life
hr
AUCinf
Area under the concentration-time curve, time 0 
extrapolated to infinity, estimated using the linear-log
trapezoidal method. 
hr*ng/mL
CL/F
Apparent clearance, extravascular dosing
L/hr
Vz/F
Apparent terminal phase volume of distribution, 
extravascular dosing
L
Rac24hr
Accumulation ratio based on AUC8hr
unitless
5.9.1.2   Pharmacokinetic Analyses
All PK analyses will be performed using the pharmacokinetic population.
Pharmacokinetic Concentrations
Descriptive statistics (number of subjects, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of variation, geometric mean, median, minimum, and maximum) will 
be used to summarize the plasma concentrations by dosing schedule, dose level and 
scheduled time.  BQL values at the beginning of the profile will be set to zero. BQL values 
that occur after the first quantifiable point will be considered missing.
Linear and semi-logarithmic plots of the mean plasma concentration versus scheduled 
sampling time will be provided for each dosing schedule, and dose level.  Linear and semi-
logarithmic plots of individual plasma concentration versus actual sampling time will be 
provided for each dosing schedule, and dose level. 
All individual subject plasma concentration data will be listed.
Pharmacokinetic Parameters
PK parameters will be estimated using non-compartmental methods with WinNonlin®
Professional Version 6.1 or higher (Pharsight Corp., Mountain View, CA).  The plasma PK 
parameters will be estimated from the concentration-time profiles for all PK population 
subjects. In estimating the PK parameters, BQL values at the beginning of the profile will be 
set to zero. BQL values that occur after the first quantifiable point will be considered 
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missing. Values that are embedded between BQLs, or quantifiable values occurring after 
two or more BQLs, will be set to missing at the discretion of the pharmacokineticist. Actual 
sampling times, rather than scheduled sampling times, will be used in all computations 
involving sampling times.
Descriptive statistics (number of subjects, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of deviation, geometric mean, median, minimum value, and maximum 
value) will be used to summarize the calculated PK parameters by dosing schedule, and 
dose level. For Tmax, only median, minimum value, and maximum value will be presented.
An analysis of dose proportionality will be performed for the PK parameters AUCinf, and 
Cmax.
5.9.2   
Pharmacodynamic Analyses
Peripheral Blood Cells
Due to issues with assay validation p4EBP1 results will be in a listing but not summarized.
Skin and Tumor Biopsies
Descriptive statistics will be used to summarize baseline, cycle 1 2-4 hour post dose, and the 
percent change from baseline [((post – pre)/ pre) * 100] for p4EBP1, pAKT, pS6, and 
pNDRG1 by schedule and dose level [ordered] for the escalation phase. Scatter plots of 
individual and mean values of the percent change from baseline vs. dose level will be 
generated for each schedule and biomarker.
Due to issues with staining the pPRAS40 results will be in a listing but not summarized.
5.10   Safety Analyses
Safety evaluations will be based on the incidence, severity, type of AEs, clinically
significant changes, or abnormalities in the subject’s physical examination, vital signs, 
ECG, and clinical laboratory results.  
These analyses will be performed using the ASaT population.
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5.10.1   Adverse Events
5.10.1.1   Adverse Events
Treatment emergent adverse events are defined as adverse events that start on or after the 
first administration of study drug and less than or equal to 30 days after the last 
administration of study drug.  Missing and partially missing adverse event start dates will be 
imputed according to the specifications described in Section 7.2.7.  The reported adverse
event term will be assigned standardized terms using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 16.0.
All adverse event tabulations will be by schedule and dose level [ordered] for the escalation 
phase and for the expansion phase as shown in Section 5.   Treatment emergent adverse 
events will be summarized based on the number and percentage of subjects experiencing 
events by MedDRA system organ class and preferred term.  Tabular summaries of the 
following treatment emergent adverse events will be provided:

All TEAEs

TEAEs related to Study Drug

Grade 3 or greater TEAEs

Grade 3 or greater TEAEs related to Study Drug

Most common (at least 2 subjects) TEAEs by maximum severity grade based on 
NCI-CTCAE (version 4.0)    [within each schedule in the escalation, and within each 
tumor type in the expansion phase]
The number of subjects with a DLT in Cycle 1 will be presented by schedule and dose level 
[ordered] for the escalation phase based on the dose-escalation evaluable population. 
Multiple concurrent adverse events leading to DLT will be considered a single DLT. 
Adverse events of interest will be tabulated for the following:
Adverse event of 
interest
MedDRA Preferred Term
Hyperglycemia
Glucose tolerance impaired, Hyperglycaemia, Impaired fasting 
glucose
Rash
Fixed eruption,  Mucocutaneous rash,  Rash, Rash generalized,
Rash macular, Rash maculo-papular,  Rash maculovesicular, 
Rash morbilliform,  Rash rubelliform,  Rash scarlatiniform, 
Rash vesicular,  Dermatitis exfoliative,  Drug eruption,  Drug 
hypersensitivity,  Drug rash with eosinophilia and systemic 
symptoms, Reaction to drug excipients, Toxic skin eruption, 
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Adverse event of 
interest
MedDRA Preferred Term
Administration related reaction,  Erythema,  Generalised 
erythema,  Rash erythematous,  Rash popular,  Rash 
papulosquamous
Renal Insufficiency
(MedDRA 
Standardized Medical 
Query)
Acute phosphate nephropathy , Acute prerenal failure (Narrow), 
Anuria (Narrow), Azotaemia (Narrow), Continuous 
haemodiafiltration (Narrow), Dialysis (Narrow), Haemodialysis 
(Narrow), Neonatal anuria (Narrow), Nephropathy toxic 
(Narrow), Oliguria (Narrow), Peritoneal dialysis (Narrow), 
Prerenal failure (Narrow), Renal failure (Narrow), Renal failure 
acute (Narrow), Renal failure neonatal (Narrow), Renal 
impairment (Narrow), Renal impairment neonatal (Narrow), 
Albuminuria (Broad), Blood creatinine abnormal (Broad), 
Blood creatinine increased (Broad), Blood urea abnormal 
(Broad), Blood urea increased (Broad), Blood urea 
nitrogen/creatinine ratio, Creatinine renal clearance abnormal, 
Creatinine renal clearance decreased, Creatinine urine abnormal 
(Broad), Creatinine urine decreased (Broad), Crystal 
nephropathy (Broad),  Glomerular filtration rate abnormal,  
Glomerular filtration rate decreased, Hypercreatininaemia 
(Broad), Nephritic syndrome (Broad),  Nephritis (Broad), 
Oedema due to renal disease (Broad), Protein urine present 
(Broad), Proteinuria (Broad), Renal function test abnormal 
(Broad), Renal transplant (Broad), Renal tubular disorder 
(Broad), Renal tubular necrosis (Broad), Tubulointerstitial
nephritis (Broad), Urea renal clearance decreased (Broad), 
Urine output decreased (Broad)
Mucosal Inflammation
Burning sensation mucosal,  Mucosal erosion,  Mucosal 
excoriation,  Mucosal exfoliation,  Mucosal hyperaemia,  
Mucosal inflammation, Mucosal necrosis, Mucosal ulceration, 
Aphthous stomatitis, Mouth ulceration, Oral mucosa erosion, 
Stomatitis, Stomatitis haemorrhagic, Stomatitis necrotizing, 
Oral discomfort, Oral mucosal blistering, Oral mucosal 
erythema, Oral mucosal exfoliation, Oropharyngeal blistering, 
Oropharyngeal discomfort, Oropharyngeal pain
Asthenic Conditions
Asthenia, Fatigue, Lethargy, Listless, Malaise, Sluggishness, 
Muscle Weakness
  
5.10.1.2   Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment emergent serious 
AE (SAE) will be summarized by MedDRA primary system organ class and preferred term:.
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
Serious TEAEs

Serious TEAEs related to Study Drug
In addition, a by-subject listing of the SAEs will be presented (the subject listing will 
contain all SAEs regardless of treatment emergent AE status).
5.10.1.3   Deaths
A listing of fatal TEAEs that occur within 30 days of the last administration of study drug
will be generated.
5.10.1.4   Adverse Events Resulting in Discontinuation of Study Drug
The following listings of TEAEs will be generated:

TEAEs resulting in discontinuation of study drug 

TEAEs resulting in modification or interruption of study drug
5.10.2   Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will 
be converted to standardized units.  Whenever available, laboratory values will be assigned 
toxicity grades using the NCI-CTCAE version 4.0.  These criteria may include qualifying 
definitions (e.g., clinical adverse event and/or requirement for concomitant medication) in 
addition to the specific laboratory value in the definition of the toxicity grades for some 
laboratory tests.  For such tests, the qualifying definitions will not be used for the 
assignment of toxicity grades. The number and proportion of subjects with shifts in CTCAE 
toxicity grades relative to the baseline toxicity grade will be summarized by schedule and 
dose level [ordered] for the escalation phase and for the expansion phase as shown in 
Section 5.
For those laboratory tests not assigned NCI-CTCAE toxicity grades the number and 
proportion of subjects with shifts in laboratory values to outside the laboratory normal range 
relative to the baseline value will be summarized by schedule and dose level [ordered] for 
the escalation phase and for the expansion phase as shown in Section 5.  The NCI-CTCAE 
version 4.0 toxicity criteria for creatinine will be modified to exclude the comparison to
baseline.
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5.10.3   Vital Signs
Vital sign results (diastolic and systolic blood pressure) and body weight will be 
summarized descriptively by schedule and dose level [ordered] for the escalation phase and 
for the expansion phase as shown in Section 5 as follows:

Baseline value

Minimum post-baseline value

Maximum post-baseline value
Changes to the minimum and maximum post-baseline values will be calculated relative to 
the baseline value.  
5.10.4   Electrocardiogram
Selected ECG parameters (ventricular rate, PR, QRS, QT, and QTc (Fridericia) ) will be 
summarized in the same manner as described for vital signs in Section 5.10.3.   All QT 
values will be converted to QTcF using Fridericia’s correction:
(sec)
[Note: convert RR recorded on ECG CRF from msec to sec, if the RR is not available use: 
60 seconds divided by the ventricular rate in beats/minute].
The change from baseline in QT/QTc interval and the number and percent of subjects with 
increases >30 ms and >60 ms will be summarized.  Shifts from baseline to maximum post 
baseline QTcF values will be summarized based on the following categories:
≤ 450 ms, > 450-480 ms, > 480-500 ms and >500 ms.
5.10.5   ECOG Performance Status
ECOG performance status scores will be summarized in the same manner as described for 
vital signs in section 5.10.3 (maximum post-baseline only).
6.   
CHANGES TO PLANNED ANALYSES FROM PROTOCOL
Reference materials for this statistical plan include Clinical Study Protocol INK128-001
Amendment 16 dated 3July2013.
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Statistical Analysis Plan, Study INK128-001
EDMS Template Version 2.0
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7.
PROGRAMMING CONSIDERATIONS
7.1   
Statistical Software 
SAS version 9.1 (or higher) will be used for all analyses.  
7.2   
Rules and Definitions
Subject 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.
7.2.1
Study Drug
The term “study drug” represents MLN0128.
7.2.2
Study Day 1
Study Day 1 corresponds to the date of the first dose of study drug.  For subjects who
receive 1 or more doses of study drug, the start date recorded on the Study Drug 
Administration (Cycle 1 – Day 1) CRF will be used to determine Study Day 1.
7.2.3
Study Day
Study Day represents the elapsed number of days from Study Day 1, inclusive.
Study Day n = (Date of assessment – Date of Study Day 1) + 1 day
Unless otherwise specified, the timing of all study-related events, assessments, and 
interventions will be calculated relative to Study Day 1.  Study Day −1 will be the day 
before Study Day 1, and in general, negative days will be measured backwards starting from 
Study Day −1.
7.2.4
Cycle k Day j
The first 28-day treatment cycle will begin with the first dose of study drug, and will be 
denoted as “Cycle 1 Day 1”.  In general, the start date of each cycle (i.e., Day 1 of Cycle k, 
where k=1 to maximum number of cycles started) equals the date of the first dose of study 
drug administered in the corresponding cycle.  
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Statistical Analysis Plan, Study INK128-001
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Day j represents the elapsed number of days since the first dose of protocol therapy in 
Cycle k and Day j = (Date of assessment – Date of Day 1 in Cycle k) + 1.  Unless otherwise 
specified, the timing of study-related visits and assessments will be calculated relative to 
Day 1 in each cycle.
7.2.5
Age at Screening
Age will be calculated in years relative to the date the informed consent is signed based on 
the following SAS programming statement:
Age = floor ((intck (‘month’, birthdt, icdt) – (day (icdt) < day (birthdt))) / 12);
For subjects whose day and month of birth may not be available due to confidentiality 
agreements, age (and any other variables where this information is needed) will be 
calculated assuming a birth day and month of July 1st.
7.2.6   Incomplete Adverse Event Start Dates
Missing and incomplete adverse event start dates will be imputed based on the algorithm 
described below.  The algorithm will be used only if the end date of the adverse event (if 
reported) indicates the event was not resolved before the first administration of study drug.  
The purpose of the imputation is to determine if an adverse event with a missing or 
incomplete start date is treatment emergent (as defined in Section 5.10.1.1).  
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:
If the start date has month and year but day is missing, the event will be considered 
treatment-emergent if both the month and year of the start date of the event are on or after 
the month and year of the date of the first dose of MLN0128 and on or before the month and 
year of the date of the last dose of MLN0128 plus 30 days.
If the start date has year, but day and month are missing, the event will be considered 
treatment -emergent if the year of the start date of the event is on or after the year of the date 
of the first dose of MLN0128 and on or before the year of the date of the last dose of 
MLN0128 plus 30 days.
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If the start date of an event is completely missing, then the event is assumed to be treatment-
emergent.
8.
REFERENCES
Not applicable.
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