Conditions: Advanced Nonhematologic Malignancies
Keywords: Drug Therapy TAK-228 TAK-117
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 101
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the safety and to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and dosing schedules of oral TAK-228+TAK-117. It also evaluated the single- and multiple-dose plasma pharmacokinetics (PK) of TAK-228+TAK-117 in participants with advanced nonhematologic malignancies.

Detailed description:
The drug being tested in this study was TAK-228. TAK-228 was tested to evaluate the safety, pharmacokinetics and efficacy, of TAK-228 in combination with TAK-117 when administered to adult participants with advanced nonhematologic malignancies.

The study enrolled 101 patients. The study consisted of 2 phases: an escalation stage followed by an expansion stage. Participants in escalation stage were assigned to the following treatment arms:

* Dose escalation treatment arm A: TAK-228 2 or 4 mg capsule
* Dose escalation treatment arm B: TAK-228 3, 4, 6 or 8 mg capsule
* Dose escalation treatment arm C: TAK-228 3 mg capsule

Upon completion of the escalation stage, 1 combination treatment regimen was selected for further safety, tolerability, pharmacokinetics, and mutual drug-drug interaction characterization in the expansion stage. During treatment, participants in both stages received TAK-228 and TAK-117 capsules at prespecified doses in repeated 28-day cycles.

This multi-center trial conducted in the United States, United Kingdom and Spain. The overall time to participate in this study was approximately 68 weeks. Participants made multiple visits to the clinic, and a final visit after 30 days after last dose of study drug.

Arms:
arm 1: TAK-228 2 or 4 mg, capsule (milled or unmilled), orally, once daily every day (QD), and TAK-117 100, 200 or 300 mg, capsule, orally, once on Monday, Wednesday and Friday each week (MWF QW) for up to 13 cycles (each cycle was 28 days), up to approximately 52 weeks. arm 2: TAK-228 3, 4, 6 or 8 mg, capsule (milled or unmilled), orally, once on Monday, Tuesday and Wednesday each week (MTuW QW), and TAK-117 100 or 200 mg, capsule, orally, once on MTuW QW for up to 9 cycles (each cycle was 28 days), up to approximately 38.7 weeks. arm 3: TAK-228 3 mg, capsule (milled or unmilled), orally, once on MTuW QW, and TAK-117 300 or 400 mg, capsule, orally, once on MTuW QW for up to 17 cycles (each cycle was 28 days), up to approximately 64.3 weeks. arm 4: TAK-228 4 mg, capsule (milled), orally, once on MTuW QW except on Days 15, 16 and 17 of Cycle 1, and TAK-117 200 mg, capsule, orally, once on MTuW QW except on Days 1, 2 and 3 of Cycle 1 for up to 8 cycles (each cycle was 28 days), up to approximately 31.4 weeks.

Interventions: intervention 1: TAK-228 intervention 2: TAK-117
Intervention descriptions: intervention 1: TAK-228 Capsules intervention 2: TAK-117 Capsules

Protocol document:
Prot_001.pdf: 


•
Title:  Multicenter, Open-label, Phase 1b Study of MLN0128 (an Oral mTORC1/2 Inhibitor) in 
Combination With MLN1117 (an Oral PI3Kα Inhibitor) in Adult Patients With Advanced 
Nonhematologic Malignancies
NCT Number: NCT01899053
Protocol Approve Date: 28 November 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information or company confidential 
information. 
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.


TAK-228 in Combination With MLN1117
Clinical Study Protocol C32001 Amendment 6, EudraCT:  2013-000466-11
Confidential
1
CLINICAL STUDY PROTOCOL C32001 AMENDMENT 6
MLN0128 in Combination With MLN1117
A Multicenter, Open-label, Phase 1b Study of MLN0128 (an Oral mTORC1/2 Inhibitor) in 
Combination With MLN1117 (an Oral PI3Kα Inhibitor) in Adult Patients With Advanced 
Nonhematologic Malignancies
Protocol Number:
C32001
Indication:
Advanced nonhematologic malignancies 
Phase:
1b
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2013-000466-11
Therapeutic Area:
Oncology
Protocol History
Original
07 March 2013
Amendment 1
29 April 2013
Amendment 2
21 January 2014
Amendment 3
05 March 2014
Amendment 4
02 April 2014
Amendment 5
25 May 2016
Amendment 6
28 November 2017
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA USA  02139
Telephone:  +1 (617) 679-7000
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may be 
found at the end of the document.
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior 
written authorization of Millennium Pharmaceuticals is expressly prohibited.
Protected Personal Data


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Rationale for Amendment 6
This document describes the changes in reference to the protocol incorporating Amendment 6.  
The primary reason for this amendment is to update those sections affected by new nonclinical 
data for MLN0128 metabolism by specific cytochrome P450 (CYP) isoforms.  The study’s 
exclusion criteria, list of prohibited concomitant medications, list of relevant CYP inhibitors and 
inducers, description of potential drug-drug interactions, and dietary restrictions related to CYP 
inhibitors and inducers have been updated accordingly.  The number of required radiographic 
disease assessments for patients who have received at least 1 year of continuous treatment has 
also been modified.
Minor grammatical, editorial, and formatting changes are included for clarification purposes 
only.
For specific descriptions of text changes and where the changes are located, see Section 14.11.
Changes in Amendment 6
1. Remove the exclusion criterion relating to treatment with strong CYP inhibitors or
inducers.
2. Update the list of concomitant medications prohibited during the study.
3. Update the list of relevant CYP inhibitors and inducers.
4. Update the description of potential drug-drug interactions.
5. Remove dietary restrictions related to CYP inhibitors and inducers.
6. Insert language to reduce the required frequency of radiographic disease assessments for
patients who have received at least 1 year of continuous MLN0128 treatment per
protocol.


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PROTOCOL SUMMARY
Study Title:  A Multicenter, Open-label, Phase 1b Study of MLN0128 (an Oral mTORC1/2 
Inhibitor) in Combination With MLN1117 (an Oral PI3Kα Inhibitor) in Adult Patients With 
Advanced Nonhematologic Malignancies
Number of Patients:  Approximately 101 patients total:  approximately 81 evaluable patients will 
be enrolled in the dose escalation stage (Escalation Stage), and approximately 20 evaluable patients 
will be enrolled in the Expansion Stage.
Study Objectives
Primary
!
To evaluate the safety profile and to determine the dose-limiting toxicities, maximum 
tolerated doses (MTDs) and/or recommended phase 2 doses (RP2Ds), and dosing schedules 
of oral MLN0128 in combination with MLN1117 (MLN0128 + MLN1117) in patients with 
advanced nonhematologic malignancies
!
To characterize the single- and multiple-dose plasma pharmacokinetics (PK) of MLN0128 + 
MLN1117 in patients with advanced nonhematologic malignancies
Secondary
!
To evaluate evidence of antitumor activity of MLN0128 + MLN1117
Exploratory
!
!
!
Overview of Study Design
This study is a multicenter, open-label, phase 1b trial of MLN0128 (an oral mechanistic target of 
rapamycin complex 1/2 [mTORC1/2] inhibitor) in combination with MLN1117 (an oral inhibitor of 
the PI3K∀isoform) when administered to adult patients with advanced nonhematologic 
malignancies for whom standard, curative, or life-prolonging anticancer treatment does not exist or is 
no longer effective.  The study will consist of 2 stages:  an Escalation Stage followed by an 
Expansion Stage.  In the Escalation Stage, 2 dosing regimens for the combination will be evaluated 
in separate treatment arms.  Throughout this protocol, “study drug” or “MLN0128 + MLN1117” 
refers to combination dosing of MLN0128 + MLN1117.
In the Escalation Stage, patients will be enrolled into dose escalation cohorts at different combination 
doses and schedules of MLN0128 and MLN1117 using a standard 3 + 3 approach to determine the 
Company Confidential Information


TAK-228 in Combination With MLN1117
Clinical Study Protocol C32001 Amendment 6, EudraCT:  2013-000466-11
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4
MTDs and/or RP2Ds in each treatment arm and optimal dosing schedules to be implemented in the 
Expansion Stage.  Study drug will be administered in 28-day cycles.  In Treatment Arm A, 
MLN0128 will be administered once daily every day (QD) and MLN1117 will be administered once 
daily on Monday, Wednesday, and Friday of each week.  In Treatment Arm B and Arm C, both 
MLN0128 and MLN1117 will be administered QD on Monday, Tuesday, and Wednesday of each 
week.
Patients will be enrolled in the Expansion Stage to further characterize the safety, tolerability, and 
PK of MLN0128 in combination with MLN1117.  A combination dose and schedule from 1 of the 
treatment arms evaluated in the Escalation Stage will be chosen to examine the mutual drug-drug 
interaction PK of MLN0128 and MLN1117; the dose and schedule to be examined during the 
Expansion Stage will be specified prior to patient enrollment into that stage.
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.  Adverse events will be 
assessed, and laboratory values, vital signs, physical exam findings, and electrocardiograms will be 
obtained to evaluate the safety and tolerability of MLN0128 + MLN1117.
Study Population:  Adult patients (# 18 years old) with advanced nonhematologic malignancies.  In 
each stage, the study population will comprise patients with any advanced nonhematologic tumor, 
except primary brain tumor, who satisfy all of the study inclusion/exclusion criteria.
Patients enrolled in this study will not be required to have measureable disease per Response 
Evaluation Criteria in Solid Tumors (RECIST) criteria (Version 1.1), but, if feasible, response may 
be evaluated using RECIST guidelines.
Duration of Study:  The maximum duration of on-study treatment for individual patients will be 
12 months.  Further treatment with MLN0128 + MLN1117, if beneficial for the patient, may be 
permitted upon discussion with the sponsor.  It is anticipated that the overall conduct of this study 
will last for approximately 40 months.
Company Confidential Information


TAK-228 in Combination With MLN1117
Clinical Study Protocol C32001 Amendment 6, EudraCT:  2013-000466-11
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Figure 1-1   
Study Overview Diagram
Abbreviations:  DDI = drug-drug interaction; DLT = dose-limiting toxicity; MTuW = Monday, Tuesday, 
Wednesday (dosing schedule); MWF = Monday, Wednesday, Friday (dosing schedule); MTD = maximum 
tolerated dose; PK = pharmacokinetics; QD = once daily every day; QW = once weekly; RP2D = 
recommended phase 2 dose.


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SCHEDULE OF EVENTS
Screeninga
TREATMENT CYCLES
EOSc
Cycle 1b
Cycle 2b
Cycles
3 and 4b
Cycl
e 5b
plus
Within 28 
days
Day 1 
Predosea
Day 
1
Day 2 
(or 3y)
Day 
8
Day 
15
Day 
22
Day 
24
Day 
25
Day 
1
Day 
8
Day 
15
Day 
22
Day 
1
Day 
15
Day 
1
Study Procedures
Informed Consentd
X
Inclusion/Exclusion 
Criteria
X
Demographics
X
Medical History
X
Physical Examination
X
X
X
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
X
X
X
Vital Signse
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
Patient Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
ECHO/MUGA
X
12-lead ECGf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Xf
Concomitant 
Medications and 
Proceduresg
Recorded from the first dose through 30 days after the last dose
SAE Collectionh
Recorded from the time the Informed Consent form is signed through 30 days after the last dose of study drug
AE Collection
Recorded from the first dose through 30 days after the last dose


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Screeninga
TREATMENT CYCLES
EOSc
Cycle 1b
Cycle 2b
Cycles
3 and 4b
Cycl
e 5b
plus
Within 28 
days
Day 1 
Predosea
Day 
1
Day 2 
(or 3y)
Day 
8
Day 
15
Day 
22
Day 
24
Day 
25
Day 
1
Day 
8
Day 
15
Day 
22
Day 
1
Day 
15
Day 
1
Samples and Laboratory Assessments
Pregnancy Testi
X
X
Urinalysisj
X
X
X
X
X
X
X
X
X
Coagulationk
Xl
Xl
X
X
X
X
X
Hematologyl
X
X
X
X
X
X
X
X
X
X
X
X
X
Chemistryl
X
X
Xw
X
X
X
X
X
X
X
X
X
X
X
HbA1cx
Xx
Xx
Xx
Fasting Glucosem
Xm
Xm
Xm
Xm,w
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Xm
Fasting Insulin and 
Insulin C-Peptide 
Leveln – Escalation 
Stage Only
Xn
Xn
Xn
Xn
Xn
Xn
Xn
Xn
Xn
Fasting Lipid Profileo
X
X
X
X
X
In-Home Daily 
Fasting Glucose
Monitoringp
Xp,w
Xp
Xp
Xp
Xp
Xp
Xp
Xp
Xp
Xp
Xp
Xp
Blood Samples for 
PKq
See Table A:  PK and Pharmacodynamic Assessment Schedule (Escalation Stage), 
Table B:  PK Assessment Schedule (Expansion Stage:  Treatment Arm A), and Table C:  
PK Assessment Schedule (Expansion Stage:  Treatment Arm B and Arm C).  Schedules 
are specific to study stage and treatment arm.
Blood Sample for 
Evaluation of 
Germline 
Polymorphisms
X


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Screeninga
TREATMENT CYCLES
EOSc
Cycle 1b
Cycle 2b
Cycles
3 and 4b
Cycl
e 5b
plus
Within 28 
days
Day 1 
Predosea
Day 
1
Day 2 
(or 3y)
Day 
8
Day 
15
Day 
22
Day 
24
Day 
25
Day 
1
Day 
8
Day 
15
Day 
22
Day 
1
Day 
15
Day 
1
Urine PKr -
Expansion Stage 
Only
See Table B:  PK Assessment Schedule (Expansion Stage:  Treatment Arm A) and 
Table C:  PK Assessment Schedule (Expansion Stage:  Treatment Arm B and Arm C).  
Schedules are specific to the treatment arm schedule implemented in the Expansion 
Stage.
Tumor Tissue 
(banked) or Fresh 
Biopsy Samples –
Escalation Stage 
Only
X
Skin Biopsyt –
Escalation Stage 
Only
X
X
X
Response Assessments
Disease Evaluation 
by RECIST 1.1 
(CT/MRI)u
X
X
X
X
Dosing
Treatment Arm Av
Escalation Stage
MLN0128 is dosed once daily every day; MLN1117 is dosed once daily on MWF of each week.
Treatment Arm B and 
Cv
Escalation Stage
MLN0128 and MLN1117 are both dosed once daily on MTuW of each week.
Treatment Arm Av
Expansion Stage
MLN0128 is dosed once daily every day except on 
Day 13 through Day 19, when dose is withheld; 
MLN1117 is dosed once daily on MWF except on 
Day 1 through Day 5 when dose is withheld.v
MLN0128 is dosed once daily every day; 
MLN1117 is dosed once daily on MWF of each 
week.


TAK-228 in Combination With MLN1117
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Screeninga
TREATMENT CYCLES
EOSc
Cycle 1b
Cycle 2b
Cycles
3 and 4b
Cycl
e 5b
plus
Within 28 
days
Day 1 
Predosea
Day 
1
Day 2 
(or 3y)
Day 
8
Day 
15
Day 
22
Day 
24
Day 
25
Day 
1
Day 
8
Day 
15
Day 
22
Day 
1
Day 
15
Day 
1
Treatment Arm B and 
Cv
Expansion Stage
MLN0128 is dosed once daily on MTuW of each 
week except on Days 15, 16, 17 when dose is 
withheld; MLN1117 is dosed once daily on MTuW 
of each week except on Days 1, 2, 3 when dose is 
withheld.v
MLN0128 and MLN1117 are both dosed once 
daily on MTuW of each week.
Abbreviations:  AE = adverse event; CA-125 = cancer antigen 125; CXDY = Cycle X Day Y; CT = computed tomography; DDI = drug-drug interaction; ECG = 
electrocardiogram; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic case report form; EOS = End of Study; h = hour(s); 
HbA1c  = glycosylated hemoglobin; MRI = magnetic resonance imaging; MTuW = Monday, Tuesday, Wednesday; MUGA = multiple gated acquisition [scan]; 
MWF = Monday, Wednesday, Friday; PE = physical exam; PK = pharmacokinetic(s); PSA = prostate-specific antigen; RECIST = Response Evaluation Criteria in 
Solid Tumors; SAE = serious adverse event.
a Screening assessments are performed within 28 days before the C1D1 dose.  Screening assessments performed no more than 3 days before Day 1 will qualify as 
baseline assessments and need not be repeated, unless otherwise specified.
b Laboratory assessments can be conducted ± 3 days of the scheduled visit, with the exception of PK/pharmacodynamic assessments or unless otherwise noted.
c The EOS visit will occur within 30 (+10) days after the last dose of study drug or before the start of subsequent antineoplastic therapy.
d Informed consent may be captured before the screening period (28 days before C1D1 dosing).
e Vital signs include blood pressure, heart rate, and temperature.
f
During the Escalation Stage, single 12-lead ECGs will be conducted at the following times:  screening; C1D1 predose, 2 h (± 30 min) postdose, and 4 h (± 30 min) 
postdose; C1D2 predose (approximately 24 h [± 2 h] after the C1D1 dose); C1D8 and C1D15 at 2 h (± 30 min) postdose; C1D22 predose; C2D1 predose and 2 h 
(± 30 min) postdose; C2D8 and C2D15 at 2 h (± 30 min) postdose; and the EOS visit.  During the Expansion Stage, single 12-lead ECGs will be conducted at the 
following times:  screening; C1D1 predose and 2 h (± 30 min) postdose; C1D8 and C1D15 at 2 h (± 30 min) postdose; C1D22 predose; C2D1 predose and 2 h 
(± 30 min) postdose; C2D8 and C2D15 at 2 h (± 30 min) postdose; and the EOS visit.  When the timing of a PK or safety laboratory blood sample coincides with the 
timing of ECG measurements, then the ECG will be completed before the collection of the blood sample.
g See Section 6.7 for medications and procedures that are prohibited during the study, Section 6.8 for medications that should be used cautiously during the study, and 
Section 6.7 for restrictions on antacids and calcium supplements.
h Only those SAEs that occur after the first dose of study drug will be collected in the eCRF; however, all SAEs occurring after consent will be reported.  See 
Sections 9.1.1, 9.1.3, 9.2, and 9.3.
i
A serum pregnancy test will be performed for women of childbearing potential at screening.  A urine pregnancy test must be performed predose on C1D1 with 
negative results available before the first dose may be administered.  A serum pregnancy test may also be performed within 3 days of dosing in place of the 


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Screeninga
TREATMENT CYCLES
EOSc
Cycle 1b
Cycle 2b
Cycles
3 and 4b
Cycl
e 5b
plus
Within 28 
days
Day 1 
Predosea
Day 
1
Day 2 
(or 3y)
Day 
8
Day 
15
Day 
22
Day 
24
Day 
25
Day 
1
Day 
8
Day 
15
Day 
22
Day 
1
Day 
15
Day 
1
C1D1 urine test.
j
See Section 7.4.14 for urinalysis panel. 
k On days where tumor or skin biopsy is required, coagulation sample is required within 24 h before obtaining any skin or tumor biopsy.  See Section 7.4.14 for full 
coagulation panel.
l Samples may be collected ± 3 days of the scheduled visit.  See Section 7.4.14 for the full Hematology and Chemistry Panel.
m During the Escalation Stage, fasting glucose will be measured at the following times:  screening, C1D1 predose and at 0.5 h (± 15 min), 1 h (± 15 min), and 2 h 
(± 30 min) after dosing; C1D2 predose; C1D8 predose and 2 h (± 30 min) postdose; C1D15 and C1D22 predose only; Cycles 2 through 4 predose on Days 1 and 15; 
C5D1 predose; and predose on Day 1 of every cycle thereafter; and the EOS visit.  During the Expansion Stage, fasting glucose will be measured at the following 
times:  screening; C1D1 predose; C1D3 predose; C1D8 predose and 2 h (± 30 min) postdose; C1D15 and C1D22 predose only; Cycles 2 through 4 predose on 
Days 1 and 15; C5D1 predose; and predose on Day 1 of every cycle thereafter; and the EOS visit.  During the Expansion Stage, fasting glucose assessment on C1D1 
will be done predose only.
n For patients in the Escalation Stage only, fasting insulin and insulin c-peptide will be measured at screening, C1D1 predose and 0.5 h (± 15 min), 1 h (± 15 min), 2 h 
(± 30 min), 4 h (± 30 min), and 8 h (± 30 min) postdose (Note that the 4 h and 8 h samples are not fasting); C1D2 at 24 ± 2 h post-C1D1 dose; C1D8 predose; C2D1 
predose; predose on Day 1 of every cycle thereafter; and the EOS visit.  No fasting insulin or insulin c-peptide assessments are required for patients in the Expansion 
Stage.  See Section 7.4.14 for meal timing on C1D1.
o See Section 7.4.14 for Fasting Lipid panel.
p Patients will be given a glucometer on C1D2 (Escalation Stage) or C1D3 (Expansion Stage) to monitor daily fasting glucose levels at home and will be instructed to 
notify the investigator when the fasting glucose is abnormal (ie, ≥140 mg/dL).  Patients will be instructed to bring the glucometer with them to each study visit so 
that the data collected can be reviewed and recorded in the source documents.  See Section 7.4.14 for further instruction.
q Time points for blood samples for PK analysis will be collected as specified in Table A:  PK and Pharmacodynamic Assessment Schedule (Escalation Stage), 
Table B:  PK Assessment Schedule (Expansion Stage:  Treatment Arm A), and Table C:  PK Assessment Schedule (Expansion Stage:  Treatment Arm B and Arm 
C).
r
Time points for urine samples for PK analysis will be collected as specified in Table B:  PK Assessment Schedule (Expansion Stage:  Treatment Arm A) and 
Table C:  PK Assessment Schedule (Expansion Stage:  Treatment Arm B and Arm C).
s For patients in the Escalation Stage only, tumor tissue (banked) will be required at screening as specified in Section 7.4.16.  For banked tissue, the sample can be 
from either paraffin-embedded tumor block or unstained slides (see Section 7.4.20).  If a paraffin-embedded tumor block or unstained slides are not available, the 
patient will be required to undergo a fresh tumor biopsy as specified in Section 7.4.16.  The sample must be collected during screening before the first dose of study 
drug.  Tumor tissue will be analyzed as described in Section 7.4.20 and will be tested retrospectively for genetic mutations.  No tumor tissue is required at screening 
for patients in the Expansion Stage.


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Screeninga
TREATMENT CYCLES
EOSc
Cycle 1b
Cycle 2b
Cycles
3 and 4b
Cycl
e 5b
plus
Within 28 
days
Day 1 
Predosea
Day 
1
Day 2 
(or 3y)
Day 
8
Day 
15
Day 
22
Day 
24
Day 
25
Day 
1
Day 
8
Day 
15
Day 
22
Day 
1
Day 
15
Day 
1
t
For patients in the Escalation Stage only, skin biopsies (approximately 2 mm in diameter) are to be collected according to the schedule given in the Table A:  PK and 
Pharmacodynamic Assessment Schedule (Escalation Stage).  No skin biopsies are required for patients in the Expansion Stage.
u Response assessments will be performed between Days 22 to 28 of Cycle 2 and every even-numbered cycle thereafter (ie, Cycle 4, 6, etc).  A CT scan with 
intravenous contrast of the chest, abdomen, and pelvis will be performed during screening.  (MRI of disease sites poorly imaged by CT is permitted; however, 
imaging modalities used for each disease site must be consistent throughout the study.)  If the patient has had an appropriate CT or MRI scan performed within 28 
days of C1D1, the results of that scan may be used for tumor lesion measurements at screening.  Prostate cancer patients should have PSA measured at screening,
and PSA alone may be used for post-screening disease assessments for these patients if they lack measurable sites of disease at screening.  Similarly, patients with 
ovarian cancer should have CA-125 measured at screening and CA-125 alone may be used.  For long term patients, defined as study participation (greater than or 
equal to) 1 year, a CT (with contrast)/MRI of chest, abdomen, and pelvis will be obtained at intervals of up to every 4 cycles (plus or minus 7 days) as clinically 
indicated.
v See Section 6.1 for details on study drug dosing.  MLN0128 and MLN1117 are to be taken at the same time on dosing days when both drugs are to be administered.
w For patients in the Expansion Stage, this assessment should be done on Cycle 1, Day 3.
x HbA1c testing is to be done at C1D1 and on the first day of every third cycle thereafter (eg, C4D1, C7D1, C10D1).
y Where noted in the Schedule of Events, assessments for patients enrolled in the Expansion Stage are to be collected on Day 3 instead of Day 2.


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Table A:  PK and Pharmacodynamic Assessment Schedule (Escalation Stage)
Screening
Cycle 1
Day 1
Day 2c
Day 24c
Day 25c
Fresh 
tumor 
biopsya
Skin 
biopsyb
PK
PK
PK
Skin Biopsy
PK
Skin Biopsy
Anytime
X
X
Predose (within 30 min of 
dosing)c
X
X
(24 h after the 
Day 1 dose 
[2 h])
X
Xd
(24 h after the 
Day 24 dose 
[2 h])
Xd
(24 h after the 
Day 24 dose 
[2 h])
0.5 h (± 10 min)
X
X
1 h (± 10 min)
X
X
2 h (± 30 min)
X
Xd
X (1 h)d
Xd
Arm A only
X (1 h)d
Arm A only
4 h (± 30 min)
X
X
8 h (± 45 min)
X
Xd
X (1 h)d
Arm B and 
Arm C only
Abbreviations:  aPTT = activated partial thromboplastin time; CXDY = Cycle X, Day Y; ECG = electrocardiogram; h = hour(s); min = minutes; PK = 
pharmacokinetic(s); PT = prothrombin time.
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the 
collection of the blood sample.
a For patients without banked tumor tissue, a fresh tumor biopsy must be collected during screening before the first dose of study drug (before dosing on 
C1D1).  The investigator must judge the tumor to be accessible to biopsy without crossing vital structures (eg, large blood vessels).  For tumors that are 
not superficially accessible, biopsies will be radiographically guided (eg, by CT scanning).  Patients who undergo biopsy of tumor tissue must have 
platelet counts ≥ 75,000/mm3 and normal PT and aPTT (within 24 h before biopsy) and no have history of excessive bleeding nor have received 
antiplatelet or anticoagulant therapy in the previous 7 days (eg, clopidogrel [Plavix®] or salicylates [aspirin]) (see Section 7.4.16).
b Screening skin biopsy must be collected within 2 weeks before the first dose of study drug (before dosing on C1D1).  Patients undergoing skin biopsies 
must have platelet counts ≥ 20,000/mm3 and normal PT and aPTT within 24 h before the scheduled skin biopsy (see Section 7.4.16).


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Table A:  PK and Pharmacodynamic Assessment Schedule (Escalation Stage)
Screening
Cycle 1
Day 1
Day 2c
Day 24c
Day 25c
Fresh 
tumor 
biopsya
Skin 
biopsyb
PK
PK
PK
Skin Biopsy
PK
Skin Biopsy
c Patients will be instructed to arrive at the clinic in the morning without taking their study drug dose(s).  The timing of the visit should occur at 
approximately the same time as the dosing times on the previous days of the cycle.
d The plasma sample for PK analysis should be taken at the same time (5 min) as the skin biopsy.  Patients undergoing skin biopsies must have platelet 
counts ≥20,000/mm3 and normal PT and aPTT within 24 h before the scheduled skin biopsy (see Section 7.4.16).


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Table B:  PK Assessment Schedule (Expansion Stage:  Treatment Arm A)
Cycle 1
Day 1
Day 5a
Day 12a
Day 13a
Day 19a
Day 20a
Urine PK
PK
Urine PKc
PK
Urine PKc
PK
PK
Urine PKc
PK
Predose (within 
30 min of dosing)a
Xb
X
X
X
(24 h after the D12 
dose [2 h])
X
X
(24 h after the 
D19 dose 
[2 h])
0.5 h (± 10 min)
X
Xc
(0 – 8 h 
[1 h])
X
Xc
(0 – 8 h 
[1 h])
X
Xc
(0 – 8 h 
[1 h])
1 h (± 10 min)
X
X
X
2 h (± 30 min)
X
X
X
4 h (± 30 min)
X
X
X
8 h (± 45 min)
X
X
X
Abbreviations:  CXDY = Cycle X, Day Y; ECG = electrocardiogram; h = hour(s); min = minutes; PK = pharmacokinetic(s).
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection 
of the blood samples.
a Patients will be instructed to arrive at the clinic in the morning without taking their study drug dose(s).  The timing of the visit should occur at 
approximately the same time as the dosing times on the previous days of the cycle.
b A predose (blank) urine sample should be collected on C1D1 before first study drug dose administration.  See the Study Manual for details on urine 
collection methodology.
c On Days 5, 12, and 19, patients will void the bladder immediately before study drug administration.  This voided urine will not contribute to the urine PK 
sample collection.  Urine voided subsequently during the 8 h postdose time frame will be collected for PK analysis.  At the end of the sampling period, the 
8 h PK sample should be collected before the patient’s final urine void.  See the Study Manual for details on urine collection methodology.


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Table C:  PK Assessment Schedule (Expansion Stage:  Treatment Arm B and Arm C)
Cycle 1
Day 1
Day 3a
Day 10a
Day 11a
Day 17a
Day 18a
Urine PK
PK
Urine PKc
PK
Urine PKc
PK
PK
Urine PKc
PK
Predose (within 
30 min of dosing)a
Xb
X
X
X
(24 h after 
the D10 
dose [2h])
X
X
(24 h after 
the D17 
dose [2h])
0.5 h (± 10 min)
X
Xc
(0 – 8 h [1 h])
X
Xc
(0 – 8 h [1 h])
X
Xc
(0 – 8 h 
[1 h])
1 h (± 10 min)
X
X
X
2 h (± 30 min)
X
X
X
4 h (± 30 min)
X
X
X
8 h (± 45 min)
X
X
X
Abbreviations:  CXDY = Cycle X, Day Y; ECG = electrocardiogram; h = hour(s); min = minutes; PK = pharmacokinetic(s).
When the timing of a PK or safety laboratory blood sample coincides with the timing of ECG measurements, the ECG will be completed before the collection of 
the blood samples.
a Patients will be instructed to arrive at the clinic in the morning without taking their study drug dose(s).  The timing of the visit should occur at approximately 
the same time as the dosing times on the previous days of the cycle.
b A predose (blank) urine sample should be collected on C1D1 before first study drug dose administration.  See the Study Manual for details on urine collection 
methodology.
c On Days 3, 10, and 17, patients will void the bladder immediately before study drug administration.  This voided urine will not contribute to the urine PK 
sample collection; however, urine voided subsequently during the 8 h postdose time frame will be collected for PK analysis.  At the end of the sampling 
period, the 8 h PK sample should be collected before the patient’s final urine void.  See the Study Manual for details on urine collection methodology.


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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................19
LIST OF FIGURES............................................................................................................19
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................20
1. BACKGROUND AND STUDY RATIONALE..............................................................23
1.1 Scientific Background ..............................................................................................23
1.1.1 Disease Under Treatment...................................................................................23
1.1.2 Study Drug ........................................................................................................23
1.2 Preclinical Experience ..............................................................................................24
1.3 Clinical Experience ..................................................................................................26
1.3.1 Clinical Experience With MLN0128..................................................................26
1.3.2 Clinical Experience With MLN1117..................................................................26
1.3.3 Clinical Experience With MLN0128 in Combination With MLN1117 ...............27
1.4 Study Rationale ........................................................................................................28
1.4.1 Original Protocol Rationale for Dosing Schedules, Starting Doses, and Dose 
Escalation Design........................................................................................29
1.4.2 Protocol Amendment 2 Rationale for Dosing Schedules, Starting Doses, and 
Dose Escalation Design...............................................................................31
1.4.3 Rationale for PK Assessments............................................................................32
1.4.4 Rationale for Pharmacodynamic Assessments....................................................33
1.5 Potential Risks and Benefits .....................................................................................34
1.5.1 Drug-Drug Interaction Risk Assessment ............................................................36
2. STUDY OBJECTIVES ..................................................................................................39
2.1 Primary Objectives ...................................................................................................39
2.2 Secondary Objectives ...............................................................................................39
2.3 Exploratory Objectives .............................................................................................39
3. STUDY ENDPOINTS....................................................................................................40
3.1 Primary Endpoints....................................................................................................40
3.2 Secondary Endpoints................................................................................................40
3.3 Exploratory Endpoints..............................................................................................40
4. STUDY DESIGN...........................................................................................................41
4.1 Overview of Study Design........................................................................................41
4.2 Number of Patients...................................................................................................42
4.3 Duration of Study.....................................................................................................42
5. STUDY POPULATION.................................................................................................43
5.1 Inclusion Criteria......................................................................................................43
5.2 Exclusion Criteria.....................................................................................................45
6. STUDY DRUG..............................................................................................................47
6.1 Study Drug Administration.......................................................................................47
6.1.1 Expansion Stage.................................................................................................48
6.2 Reference/Control Therapy.......................................................................................49
6.3 Definitions of Dose-Limiting Toxicity......................................................................49
6.4 Dose Escalation Plan ................................................................................................50
6.5 Dosing Group Assignments......................................................................................51
6.6 Dose-Modification Guidelines..................................................................................53


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6.6.1 General Principles..............................................................................................53
6.6.2 Intrapatient Dose Escalation...............................................................................54
6.6.3 Dose Modification Guidelines............................................................................55
6.6.4 Criteria for Beginning or Delaying a Subsequent Treatment Cycle.....................56
6.6.5 Causality Assessment Guidance of Adverse Events for MLN0128 and 
MLN1117 ...................................................................................................56
6.6.6 Criteria for Dose Interruption During a Cycle ....................................................56
6.6.7 Criteria for Dose Reduction ...............................................................................57
6.6.8 Criteria for Discontinuation of MLN0128 + MLN1117......................................57
6.7 Excluded Concomitant Medications and Procedures.................................................57
6.8 Precautions and Restrictions .....................................................................................58
6.9 Management of Clinical Events................................................................................59
6.10 Blinding and Unblinding ........................................................................................66
6.11 Description of Investigational Agents .....................................................................66
6.12 Preparation, Reconstitution, and Dispensation ........................................................66
6.13 Packaging and Labeling..........................................................................................67
6.14 Storage, Handling, and Accountability....................................................................67
7. STUDY CONDUCT ......................................................................................................67
7.1 Study Personnel and Organizations...........................................................................67
7.2 Arrangements for Recruitment of Patients ................................................................67
7.3 Treatment Group Assignments .................................................................................68
7.4 Study Procedures......................................................................................................68
7.4.1 Informed Consent ..............................................................................................68
7.4.2 Patient Demographics ........................................................................................68
7.4.3 Medical History.................................................................................................69
7.4.4 Physical Examination.........................................................................................69
7.4.5 Patient Height and Weight .................................................................................69
7.4.6 Vital Signs .........................................................................................................69
7.4.7 ECOG Performance Status.................................................................................69
7.4.8 Pregnancy Test ..................................................................................................69
7.4.9 Concomitant Medications and Procedures..........................................................69
7.4.10 Adverse Events................................................................................................70
7.4.11 Enrollment .......................................................................................................70
7.4.12 Electrocardiogram............................................................................................70
7.4.13 Echocardiogram or Multiple Gated Acquisition Scan.......................................71
7.4.14 Clinical Laboratory Evaluations.......................................................................71
7.4.15 Disease Assessment .........................................................................................73
7.4.16 Biopsy Samples ...............................................................................................74
7.4.17 PK Assessments...............................................................................................75
7.4.18 Pharmacodynamic Assessments.......................................................................76
7.4.19 Pharmacogenomic Assessments.......................................................................76
7.4.20 Banked (Archived) Tumor Specimen Measurements........................................77
7.5 Completion of Study.................................................................................................77
7.6 Withdrawal of Patients From Study..........................................................................77
7.7 Study Compliance ....................................................................................................78
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................78


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8.1 Statistical Methods ...................................................................................................78
8.1.1 Determination of Sample Size............................................................................79
8.1.2 Randomization and Stratification .......................................................................79
8.1.3 Populations for Analysis ....................................................................................79
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................80
8.1.5 Demographic and Baseline Characteristics.........................................................80
8.1.6 Efficacy Analysis...............................................................................................80
8.1.7 PK/Pharmacodynamics/Biomarkers ...................................................................81
8.1.8 Safety Analysis ..................................................................................................82
8.1.9 Interim Analysis.................................................................................................84
8.2 PK Modeling............................................................................................................84
9. ADVERSE EVENTS .....................................................................................................84
9.1 Definitions................................................................................................................84
9.1.1 Pretreatment Event Definition............................................................................84
9.1.2 Adverse Event Definition...................................................................................84
9.1.3 Serious Adverse Event Definition ......................................................................85
9.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................86
9.3 Monitoring of Adverse Events and Period of Observation.........................................87
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........87
10. ADMINISTRATIVE REQUIREMENTS .....................................................................88
10.1 Good Clinical Practice............................................................................................88
10.2 Data Quality Assurance ..........................................................................................88
10.3 Electronic Case Report Form Completion...............................................................88
10.4 Study Monitoring ...................................................................................................89
10.5 Ethical Considerations............................................................................................89
10.6 Patient Information and Informed Consent..............................................................89
10.7 Patient Confidentiality............................................................................................90
10.8 Investigator Compliance.........................................................................................90
10.9 On-site Audits ........................................................................................................90
10.10 Investigator and Site Responsibility for Drug Accountability................................90
10.11 Product Complaints ..............................................................................................91
10.12 Closure of the Study .............................................................................................91
10.13 Record Retention..................................................................................................92
11. USE OF INFORMATION............................................................................................92
12. INVESTIGATOR AGREEMENT................................................................................94
13. REFERENCES.............................................................................................................95
14. APPENDICES .............................................................................................................97
14.1 Cockcroft-Gault Equation.......................................................................................97
14.2 Eastern Cooperative Oncology Group Scale for Performance Status.......................97
14.3 New York Heart Association Classification of Cardiac Disease ..............................98
14.4 List of Relevant Cytochrome P450 Inhibitors and Inducers.....................................99
14.5 List of Breast Cancer Resistance Protein, Organic Cation Transporter Proteins 1 
and 2 Substrates................................................................................................99
14.6 Amendment 1 Rationale and Purposes..................................................................100
14.7 Amendment 2 Rationale and Purposes..................................................................100


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14.8 Amendment 3 Rationale and Purposes..................................................................102
14.9 Amendment 4 Rationale and Purposes..................................................................103
14.10 Amendment 5 Rationale and Purposes................................................................104
14.11 Amendment 6 Detailed Summary of Changes.....................................................105
LIST OF TABLES
Table 1-1   
Predicted Plasma Exposures of MLN0128 and MLN1117 at the Starting 
Doses for Treatment Arm A and Arm B ......................................................30
Table 6-1   
Dose Escalation Table by Treatment Arm ...................................................53
Table 6-2   
Dose Modification Guidelines for MLN0128 and/or MLN1117 During the 
Escalation Stage, after Cycle 1, and the Expansion Stage ............................55
Table 6-3   
Guidelines for Assessment of a Potential Causal Relationship Based on 
Grade 3 or Higher Treatment-Related AEs Occurring in 5% or More of 
Patients in Each Single-Agent Clinical Program, Respectively....................56
Table 6-4   
Management of Hyperglycemia...................................................................60
Table 6-5   
Management of Hyperlipidemia ..................................................................61
Table 6-6   
Management of Oral Mucositis ...................................................................61
Table 6-7   
Management of Rash...................................................................................62
Table 6-8   
Management of Nausea/Vomiting ...............................................................63
Table 6-9   
Management of Left Ventricular Dysfunction .............................................63
Table 6-10   
Management of QTc Prolongation...............................................................64
Table 6-11   
Management of AST/ALT elevations..........................................................65
Table 6-12   
Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue)...............................................................................66
LIST OF FIGURES
Figure 1-1   
Study Overview Diagram..............................................................................5
Figure 6-1   
Dose Escalation Flowchart by Treatment Arm ............................................52


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
4E-BP
4E-binding protein
AE
adverse event
AKT
protein kinase B (PKB)
ALT
alanine aminotransferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration versus time curve
AUC24h
area under the plasma concentration versus time curve from zero to 24 hours
AUCinf
area under the plasma concentration versus time curve from zero to infinity
AUClast
area under the concentration-time curve from time 0 to the end of the dosing 
interval
AUCτ
area under the plasma concentration versus time curve from zero to next dose
BCRP
breast cancer resistance protein
BID
twice daily
Cmax
single-dose maximum (peak) concentration  
Cmax,ss
steady-state maximum peak concentration
CT
computed tomography
CYP
cytochrome P450
DDI
drug-drug interaction
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DPP-4
dipeptidyl peptidase 4
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EOS
End of Study (visit)
Escalation Stage
dose Escalation Stage
FDA
United States Food and Drug Administration
GCP
Good Clinical Practice


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Abbreviation
Term
GI
gastrointestinal
HCSD
highest current safe dose
HER2
human epidermal growth factor receptor 2
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IGF1R
insulin-like growth factor 1 receptor
IRB
institutional review board
KRAS
Kirsten rat sarcoma viral oncogene homolog
LVEF
left ventricular ejection fraction
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTOR
mechanistic (formerly mammalian) target of rapamycin
mTORC1
mechanistic target of rapamycin complex 1
mTORC2
mechanistic target of rapamycin complex 2
MTuW
Monday, Tuesday, Wednesday (dosing schedule)
MUGA
multiple gated acquisition (scan)
mRNA
messenger ribonucleic acid
MWF
Monday, Wednesday, Friday (dosing schedule)
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OATP
organic anion-transporting polypeptide
OCT1/2
organic cation transporter proteins 1 and 2
P-gp
P-glycoprotein
PI3K
phosphoinositol-3-kinase
PI3K
phosphoinositol-3-kinase alpha catalytic subunit; also p110and PIK3CA
PIK3CA
phosphoinositol 3-kinase alpha catalytic subunit; also p110and PI3K,
PK
pharmacokinetic(s)
PPI
proton pump inhibitor
PSA
prostate-specific antigen
PT
prothrombin time
PTEN
phosphatase and tensin homolog


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Abbreviation
Term
QD
once daily every day
QT interval
time between the start of the Q wave and the end of the T wave on an 
electrocardiogram
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QW
once weekly; each week
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
RTK
receptor tyrosine kinase
S6K
ribosomal protein S6 kinase
SAE
serious adverse event
study drug
MLN0128 in combination with MLN1117 or MLN0128 + MLN1117
t1/2
terminal disposition half-life
TEAE
treatment-emergent adverse event
Tmax
single-dose time to reach maximum (peak) concentration
Treatment Arm A
once daily every day dosing for MLN0128 and once daily dosing on Monday, 
Wednesday, and Friday of each week for MLN1117
Treatment Arm B and 
Arm C
once daily dosing on Monday, Tuesday, and Wednesday of each week for both 
MLN0128 and MLN1117
ULN
upper limit of the normal range


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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Disease Under Treatment
This study will investigate the administration of MLN0128 in combination with MLN1117 
in patients with advanced solid (nonhematologic) tumors.  The dose escalation stage 
(Escalation Stage) and mutual drug-drug interaction (DDI) pharmacokinetic (PK) expansion 
stage (Expansion Stage) will be made up of patients with any advanced solid tumor, except 
primary brain tumor, who satisfy all of the study inclusion/exclusion criteria.  The 
administration schedule and dose to be explored in the Expansion Stage will be determined 
prior to patient enrollment into that stage.
1.1.2   
Study Drug
Throughout this protocol, “study drug” refers to combination dosing of MLN0128 
+ MLN1117.  Properties of these 2 agents are briefly described in the following sections.
1.1.2.1   
MLN0128
MLN0128, also known as TAK-228 and INK128, is an orally bioavailable, potent, and 
highly selective adenosine triphosphate (ATP)-competitive inhibitor of the serine/threonine 
kinase mechanistic (formerly mammalian) target of rapamycin (mTOR). mTOR operates in 
2 distinct multi-protein complexes, mechanistic target of rapamycin complex 1 (mTORC1) 
and mechanistic target of rapamycin complex 2 (mTORC2), and MLN0128 inhibits both 
complexes. Although the component proteins of these complexes differ, both complexes 
contain mTOR and activate cell cycle progression.(3) mTORC1, stimulated by growth factors 
and amino acids, regulates cell growth by controlling the activity of ribosomal protein S6 
kinase (S6K) and 4E-binding proteins (4E-BP).(4) mTORC2 regulates cell polarity and the 
spatial control of cell growth.(5)
Temsirolimus and everolimus, 2 mTORC1 inhibitors and analogs of rapamycin (rapalogs), 
were approved by the United States Food and Drug Administration (FDA).  Both agents 
were approved for the treatment of advanced renal cell cancer.  Temsirolimus was approved 
in 2007, and everolimus was approved in 2009 initially for the treatment of advanced renal 
cancer after failure of treatment with sunitinib or sorafenib.(6, 7)  In addition, the FDA has 
recently approved everolimus in combination with exemestane for the treatment of 
hormone-receptor positive breast cancer.(8)  Rapamycin and the other rapalogs bind to a 


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different site than the newly developed ATP-competitive mTOR inhibitors (such as 
MLN0128) and inhibit mTORC1 only.  Also, of S6K and 4E-BP1, the 2 substrates 
phosphorylated by mTORC1, rapamycin suppresses only the phosphorylation of S6K.  In 
contrast, MLN0128 inhibits the activities of both mTORC1 and mTORC2, including the 
phosphorylation of 4E-BP1 by mTORC1, and therefore, induces a significantly broader 
transcriptional response compared with rapamycin and the other rapalogs.(9)
1.1.2.2   
MLN1117
MLN1117 is a potent and highly selective small molecule inhibitor of the class I 
phosphoinositol-3-kinase (PI3K) isoform.  It also equipotently inhibits activating somatic 
missense mutations (eg, E542K, E545K, and H1047R) in the phosphoinositol 3-kinase alpha 
catalytic subunit (PIK3CA) gene, encoding the p110-catalytic subunit of PI3Kisoform.  
These mutations have been identified as a major mechanism for PI3K-dependent malignant 
transformation, proliferation, and survival of cells.  Mutations in the PIK3CA gene have 
been reported in various solid tumors, with the highest rates occurring in breast (27%), 
endometrial (24%), bladder (23%), colon (15%), and ovarian (10%) cancers.(10, 11, 12, 13)  In 
addition, PI3Kcan be further activated by genetic mutation/amplification or activation of 
upstream receptor tyrosine kinases (RTKs) such as EGF receptors, human epidermal growth 
factor receptor 2 (HER2), insulin-like growth factor 1 receptor (IGF1R), and insulin 
receptors, and possibly by activated Ras.  Robust antitumor activity was observed with 
MLN1117 in human tumor cell lines with PIK3CA mutations; clinically, partial responses 
have been seen in cancer patients with PIK3CA mutations treated with MLN1117.
1.2   
Preclinical Experience
In compliance with the current International Conference on Harmonisation (ICH) 
Harmonised Tripartite Guidance S9, “Nonclinical Evaluation for Anticancer 
Pharmaceuticals, ”(24 [ICH S9]) the nonclinical antitumor activity of MLN0128 in 
combination with MLN1117 has been explored in a number of experimental in vitro and 
in vivo tumor models.  To investigate the effect of MLN0128 + MLN1117 on the 
downstream cellular signaling of the PI3K/protein kinase B (AKT)/mTOR pathway, 
Western blot analysis was performed using a diverse group of human tumor cell lines treated 
with MLN0128 and MLN1117 as a single agent or in combination.  The treatment of 
MLN0128 + MLN1117 resulted in greater inhibition of these targets than either single 
agent.  Additionally, treatment with MLN0128 + MLN1117 induced greater apoptosis, as 
indicated by decreased levels of total poly ADP ribose polymerase.  Further, the 


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antiproliferative effect of MLN0128 + MLN1117 was determined against a diverse group of 
human tumor cell lines in vitro and in vivo.  The combination exhibited at least additive 
activity in all other cell lines tested (HCC1419, HCC1954, MDA-MB-468, MDA-MB-436 
[breast tumor], A549, NCI-H460, and NCI-H596 [lung carcinoma]).  The level of inhibition 
observed was greater for MLN0128 + MLN1117 than either single agent alone.  Antitumor 
activity of MLN0128 + MLN1117 was assessed in 3 xenograft models in mice:  2 breast 
cancer cell line models, HCC70 (triple negative breast cancer, phosphatase and tensin 
homolog [PTEN] null) and MDA-MB-361 (HER2-amplified breast cancer with mutated 
PIK3CA), and 1 colorectal cancer HCT-116 (Kirsten rat sarcoma viral oncogene homolog 
[KRAS] and PIK3CA mutations) models.  MLN0128 and MLN1117 were administered 
orally as single agents or in combination concurrently using daily and intermittent schedules 
over 21, 28, or 30 days.  The treatment of MLN0128 + MLN1117 was tolerated and resulted 
in a statistically significant (p 0.001) increase in antitumor effects when compared with 
single-agent treatment in multiple treatment schedules in mice bearing HCC70 and MDA-
MB-361 human breast cancer xenografts, in the latter of which substantial tumor growth 
delay was demonstrated.  The treatment of MLN0128 + MLN1117 was also tolerated and 
resulted in a statistically significant (p = 0.003) increase in antitumor effects when compared 
to single-agent treatment in mice bearing HCT-116 human colorectal carcinoma xenografts.
The principal adverse effects associated with the administration of each agent are consistent 
with their respective mechanisms of action.  Based on the available single-agent nonclinical 
and clinical safety data for MLN0128 or MLN1117, the expected overlapping nonclinical 
combination toxicities (including bone marrow and lymphoid depletion, effects on 
glucose/insulin homeostasis including hyperglycemia, and potential effects on chloride and 
cholesterol levels) can be monitored with routine clinical hematology and serum chemistry 
evaluations and are expected to be reversible and manageable in the clinic.  Results from in 
vitro drug metabolism and PK studies suggest that the potential for DDIs between 
MLN0128 and MLN1117 in humans is low.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN0128 
and of MLN1117 may be found in the respective Investigator’s Brochures (IBs) for 
MLN0128, MLN1117, and MLN0128 + MLN1117.


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1.3   
Clinical Experience
Clinical experience with MLN0128, MLN1117, and MLN0128 + MLN1117 is summarized 
in the subsections that follow.  Further details are provided in the respective IBs for 
MLN0128, MLN1117, and MLN0128 + MLN1117.
1.3.1   
Clinical Experience With MLN0128
The clinical development program studying MLN0128 in patients with advanced solid 
malignancies includes 5 ongoing or completed phase 1 studies (INK128-001, INK128-003, 
MLN0128-1004, and C31002) and 1 ongoing phase 1b/2 study (C31001).  A sixth phase 1 
study in patients with multiple myeloma or Waldenström macroglobulinemia (INK128-002) 
has also been completed.  These studies were designed to investigate the safety, PK, 
pharmacodynamics, and preliminary efficacy of MLN0128 for the treatment of advanced 
solid tumors and hematologic malignancies either as a single agent or in combination with 
chemotherapy and/or HER2-targeting agents.
1.3.1.1   
Clinical PK of MLN0128
The PK parameters measured for MLN0128 in the phase 1 clinical studies have been 
generally consistent across a range of doses and multiple schedules.  MLN0128 has shown 
linear PK and fast oral absorption with single-dose time to reach maximum (peak)
concentration (Tmax) occurring between 1 and 4 hours after dosing.  The mean plasma 
terminal disposition half-life (t1/2) of MLN0128 is approximately 8 hours, and no 
accumulation has been observed in plasma after repeat dosing.
The PK properties of MLN0128 are detailed in the MLN0128 IB.
1.3.2   
Clinical Experience With MLN1117
As of 23 June 2014, 78 patients have been enrolled into the Dose Escalation phase of 
Study INK1117-001 and have received at least 1 dose of MLN1117.
Patients have been treated according to 4 dosing schedules:  once daily every day (QD; 
24 patients) at doses ranging from 100 to 300 mg; once daily on Monday, Wednesday, and 
Friday of each week (MWF QW; 30 patients) at doses ranging from 200 to 1200 mg; once 
daily on Monday, Tuesday, and Wednesday of each week (MTuW QW; 23 patients) at 
doses ranging from 200 to 900 mg; and twice daily on Monday, Wednesday, and Friday of 
each week (BID MWF QW; 1 patient) at a dose of 300 mg.


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1.3.2.1   
Clinical PK of MLN1117
The preliminary PK data from patients under the QD, MTuW QW, and MWF QW dosing 
schedules in study INK1117-001 show that MLN1117 exhibits fast oral absorption with Tmax
occurring approximately 2 hours after dosing and a mean plasma t1/2 of approximately 
11 hours (range, 7.82 to 13.2 hours) across all cohorts.  MLN1117 did not accumulate in 
plasma to any meaningful extent under QD dosing (accumulation ratio of approximately 1.2) 
in either of the intermittent dosing schedules.  With the t1/2 of approximately 11 hours and 
treatment-free periods for the MWF QW and MTuW QW schedules of 48 hours and 
96 hours, respectively, no appreciable accumulation is expected for either the MTuW QW or 
MWF QW MLN1117 dosing schedules of MLN0128 + MLN1117.
Systemic exposures of MLN1117 increased with escalating doses, and there was a 9-fold 
increase in exposure with a 12-fold increase in dose from 100 to 1200 mg.  However, a high 
degree of PK variability was observed across cohorts (percent coefficient of variation 
[CV%] values ranging from 52% to 103% for area under the plasma concentration versus 
time curve [AUC] from zero to 24 hours [AUC24h] and 63% to 113% for area under the 
plasma concentration versus time curve from zero to infinity [AUCinf]).
Because MLN1117 exhibits pH-dependent aqueous solubility with values of approximately 
1 mg/mL at pH 1.3 and approximately 0.001 mg/mL at pH 5 and above, gastric 
pH-modifying agents have the potential to interfere with MLN1117 absorption.  The risk for 
DDI therefore does exist if antacids are co-administered with MLN1117, as such agents can 
decrease the oral absorption and systemic exposure of MLN1117.  See Section 6.7 for 
prohibited medications.
Details on the PK properties of MLN1117 are provided in the MLN1117 IB.
1.3.3   
Clinical Experience With MLN0128 in Combination With MLN1117
This study initiated with enrollment into Treatment Arm A at 2 mg MLN0128 QD and 
100 mg MLN1117 MWF QW.  Dose escalation proceeded according to the 3 + 3 design 
dose escalation rules, outlined in Section 6.4, by 1 dose level of MLN0128 (Cohort 2A; refer 
to Table 6-1).  Enrollment into Treatment Arm B was planned to begin, at the combination 
dose and schedule of 6 mg MLN0128 QD and 100 mg MLN1117 MTuW QW, after 
evaluation of safety in Treatment Arm A; however, dose escalation and the initiation of 
additional cohorts were stopped because the study drug combination of 4 mg MLN0128 and 
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Preliminary skin pharmacodynamic data assessed from Cohorts 1A and 2A of this study 
suggest meaningful target inhibition of both mTORC1 and mTORC2 downstream markers.
1.4   
Study Rationale
It is hypothesized that the combined inhibition of mTOR (by MLN0128) and of PI3K(by 
MLN1117) will disrupt negative-feedback signaling through AKT and thereby result in 
higher rates of cancer cell death and enhanced tumor control than observed with either agent 
alone.  In a variety of different nonclinical and clinical settings, it has become clear that 
using targeted signal transduction monotherapy can lead to pathway reactivation by 
feedback mechanisms including ones targeting the PI3K/AKT/mTOR pathway.(14)
Although inhibition of key mediators of both mTORC1 and mTORC2 signaling by 
MLN0128 has demonstrated antiproliferative activity in a broad range of nonclinical cancer 
models, the existence of several negative feedback loops in the mTOR pathway may limit 
the therapeutic efficacy of MLN0128.(15)  It has been demonstrated that inhibition of 
mTORC1 and mTORC2 leads to AKT (S473) dephosphorylation and a rapid but transient 
inhibition of AKT (T308) phosphorylation and AKT signaling.  However, inhibition of 
mTOR also relieves feedback inhibition of RTKs, leading to subsequent PI3K activation and 
rephosphorylation of AKT (T308) sufficient to reactivate AKT activity.(16)  Thus, it is 
hypothesized that inhibition of mTORC1/2 by MLN0128 could induce reactivation of the 
PI3K/AKT/mTOR pathway, thereby limiting sustained regulation of downstream effector 
proteins of mTOR.  The addition of the PI3Kα inhibitor MLN1117 should counteract this 
pathway reactivation by suppressing 2 different nodes of the PI3K/AKT/mTOR pathway.
While the strategy of combining the mTORC1/2 inhibitor MLN0128 with the PI3K
inhibitor MLN1117 could be considered analogous to the use of dual mTOR/PI3K inhibitors 
currently being evaluated clinically, there are several distinct and important differences.  
First, the relative potencies of the dual mTOR/PI3K inhibitors against mTOR and PI3K 
isoforms are predetermined and may not be optimal for achieving maximal anti-tumor 
activity and avoiding overlapping toxicities.  Second, combination of MLN0128 + 
MLN1117 allows for the evaluation of different dosing schedules of each agent to determine 
the most optimal overlap in exposure of MLN0128 and MLN1117 for effective antitumor 
activity and safety.  Early clinical data recently published on leading dual mTOR/PI3K 
inhibitors has shown that tolerated doses lead to only partial pathway inhibition and limited 
clinical benefit, suggesting the limitations of a dual mTOR/PI3K inhibitor in a single 


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molecule.(17)  More complete suppression of the PI3K/AKT/mTOR pathway is expected by 
the combination of MLN0128 and MLN1117.
As described in Section 1.2, MLN0128 in combination with MLN1117 leads to additive or 
synergistic anti-tumor activity in a broad array of tumor types irrespective of genotype.  
Treatment with MLN0128 + MLN1117 also displays stronger inhibition of AKT and 
induces greater apoptosis in tumor cells than either agent alone.  Similarly, in vivo 
combination studies also support these findings, as evidenced by enhanced antitumor 
activity and longer tumor regrowth delay in nonclinical xenograft models.
MLN0128 + MLN1117 was well-tolerated when dosed in mice with human tumor 
xenografts.  Based on these studies and the single-agent clinical experience to date, the 
expected overlapping toxicities of MLN0128 + MLN1117 can be monitored and are 
expected to be reversible and manageable in the clinic.  Furthermore, the potential for DDIs 
between MLN0128 and MLN1117 in humans is expected to be low.
Taken together, the addition of MLN1117 to MLN0128 is considered to be an optimal 
strategy to mitigate the reactivation of the PI3K/AKT/mTOR pathway with single-agent 
MLN0128 treatment as well as induce a more complete suppression of the 
PI3K/AKT/mTOR pathway.
1.4.1   
Original Protocol Rationale for Dosing Schedules, Starting Doses, and Dose 
Escalation Design
The combination dosing schedules of MLN0128 and MLN1117 were selected on the basis 
of predicted safety and tolerability profiles of each agent in the single-agent studies 
INK128-001 (MLN0128) and INK1117-001 (MLN1117).  On the basis of data from these 
studies, the MLN0128 QD and MLN1117 MWF QW dosing schedules allow for continuous 
mTORC1/2 inhibition by MLN0128 with QD dosing and concurrent inhibition of the PI3K 
and mTORC1/2 pathways for 3 days of the week (MWF) through the addition of MLN1117.  
Additionally, on the basis of data from these studies, the dosing schedule for MLN0128 and 
MLN1117 on MTuW QW allows for inhibition of PI3K and mTORC1/2 pathways on 
MTuW followed by a 4-day dosing holiday from both agents.
The initial proposed starting dose for Treatment Arm A of 2 mg MLN0128 QD was 1 dose 
level below the single-agent maximum tolerated dose (MTD) in Study INK128-001 
(ie, 4 mg QD).  This dose was considered a safe starting dose, as no dose-limiting toxicities 
(DLTs) were observed with this dose in study INK128-001.  The initial proposed starting 


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dose of 100 mg MLN1117 MWF QW was 9-fold lower than the single-agent highest current 
safe dose (HCSD; ie, 900 mg MWF QW) in Study INK1117-001.  In Study INK1117-001, 
dose escalation for MWF QW dosing of MLN1117 started with 200 mg; none of the 
3 treated patients experienced a DLT.
The initial proposed starting dose for Treatment Arm B was to be 6 mg MLN0128 and 
100 mg MLN1117, both on MTuW QW.  These proposed starting doses were, for 
MLN0128, 66.7% of the single-agent MTD in Study INK128-001 (ie, 9 mg) and, for 
MLN1117, 9-fold reduction of the single-agent HCSD for MTuW QW dosing in 
Study INK1117-001 (ie, 900 mg).
Additionally, since no PK-based DDIs between MLN0128 and MLN1117 are expected, it 
was projected that the plasma exposures of the starting doses of MLN0128 and MLN1117 
would be less than those at the respective single-agent exposures at the MTDs or the HCSDs 
in the MLN0128 QD schedule and the MLN1117 MWF QW schedule.
As shown in Table 1-1, the initially planned starting dose of 2 mg of MLN0128 and 100 mg 
of MLN1117 in Treatment Arm A was predicted to provide plasma AUC on dosing days 
below those considered bioactive in preclinical pharmacology studies conducted in tumor 
xenograft models and associated with stasis.  For Treatment Arm B, at the combination 
starting dose of 6 mg MLN0128 and 100 mg MLN1117, exposures are predicted to be 
within the bioactive range.
Table 1-1   
Predicted Plasma Exposures of MLN0128 and MLN1117 at the 
Starting Doses for Treatment Arm A and Arm B
Drug
Starting 
Dose (mg)
Projected AUC24h
(ng*h/ml)a
Bioactive AUC24h or
AUC range (ng*h/ml)b
Treatment Arm A
MLN0128
2
95
137-372
MLN1117
100
23680
50,000
Treatment Arm B
MLN0128
6
240
137-372
MLN1117
100
23680
50,000
Abbreviations:  AUC = area under the plasma concentration versus time curve; AUC24h = area under the 
plasma concentration versus time curve from time 0 to 24 h postdose; h = hour; mg = milligrams; ml = 
milliliters; ng = nanogram.
a AUC24h on dosing days.
b Projected human bioactive AUC associated with stasis in preclinical pharmacology studies after 
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In addition, preliminary pharmacodynamic assessments (in skin) in the single-agent studies 
(INK128-001 and INK1117-001) showed that neither the 2 mg dose of MLN0128, nor the 
100 mg dose of MLN1117 (in the QD regimen), provide any meaningful pharmacodynamic 
effects in skin, as measured by inhibition of downstream markers of mTORC1 and 
mTORC2 (for MLN0128) and inhibition of AKT (for MLN1117).  The collective data 
available for Protocol Amendment 1 supported the selection of the adjusted starting doses 
for MLN0128 in combination with MLN1117 in this study.
Dose escalation of the combination in this study began according to the 3 + 3 rules shown in 
Section 6.4.  In each treatment arm, MLN0128 dose levels were to be escalated at fixed 
MLN1117 dose levels.  This approach allows for the titration of MLN0128 up to a dose that 
is bioactive, while maintaining a low enough dose of MLN1117 to allow the safety and 
tolerability of the combination to be established.  MLN1117 would then be titrated up to 
pharmacologically active levels.  The serial dose escalation of each agent separately enables 
the determination of the minimum exposure required for effective inhibition of the 
mTOR/PI3K/AKT pathway that is safe and tolerable.
1.4.2   
Protocol Amendment 2 Rationale for Dosing Schedules, Starting Doses, and 
Dose Escalation Design
As of Protocol Amendment 2, new starting combination doses are planned, the dose 
escalation schedule adjusted, and a third treatment arm added (Treatment Arm C) to further 
evaluate the combination during the Escalation Stage (refer to Table 6-1).
The starting dose of MLN0128 in Treatment Arm A will be reduced to the initial starting 
dose administered in this study (2 mg QD) due to DLTs.  In this manner, the combination 
may be re-evaluated at higher dose levels of MLN1117.  The starting dose of MLN1117 for 
Treatment Arm A is 200 mg, approximately 22% of the single-agent MTD in both the MTW 
QW and MWF QW dosing schedules in Study INK1117-001 (ie, 900 mg) and 1 dose level 
higher than the initial dose of MLN1117; however, it is still predicted to be safe, tolerable, 
and within the bioactive range (projected AUC24h of approximately 43,000 ng*h/ml).
Treatment Arm C has been added at the same dosing schedule as Arm B (MTuW QW for 
both agents).  The starting dose of MLN0128 for Treatment Arm B and Arm C is 3 mg 
MLN0128, approximately 33% of the single-agent MTD in study INK128-001 (ie, 9 mg) 
and 1 dose level higher than the initial dose of MLN0128; however, it is still predicted to be 
safe, tolerable, and within the bioactive range (projected AUC24h of approximately 


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205-558 ng*h/ml).  The starting dose of MLN1117 for Treatment Arm B is 100 mg.  The 
starting dose for MLN1117 in Treatment Arm C is dependent on the safety and tolerability 
observed in Treatment Arm B.
Dose escalation will continue to proceed according to the same 3 + 3 design and dose 
escalation rules (refer to Section 6.4).  The dose escalation plan is designed such that 
Treatment Arm A will evaluate increasing levels of MLN1117 in combination with fixed 
doses of MLN0128.  Treatment Arm B will evaluate increasing levels of MLN0128 in 
combination with a fixed dose of MLN1117 as tolerated.  Treatment Arm C will evaluate 
increasing levels of MLN1117 in combination with MLN0128 at a fixed dose.
Dose escalation will begin in Treatment Arm A (Cohort 3A) and Arm B (Cohort 1B) in 
parallel.  Dose escalation in Treatment Arm C will only initiate after confirmation of the 
safety and tolerability of study drug administration in Cohort 2B of Treatment Arm B.
1.4.3   
Rationale for PK Assessments
The rationale for the PK assessments planned for this study is given in the following section.
PK Assessments During the Escalation Stage
Serial PK sampling in the Escalation Stage will evaluate systemic exposures of MLN0128 
and MLN1117 and provide data on the dose/exposure/toxicity relationship of the 
combination.  Data will inform the selection of the recommended phase 2 doses (RP2Ds) 
and schedules, which will be evaluated in the Expansion Stage of the study.  See Table A:  
PK and Pharmacodynamic Assessment Schedule (Escalation Stage) in the Schedule of 
Events for the PK sampling scheme used in the Escalation Stage.
PK Assessments in the Expansion Stage
Patients with any advanced solid tumor and who meet all inclusion/exclusion criteria can be 
enrolled into the Expansion Stage.  This stage will be dedicated to collecting DDI data to 
characterize the effect of MLN0128 on MLN1117 PK and, conversely, the effect of 
MLN1117 on MLN0128 PK at the RP2D.  Serial PK sampling will evaluate the systemic 
exposures of MLN0128 and MLN1117 when the agents are administered either alone or 
together.
In addition, patients in the Expansion Stage will also provide urine samples on 3 separate 
occasions during Cycle 1 (collected as single predose voids and single cumulative 0- to 
8-hour postdose duration on prespecified days during Cycle 1).  Urine will be collected to 


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understand the extent to which MLN0128 and MLN1117 are excreted in urine (renal 
clearance of both agents).  The collection of urine when these agents are administered alone 
and when these agents are co-administered will also help evaluate whether each agent 
affects the renal clearance of the other when co-administered.
The PK sampling schemes for the mutual DDI assessments during the Expansion Stage are 
provided in Table B:  PK Assessment Schedule (Expansion Stage:  Treatment Arm A) and 
Table C:  PK Assessment Schedule (Expansion Stage:  Treatment Arm B and Arm C).
1.4.4   
Rationale for Pharmacodynamic Assessments
Assessment of Biomarkers in Tumor Tissue (Banked or Pretreatment Tumor Biopsy)
Clinical response to MLN1117 has been seen in patients with PIK3CA mutations.  When 
using in vitro proliferation as an endpoint it has been demonstrated that PTEN loss confers 
insensitivity to MLN1117 with concentration producing 50% inhibition (IC50)
values > 10 ∋M.  However, more recently in a PTEN null human tumor breast cancer 
xenograft model, MLN1117 did show some tumor growth inhibition that was significantly 
enhanced when assessed in the combination of MLN0128 + MLN1117.  
 
 
 
 
 
 
Assessment of Pharmacodynamic Markers in Skin
The evaluation of PI3K/mTOR pathway markers in both tumor and surrogate tissues in 
clinical studies has contributed to the identification of an optimal dosing regimen.(18)  
Although pharmacodynamic effects in tumor tissues are more important to estimate 
antitumor activities of an anticancer agent, those in surrogate tissues such as skin have been 
shown concordant to changes in pharmacodynamic markers in tumor tissues and can be used 
as supportive evidence of the inhibition of intended target(s).  In both MLN0128 and 
MLN1117 phase 1 studies, analyses of skin biopsy samples have revealed inhibition of 
PI3K/mTOR pathway marker expression.  Further details are in the IBs for MLN0128, 
MLN1117, and MLN0128 + MLN1117.  Although the number of paired skin and tumor 
samples analyzed to date was small, concordance in pharmacodynamic effects has been seen 
Company
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between skin and tumor samples collected in the MLN0128 phase 1 study (INK128-001).  
Thus, in addition to characterization of safety profiles and PK, all patients in the Escalation 
Stage will undergo skin biopsies and PI3K/mTOR pathway markers will be evaluated to 
support identification of a regimen of MLN0128 + MLN1117 that can produce better 
antitumor activity, with an acceptable toxicity profile, than either single agent alone.
Pharmacogenomic Assessments
Genetic variation has been observed in the drug metabolizing enzymes that contribute to 
MLN0128 and MLN1117 metabolism (eg, cytochrome P450 [CYP] 2C9 and CYP2C19).  
Such variations can contribute to the interindividual variability in the PK and, in turn, the 
safety and efficacy of MLN0128 and MLN1117.  Accordingly, blood samples will be 
obtained from all patients at screening to allow for the evaluation of germline 
polymorphisms in CYP2C9 and CYP2C19 genes.  See Section 7.4.19 for more details.
1.5   
Potential Risks and Benefits
Across the MLN0128 + MLN1117 dose levels and schedules to be investigated in this study, 
the most common treatment-emergent adverse events (TEAEs) are expected to be consistent 
with the pharmacodynamic mechanism of mTOR inhibition that is seen with rapalogs 
(mTORC1 inhibition) or dual mTORC1/2 inhibitors; these TEAEs were generally 
manageable with supportive care, and/or interruption or dose reduction of study drug.  The 
most commonly reported study drug-related adverse events (AEs) across the MLN0128 
single-agent studies include diarrhea, fatigue, vomiting, rash, mucosal inflammation, 
asthenia, dysgeusia, thrombocytopenia, stomatitis, and blood creatinine increased.
Although clinical experience with MLN1117 is limited, preliminary data show that the 
reported AEs have been expected from the clinical profiles observed with other PI3K 
inhibitors.  The commonly encountered class-related toxicities, including diarrhea, 
hyperglycemia, and rash, have been milder after MLN1117 administration compared with 
those reported following administration of unselective pan-PI3K inhibitors.  Although most 
of the AEs considered by the investigator to be related to MLN1117 administration have 
been mild in severity and manageable with routine standard of care, Grade 2 to 3 
asymptomatic aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations 
have been dose-limiting when administered on a QD schedule.  Upon dose interruption, 
these AST/ALT elevations were reversible and manageable.


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To determine the potential overlapping toxicities associated with MLN0128 and MLN1117, 
the identified and potential risks of both drugs, including data from nonclinical and clinical 
studies for each product, have been reviewed.  More detailed information on the identified 
and potential risks of both drugs is included in their individual single-agent IBs.  Class 
effects of mTOR inhibitors (for MLN0128) and PI3K inhibitors (for MLN1117) have also 
been considered.  Potential overlapping toxicities for both agents include:

Dermatologic disorders (pruritus, rash)

Gastrointestinal (GI) disorders (diarrhea, mucosal inflammation, nausea, stomatitis, 
vomiting)

Generalized disorders (anorexia, asthenia, decreased appetite, fatigue)

Hematologic disorders (lymphoid, bone marrow depletion)

Metabolic disorders (decreased blood chloride, hypercholesterolemia, 
hyperglycemia)
Based on the current clinical experience and the previous list of potential overlapping 
toxicities, hyperglycemia, diarrhea, nausea, vomiting, fatigue, and rash are the most 
anticipated AEs associated with the MLN0128 + MLN1117 combination regimen.  These 
events are expected to be manageable.
Risk mitigation strategies for potential AEs include, but are not limited to, strict application 
of the study inclusion and exclusion criteria, frequent clinical and laboratory results 
monitoring, guidelines for management of potential toxicities, criteria for dose modification, 
criteria for determining DLTs, and regular monitoring of AEs and serious adverse events 
(SAEs) by the sponsor.  In addition, patients will be given a glucometer to monitor daily 
predose fasting glucose levels at home and will be instructed to notify the study staff when 
the fasting glucose is abnormal.  All patients developing hyperglycemia during the study 
should have their glucose closely monitored by study staff.


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1.5.1   
Drug-Drug Interaction Risk Assessment
1.5.1.1   
Drug Interaction Risk With MLN0128
Drug Metabolism
Recently completed in vitro metabolism experiments in human hepatocytes using 
14C-labeled MLN0128 suggest that MLN0128 is metabolized primarily via CYP1A2 
(approximately 31% to 40%), with a minor contribution from CYP3A4 (approximately 
11% to 22%).  These data suggest that MLN0128 is also metabolized by direct 
glucuronidation (approximately 22%) and an unidentified non-uridine diphosphate 
glucuronosyltransferase (UGT) pathway (approximately 18%).  The new data differ from 
the previous in-vitro CYP phenotyping data obtained using recombinant CYP enzymes, 
which suggested the involvement of CYP2C9 (approximately 35%), CYP2C19 
(approximately 28%), and CYP3A4 (approximately 28%) in MLN0128 metabolism. 
In addition, physiologically based PK modeling and simulation using the new metabolism 
data for MLN0128 suggest that the risk for a metabolism-based drug-drug interaction with 
MLN0128 appears to be low.  Therefore, strong CYP1A2 inhibitors and CYP inducers (see 
Appendix 14.4) should only be administered with caution and at the discretion of the 
investigator during the study.  Alternative treatments, if available, should be considered.
In vitro, MLN0128 neither inhibited any of the major CYP enzymes (CYP1A2, 2B6, 2C8, 
2C9, 2C19, 2D6, and 3A4/5, with IC50 values > 25 µM) nor induced CYPs 1A2, 2B6, or 
3A4/5 at concentrations less than or equal to 10 µM.  The projected total plasma steady state 
maximum peak concentration (Cmax,ss) of MLN0128 at the proposed highest QD dose of 
5 mg MLN0128  (mean projected total Cmax,ss of 0.07 µM) and a QD3d QW dose of 12 mg 
MLN0128 (mean projected total Cmax,ss of 0.22 µM) are substantially lower than the IC50
value of 25 µM for CYP inhibition and the highest tested CYP-induction concentration of 
10 µM, where CYP-induction was not observed.  MLN0128 is thus unlikely to precipitate a 
CYP inhibition- or induction-mediated interaction for substrates of these enzymes.
Drug Transporter
In vitro, MLN0128 was neither a substrate nor an inhibitor of P-glycoprotein (P-gp) but did 
inhibit breast cancer resistance protein (BCRP, IC50 approximately 51.9 µM) and organic 
cation transporter proteins 1 and 2 (OCT1 and OCT2, with IC50 values of 21.6 and 18.9 µM, 
respectively).


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At the doses to be administered in this study, MLN0128 is unlikely to precipitate a clinically 
meaningful drug interaction with substrates of BCRP, OCT1, or OCT2 based on 
comparisons of the potencies for inhibition of these transporters to the systemic exposures of 
MLN0128 expected to be achieved clinically.
1.5.1.2   
Drug Interaction Risk With MLN1117
Drug Metabolism
On the basis of preliminary in vitro metabolism experiments, MLN1117 is primarily 
metabolized by CYP3A4 (72%), with minor contributions from CYPs 1A2 (12%), 
2C9 (9%), and 2C8 (6%). In vitro, MLN1117 did not inhibit any of the major CYP enzymes 
(CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5, with IC50 values > 100 µM). The mean 
observed total plasma Cmax,ss at the highest studied QD dose of 300 mg MLN1117 is 
approximately 21 µM (single-agent study INK1117-001). In the current study, MLN1117 is 
administered at ≥100 mg on 2 QD3d QW dosing schedules. Because the projected plasma 
concentration of MLN1117 at doses of approximately 300 mg is substantially lower than the 
CYP inhibition IC50 of 100 µM in either QD3d QW dosing schedule, the risk of a CYP 
inhibition-mediated DDI with MLN1117 is considered to be low.
In vitro CYP-induction experiments evaluating CYPs 1A2, 2B6, and 3A4/5 have shown that 
MLN1117 increases CYP messenger ribonucleic acid (mRNA) expression (generally 
< 2-fold and 20% of positive controls, omeprazole, phenobarbital, and rifampin, 
respectively, for CYPs 1A2, 2B6, and 3A4/5) but not CYP activity at concentrations 
≤30 µM MLN1117. Hepatocyte preparation from 1 donor showed increased CYP3A 
mRNA expression > 20% (approximately 42.2%) of that of positive-control rifampin but no 
increase in CYP3A activity. Rather, there was a slight decrease (approximately 16%) in 
CYP activity at a concentration of 30 µM MLN1117. These data suggest that at doses up to 
30 µM, MLN1117 does not increase CYP1A2, 2B6, or 3A4/5 activity. Based on available 
information and understanding of MLN1117 PK, it is also unlikely that free plasma 
Cmax,ss > 30 µM would be expected in either of the 2 dosing schedules, even at a dose of 
400 mg of MLN1117. Thus, although a risk for CYP induction-mediated DDI cannot be 
excluded, there appears to be a low likelihood that MLN1117 would precipitate a CYP 
induction-mediated DDI at the doses planned for this study. Based upon the preliminary 
metabolism data for MLN1117, the cautious use of strong CYP1A2 inhibitors is allowed 
only at the discretion of the investigator during the study (see Appendix 14.4).


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Drug Transporter
In vitro, MLN1117 was neither a substrate nor an inhibitor of P-gp.  However, MLN1117 
did inhibit BCRP (IC50 of 29.9 µM), OCT1 (IC50 of 2.3 µM), and OCT2 (IC50 of 5.8 µM) in 
vitro.  Because the projected plasma concentrations of MLN1117 at doses > 200 mg do meet 
the criteria defined by the FDA in the draft DDI guidance (estimated accumulation 
ratio > 1.25, based on total plasma Cmax,ss of MLN1117, for transporters such as BCRP and 
OCT1, and ratio of free Cmax,ss/IC50 being > 0.1 for transporters such as OCT2), there is a 
potential for MLN1117 to affect the PK of BCRP substrates (eg, methotrexate, imatinib, 
topotecan, lapatinib, rosuvastatin) as well as OCT1 or OCT2 substrates (eg, metformin, 
cimetidine, amantadine, famotidine, pindolol).  Thus, if patients require treatment with 
medications that are known substrates of these transporters, these agents should be 
administered with caution or alternate treatment options should be considered.  It is 
recommended that patients requiring metformin for hyperglycemia resulting from MLN0128 
+ MLN1117 administration begin treatment with the lowest effective dose of metformin and 
have glycemic levels closely monitored.
Physicochemical
MLN1117 exhibits pH-dependent aqueous solubility (solubility is approximately 1 mg/mL 
at pH = 1.3 and 0.001 mg/mL at pH 5).  Therefore, there exists a risk for a DDI as a result 
of concomitant administration with gastric pH-altering agents (eg, proton pump inhibitors 
[PPIs], H2-receptor antagonists, or neutralizing antacids).  Such agents are prohibited from 
being co-administered with MLN1117, because they could significantly decrease the oral 
absorption and hence the systemic exposure of MLN1117.
1.5.1.3   
Drug Interaction Risk Between MLN0128 and MLN1117
Based on the available in vitro data, projected exposures, and clinically relevant dose ranges 
for each agent, the likelihood of meaningful drug metabolism or transporter mediated DDI 
between these agents is considered low.  Following the determination of the RP2Ds and 
schedules of MLN0128 + MLN1117 in the Escalation Stage, the PK of MLN0128 and 
MLN1117 administered in combination will be evaluated in reference to the PK of 
MLN0128 and MLN1117 administered alone in the Expansion Stage.  This stage will permit 
a formal estimation of the magnitude of mutual DDI between the 2 agents, which will 
support future clinical development of the combination at the RP2D determined in this 
study.


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2.   
STUDY OBJECTIVES
2.1   
Primary Objectives
The primary objectives are as follows:
!
To evaluate the safety profile and to determine DLTs, MTDs and/or RP2Ds, and 
dosing schedules of oral MLN0128 + MLN1117 in patients with advanced 
nonhematologic malignancies
!
To characterize the single- and multiple-dose plasma PK of MLN0128 + MLN1117 
in patients with advanced nonhematologic malignancies
2.2   
Secondary Objectives
The secondary objective is as follows:
!
To evaluate evidence of antitumor activity of MLN0128 + MLN1117
2.3   
Exploratory Objectives
The exploratory objectives are as follows:
!
!
!
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3.   
STUDY ENDPOINTS
3.1   
Primary Endpoints
The primary endpoints are as follows:
!
AEs, SAEs, assessments of clinical laboratory values, physical exam findings, 
electrocardiograms (ECGs), and vital sign measurements
!
MLN0128 and MLN1117 plasma PK parameters including, but not limited to, 
single-dose maximum (peak) concentration (Cmax), Tmax, area under the 
concentration-time curve from time 0 to the end of the dosing interval (AUClast), t1/2, 
apparent oral clearance, peak-to-trough ratio, and accumulation ratio
3.2   
Secondary Endpoints
The secondary endpoint is as follows:
!
Measures of disease response including objective response rate and duration of 
response, based on investigator’s assessment and using, if feasible, the Response 
Evaluation Criteria in Solid Tumors (RECIST) guideline (Version 1.1)
3.3   
Exploratory Endpoints
The exploratory endpoints are as follows:
!
!
!
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4.   
STUDY DESIGN
4.1   
Overview of Study Design
This study is a multicenter, open-label, phase 1b trial of MLN0128 (an oral mTORC1/2 
inhibitor) in combination with MLN1117 (an oral inhibitor of the PI3Kisoform) when 
administered to adult patients with advanced nonhematologic malignancies for whom 
standard, curative, or life-prolonging anticancer treatment does not exist or is no longer 
effective.  The study will consist of 2 stages:  a (dose) Escalation Stage followed by an 
Expansion Stage.  In the Escalation Stage, 2 dosing regimens for the combination will be 
evaluated in 3 separate treatment arms to identify the MTDs and/or RP2Ds and schedules to 
be implemented in the Expansion Stage.  Throughout this protocol, “study drug” or 
“MLN0128 + MLN1117” refers to MLN0128 in combination with MLN1117.
In the Escalation Stage, patients will be enrolled into dose escalation cohorts at different 
combination doses and schedules of MLN0128 and MLN1117 using a standard 3 + 3 
approach to determine the MTDs and/or RP2Ds in each treatment arm and optimal dosing 
schedules to be implemented in the Expansion Stage.  Study drug will be administered in 
28-day cycles.  In Treatment Arm A, MLN0128 will be administered QD and MLN1117 
will be administered once daily on MWF QW.  In Treatment Arm B and Arm C, both 
MLN0128 and MLN1117 will be administered on MTuW QW.  MLN1117 dose levels will 
be escalated in combination with fixed doses of MLN0128 in Treatment Arm A and Arm C; 
the MLN0128 dose level will be escalated in combination with a fixed dose of MLN1117 in 
Treatment Arm B.
Patients will be enrolled in the Expansion Stage to further characterize the safety, 
tolerability, and PK of MLN0128 in combination with MLN1117.  A combination dose and 
schedule from 1 of the treatment arms evaluated in the Escalation Stage will be chosen to 
examine the mutual DDI PK of MLN0128 and MLN1117; the dose and schedule to be 
examined during the Expansion Stage will be specified prior to patient enrollment in that 
stage.
Patients enrolled in this study will not be required to have measureable disease per RECIST 
criteria (Version 1.1); however, if feasible, response may be evaluated using RECIST 
guidelines.(2)
Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.(1)  


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DLTs are defined in Section 6.3.  AEs will be assessed, and laboratory values, vital signs, 
physical exam findings, and ECGs will be obtained to evaluate the safety and tolerability of 
MLN0128 + MLN1117.
4.2   
Number of Patients
Approximately 101 evaluable patients total will be enrolled in this study from approximately 
12 study centers located in North America and Europe.  Approximately 81 evaluable 
patients will be enrolled in the Escalation Stage, and approximately 20 evaluable patients 
will be enrolled in the Expansion Stage.
A patient will be considered enrolled at the time of administration of the first study drug 
dose.
4.3   
Duration of Study
Patients, including those who achieve a clinical response, may receive study drug until they 
experience disease progression.  Patients will discontinue treatment if they have an 
unacceptable drug-related toxicity.  The maximum duration of treatment, however, will be 
12 months unless it is determined that a patient would benefit from continued therapy 
beyond 12 months.
Patients will be followed for 30 days after the last dose of study drug or the start of 
subsequent anticancer therapy, whichever occurs first, to permit the detection of any delayed 
treatment-related AEs.
It is anticipated that the overall conduct of this study will last for approximately 40 months.
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5.   
STUDY POPULATION
5.1   
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older.
2. Patients must have a diagnosis and documented disease progression of a solid tumor
malignancy, excluding primary brain tumor, for which standard, curative, or 
life-prolonging treatment does not exist or is no longer effective.  Patients with 
locally advanced or metastatic solid tumors who have a history of brain metastasis 
are eligible for the study as long as their brain metastases have been treated and there 
is no evidence of progression or hemorrhage after treatment; they have discontinued 
dexamethasone for 4 weeks before first administration of study drug; and they have 
no ongoing requirement for dexamethasone or anti-epileptic drugs.
3. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (see 
Section 14.2).
4. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, or

Are surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
form (ICF) through 90 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 90 days after the last dose of study drug, or


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
Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.)
5. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care.
6. Suitable venous access for the study-required blood sampling, including PK and 
pharmacodynamic sampling.
7. In the Escalation Stage only, patients must have a block of banked tumor tissue 
and/or fresh tumor tissue or at least 10 unstained slides available to be sent to the 
central laboratory.  A patient who satisfies all of the inclusion and exclusion criteria 
but does not have banked tumor tissue or slides must consent to a tumor biopsy 
described in Section 7.4.16.  Patients participating in the Expansion Stage are not 
required to provide tumor tissue.
8. Clinical laboratory values as specified below before the first dose of study drug:

Total bilirubin must be within normal limit range.

ALT or AST must be 1.5 the upper limit of normal (ULN) ranges.

Serum creatinine must be 1.5 mg/dL and/or creatinine clearance or calculated 
creatinine clearance 50 mL/minute (Cockcroft-Gault formula; see 
Section 14.1).

Bone marrow reserve consistent with absolute neutrophil count (ANC) 
1.5109/L; platelet count 100109/L; and hemoglobin 9 g/dL.

Metabolic fasting glucose must be 120 mg/dL and fasting triglycerides 
300 mg/dL.
9. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of 
institutional standard of normal as measured by echocardiogram (ECHO) or multiple 
gated acquisition scan (MUGA) within 4 weeks before the first study drug 


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administration (for example, if the institutional normal is 50%, subject’s LVEF may 
be as low as 45% to be eligible for the study).
10. Patients must have radiographically or clinically evaluable tumor.

In the Escalation Stage and Expansion Stage of the study, patients must 
have radiographically or clinically evaluable tumor.

In the Expansion Stage of the study, patients must have radiographically 
measurable disease per RECIST guidelines (Version 1.1) or clinically 
measurable disease for evaluation of antitumor response.
5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria will not be enrolled in the study.
1. Female patients who are lactating and breastfeeding or have a positive serum 
pregnancy test during the screening period or a positive urine pregnancy test on 
Day 1 before first dose of study drug.
2. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol.
3. Treatment with any investigational products within 30 days before the first dose of 
study drug.
4. Previous treatment with MLN1117 and/or MLN0128; previous treatment with dual 
mTORC1/2 or dual PI3K-mTOR inhibitors.
5. Patients who received previous therapy with PI3K inhibitors or rapalogs will be 
allowed in the study if all other inclusion/exclusion criteria are met.
6. Diagnosis of primary brain tumor or symptomatic brain metastasis.  Patients with 
brain metastases must be without neurologic dysfunction that would confound the 
evaluation of neurologic and other AEs.
7. Failed to have recovered (ie, Grade 1 toxicity or baseline) from the reversible 
effects of previous anticancer therapies (except alopecia).


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8. Have received systemic corticosteroid (inhalers are allowed) within 7 days before the 
first administration of study drug.
9. Known GI disease or GI procedure that could interfere with the oral absorption or 
tolerance of study drug, including difficulty swallowing capsules.
10. Diagnosis of diabetes mellitus; patients with a history of transient glucose 
intolerance due to corticosteroid administration are allowed in this study if all other 
inclusion/exclusion criteria are met.
11. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active central nervous system disease, active infection, or any other condition that 
could compromise patient’s participation in the study.
12. Known human immunodeficiency virus infection.
13. History of any of the following within the last 6 months before administration of the 
first dose of study drug:

Ischemic myocardial event, including angina requiring therapy and artery 
revascularization procedures

Ischemic cerebrovascular event, including transient ischemic attack and artery 
revascularization procedures

Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) 
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation, or 
ventricular tachycardia)

Placement of a pacemaker, or implantable cardiac defibrillator to control rhythm

New York Heart Association Class III or IV heart failure (see Section 14.3)

Pulmonary embolism


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14. Significant active cardiovascular or pulmonary disease before administration of the 
first dose of study drug, including:

Uncontrolled hypertension (ie, systolic blood pressure >180 mm Hg; diastolic 
blood pressure > 95 mm Hg)

Pulmonary hypertension  

Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis 
or pulse oximetry on room air

Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention; or history of valve 
replacement

Medically significant (symptomatic) bradycardia 

History of arrhythmia requiring an implantable cardiac defibrillator
15. Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated 
demonstration of QTc > 480 msec, or history of congenital long QT syndrome, or 
torsades de pointes).
16. Patients who are taking PPIs within 7 days of the first dose of MLN0128 + 
MLN1117 or who require treatment with PPIs throughout the trial or those who are 
taking H2 receptor antagonists within 24 hours of the first dose of MLN0128 + 
MLN1117.
6.   
STUDY DRUG
6.1   
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration.  Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).  MLN0128 and 
MLN1117 will be administered on an empty stomach.  Patients should be instructed to 
refrain from eating and drinking (except for water and prescribed medications) for 2 hours 
before and 1 hour after each dose.  On Cycle 1, Day 1 and Cycle 1, Day 8, patients will be 


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required to fast for 2 hours after dosing, until the completion of any scheduled 2-hour 
postdose fasting glucose, insulin, and insulin C-peptide samples.  Each dose of MLN0128 
and MLN1117 will be given orally with 8 ounces (240 mL) of water.  For information 
regarding excluded concomitant medications refer to Section 6.7 and the Pharmacy Manual.
Cycle lengths are 28 days in all treatment arms.  In Treatment Arm A, MLN0128 will be 
administered QD every day and MLN1117 will be administered QD on MWF of every 
week.  In Treatment Arm B and Arm C, both MLN0128 and MLN1117 will be administered 
on MTuW QW.
Patients should be instructed to take their study medication at approximately the same time 
on each scheduled dosing day and not to take more than the prescribed dose at any time.  
MLN0128 and MLN1117 should always be taken together, at the same time, when dosed on 
the same day.  Patients should swallow the study medication whole and not chew it, open it, 
or manipulate it in any way before swallowing.  If a patient fails to take their MLN0128 
and/or MLN1117 doses within the time frame specified (6 hours of the scheduled dosing 
time), then the dose should be skipped and considered a missed dose.  Patients should record 
any missed doses in their dosing diary (see the Study Manual) and resume dosing at the next 
scheduled time with the prescribed dosage.
If severe emesis or mucositis prevents the patient from taking scheduled doses, that dose 
will be skipped.  If emesis occurs after study medication ingestion, the dose will not be 
readministered, and patients should resume dosing at the next scheduled time with the 
prescribed dosage.  Patients should record the occurrence of the emesis in their dosing 
diaries (see the Study Manual).  Under no circumstance should a patient repeat a dose or 
double-up doses.
6.1.1   
Expansion Stage
An exception to the previous study drug administration schedule occurs in Cycle 1 for 
patients in the Expansion Stage.  The sponsor will determine 1 combination dose and 
schedule to be evaluated in this stage (ie, either that of Treatment Arm A, Arm B, or 
Arm C).  The modified dosing schedules described in the following allow for plasma PK 
characterization of MLN0128 in the absence of concomitantly administered MLN1117 and, 
likewise, PK characterization of MLN1117 in the absence of concomitantly administered 
MLN0128.


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Treatment Arm A:  During Cycle 1, patients will be instructed to take MLN0128 every 
day, except on Days 13 through 19, when the MLN0128 dose will be withheld.  MLN1117 
will be administered on every MWF, except on Days 1 through 5 when the MLN1117 dose 
will be withheld.  The regular dosing schedule will be followed in subsequent cycles.  Refer 
to Table B:  PK Assessment Schedule (Expansion Stage:  Treatment Arm A).
Treatment Arm B or Arm C:  During Cycle 1, patients will be instructed to take 
MLN0128 on every MTuW, except on Days 15, 16, and 17, when the MLN0128 dose will 
be withheld.  MLN1117 will be administered every MTuW except on Days 1, 2, and 3 when 
the MLN1117 dose will be withheld.  The regular dosing schedule will be followed in 
subsequent cycles.  Refer to Table C:  PK Assessment Schedule (Expansion Stage:  
Treatment Arm B and Arm C).
6.2   
Reference/Control Therapy
Not applicable.
6.3   
Definitions of Dose-Limiting Toxicity
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 
14 June 2010.(1)  These criteria are provided in the Study Manual.  DLT will be defined as 
any of the following events that are considered by the investigator to be at least possibly 
related to treatment with MLN0128 + MLN1117:

Grade 4 neutropenia (ANC 500 cells/mm3) lasting longer than 7 consecutive 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 study drug within Cycle 1 
due to treatment-related toxicity or delay in the initiation of the subsequent cycle of 
therapy by more than 14 days due to treatment-related toxicity (lack of adequate 
recovery of treatment-related hematological or nonhematologic toxicities)

Any clinically significant occurrence which the investigators and sponsor agree 
would place patients at undue safety risk


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
Any Grade 3 or greater nonhematologic toxicity with the following exceptions:
o
Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all 
patients should receive optimal antiemetic and/or antidiarrheal prophylaxis 
and/or treatment)
o
Grade 3 hyperglycemia lasting ≤ 14 days (all patients should receive optimal 
antiglycemic treatment, including insulin)
o
Grade 3 rash lasting ≤ 3 days (all patients should receive topical steroid 
treatment, oral antihistamines, and pulse oral steroids, if necessary)
6.4   
Dose Escalation Plan
The rationale for the approach to dose escalation is provided in Section 1.4.  The dose 
escalation scheme is shown in Figure 6-1 (and in Table 6-1).  The following rules apply to 
all cohorts as shown in Figure 6-1 (and in Table 6-1).
The dose intervals will adhere to the 3 + 3 traditional escalation rules, starting with the 
treatment of 3 patients at a planned dose level, as follows:
1. If 0 of 3 patients experiences DLT, dose escalation will proceed to the next higher 
dose level at which 3 patients will be enrolled.
2. If 1 of 3 patients experiences DLT, 3 more patients will be enrolled at that same dose 
level.
3. Escalation will continue if 1 of 6 patients experiences DLT.
4. If 2 or more patients in any dose level experience DLT, dose escalation will stop, and 
the previous dose level is considered the MTD.
MLN0128 or MLN1117 doses may be escalated up to 100% dose increments until such time 
that a Grade ≥2 treatment-related toxicity is observed.  For cohorts where 200 mg 
INK1117 is administered, once it is agreed that a toxicity of severity Grade ≥2 is likely 
related to treatment, subsequent dose escalations will occur based on the observed toxicities 
at increments of 25% to 66%.


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This escalation scheme allows for the determination of MTDs in each treatment arm.  The 
MTD for each agent is defined as any dose level that meets the following criteria (after dose 
escalation has ended):
1. The dose combination has been tested with at least 6 patients.
2. No more than 1 of 6 patients has experienced a DLT during Cycle 1.
In addition, more conservative dose escalation, reduction, or evaluation of intermediate 
doses of either study drug in any treatment arm, including further escalation of study drug 
that was previously fixed and expansion of up to 12 patients in an existing dose cohort, are 
all permissible following discussions between the sponsor and the investigators, if such 
measures are needed for patient safety or for a better understanding of the dose–related 
toxicity, exposure, or pharmacodynamics of MLN0128 + MLN1117.  The highest dose 
evaluated for either agent in combination will not exceed the single-agent MTD (12 mg 
MLN0128 and 900 mg MLN1117).  The RP2Ds will be determined based on the totality of 
data, including, but not limited to, safety, tolerability, PK, and clinical response.
6.5   
Dosing Group Assignments
The starting combination dose in Treatment Arm A was 2 mg MLN0128 and 100 mg 
MLN1117 (Cohort 1A); the starting combination dose in Treatment Arm B was 6 mg 
MLN0128 and 100 mg MLN1117 (Cohort 2A).  Treatment Arm A and Arm B were planned 
to be evaluated in series, with the first 2 cohorts from Treatment Arm A (ie, Cohort 1A and 
Cohort 2A) completing before Cohort 1B of Treatment Arm B began; however dose 
escalation and the initiation of additional cohorts were stopped because the study drug 
combination of 4 mg MLN0128 and 100 mg MLN111 administered in Cohort 2A was not 
tolerable.
As of Protocol Amendment 2, dose escalation will start with 3 patients enrolled in Treatment 
Arm A, Cohort 3A, in parallel with 3 patients enrolled in Treatment Arm B, Cohort 1B.  The 
safety of Treatment Arm B, Cohort 2B, will be confirmed before Cohort 1C of Treatment 
Arm C is initiated.  Depending on review of safety and tolerability data, an escalation 
scheme where 1 agent is fixed, while the other agent is escalated, will continue in this 
manner until MTD is reached for the combination of MLN0128 + MLN1117 for each 
treatment arm.


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The dose of MLN0128 will remain fixed in Treatment Arm A and Arm C; however, in 
Arm B, MLN0128 dosing will remain fixed for the first 2 cohorts after which point, the dose 
level will escalate.  Concomitantly, MLN1117 dosing will escalate in Treatment Arm A and 
Arm C; however, in Arm B, after 1 dose escalation between Cohorts 1B and 2B, MLN1117 
dosing will remain fixed.  The highest dose evaluated for either agent in combination will 
not exceed the single-agent MTDs.  Additionally, the dose of MLN0128 or MLN1117 may 
be further escalated within a cohort to an intermediate dose level once an MTD of either 
agent is identified.
Figure 6-1   
Dose Escalation Flowchart by Treatment Arm


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Table 6-1   
Dose Escalation Table by Treatment Arm
Treatment Arm Aa
MLN0128 QD +
MLN1117 MWF QW
Treatment Arm Bb
MLN0128 + MLN1117
MTuW QW
Treatment Arm Cc
MLN0128 + MLN1117
MTuW QW
Cohort
MLN0128
MLN1117
Cohort
MLN0128
MLN1117 Cohort MLN0128
MLN1117
1Ad
2 mg
100 mg
--
--
2Ad
4 mg
100 mg
--
--
3A
2 mg
200 mg
1B
3 mg
100 mg
--
4A
2 mg
dose level 4A 
(not to exceed 
400 mg)
2B
3 mg
200 mg
--
5A
2 mg
dose level 5A 
(not to exceed 
800 mg)
3B
dose level 3B 
(not to exceed 
6 mg)
200 mg
1C
3 mg
dose level 1C 
(not to exceed 
400 mg)
6A
2 mg
dose level 6A 
(not to exceed 
900 mg)
4B
dose level 4B 
(not to exceed 
12 mg)
200 mg
2C
3 mg
dose level 2C 
(not to exceed 
800 mg)
Abbreviations:  MTD = maximum tolerated dose; MTuW = Monday, Tuesday, Wednesday; MWF = Monday, 
Wednesday, Friday; QW = each week.
Shading of dose cohorts across treatment arms indicates those that may be initiated in parallel (eg, enrollment 
into Cohort 1B and 3A may begin in parallel, enrollment into Cohort 1C and 3B may begin in parallel, etc.). 
Cohorts 5A, 4B, and 2C are included for reference only.  Based on tolerability observed in previous cohorts, 
cohorts may never be evaluated and cohorts with higher dose levels may be added and escalated according 
to 3 + 3 rules.  Dose increases during escalation are contingent upon the safety observed in the previous 
cohort and the dose strength available.  Once it is agreed that a toxicity of severity Grade ≥ 2 is likely 
treatment related, subsequent dose escalations will occur based on the observed toxicities at increments of 
25% to 66% (eg, dose level 4A and above or cohorts where 200 mg INK1117 is administered).  The 
highest dose evaluated for either agent in combination will not exceed the single-agent MTD (12 mg 
MLN0128 and 900 mg MLN1117).
a The dose ofMLN0128 will be fixed at 2 mg and the dose of MLN1117 will be escalated based on observed 
tolerability. 
b Based on tolerability in Cohort 1B, 3 mg MLN0128 + 200 mg MLN1117 will be evaluated in Cohort 2B.  
Doses of MLN1117 will then be fixed at 200 mg and MLN0128 doses will be escalated based on observed 
tolerability.  Initiation of Cohort 1C does not start until Cohort 2B is determined safe.
c The starting dose of MLN0128 will be 3 mg and the starting dose of MLN1117 will be determined based on 
tolerability observed in Treatment Arm B.  The dose of MLN0128 may be adjusted and the dose of 
MLN1117 will continue to be escalated based on tolerability.
d Study drug doses in Cohorts 1A and 2A were evaluated under Protocol Amendment 1.
6.6   
Dose-Modification Guidelines
6.6.1   
General Principles
Treatment cycles with MLN0128 + MLN1117 will occur in 28-day increments.  The patient 
will be evaluated weekly during Cycles 1 and 2, every other week during Cycles 3 and 4, 
and every cycle thereafter for possible toxicities that may have occurred after the previous 
dose(s).  Toxicity assessment and grading will be based on NCI CTCAE Version 4.03.


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For management of toxicity for individual patients, dose adjustment may include 
interruption of the study drug treatment, a dose reduction of a single agent in the 
combination (ie, either MLN0128 or MLN1117) or a dose reduction of both agents 
(ie, MLN0128 and MLN1117).  Patients who dose-reduce will not be allowed to re-escalate.  
Alternative dose modifications may be recommended after discussion with the investigator 
and the sponsor’s project clinician to maximize exposure of study treatment while protecting 
patient safety.
See Section 6.9 for instructions on managing the following specific clinical events:  
hyperglycemia (Section 6.9.1.1), hyperlipidemia (Section 6.9.1.2), oral mucositis 
(Section 6.9.1.3), rash (Section 6.9.1.4), nausea/vomiting (Section 6.9.1.5), cardiac 
abnormalities (Section 6.9.1.6), AST/ALT elevations (Section 6.9.1.7), and other 
nonhematologic toxicities (Section 6.9.1.8).
Although DLTs may happen any time during the study, only DLTs occurring during Cycle 1 
of the Escalation Stage will impact decisions regarding dose escalation, dose escalation 
cohort expansion, or intermediate dose level evaluation.
During Cycle 1 of the Escalation Stage, if a patient experiences a DLT (see Section 6.3 for 
DLT definitions), then treatment will be interrupted and the event will be counted toward the 
MTD assessment for that dose escalation cohort.  Once the toxicity resolves and if the 
investigator believes the patient will benefit from treatment, then the patient may continue 
study drug with dose reduction to an established safe dose of MLN0128  + MLN1117.  A 
patient who dose-reduces will not be allowed to re-escalate.  Patients enrolled in Cohorts 1A 
or 1B with DLTs must discontinue from the study.  For management of toxicities beyond 
Cycle 1, see Section 6.6.3
6.6.2   
Intrapatient Dose Escalation
Once an MTD has been determined for a respective dosing schedule of MLN0128  + 
MLN1117, intrapatient dose escalation within this given dosing schedule may be allowed (at 
the investigator’s discretion and with the sponsor’s approval) in patients actively receiving 
MLN0128  + MLN1117 at a dose lower than the MTD, for a minimum of 2 cycles, in the 
absence of disease progression or unacceptable treatment-related toxicity.
Patients are not allowed to switch from 1 dosing schedule to another or participate in more 
than 1 treatment arm at any time.


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6.6.3   
Dose Modification Guidelines
The causal relationship of each AE should be assessed in relation to MLN0128  and in 
relation to MLN1117 so that dose modifications can be made accordingly.  Reduction of 
1 agent and not the other is appropriate if toxicity is assessed as primarily related to 1 of the 
agents.  If multiple toxicities are noted, the dose adjustments and/or delays should be made 
according to the most severe toxicity guidelines.
A decision regarding which study drug requires dose reduction will depend on the toxicity, 
its onset, and time course.  Dosing should be withheld for ≥ Grade 3 MLN0128 - and/or 
MLN1117-related toxicities.  If the event resolves to Grade 1 or baseline values within 
14 days of interrupting therapy, the patient may resume combination study treatment if 
treatment with study drug is thought beneficial by the investigator and with the sponsor’s 
approval based on the guidelines that are provided in Table 6-2.  Alternative dose 
modifications may be recommended after discussion with the investigator and Millennium 
clinician to maximize exposure of study treatment while protecting patient safety.
Table 6-2   
Dose Modification Guidelines for MLN0128  and/or MLN1117 During 
the Escalation Stage, after Cycle 1, and the Expansion Stage
AE Requiring Dose 
Modification
Effect on MLN0128 Dose
Effect on MLN1117 Dose
Grade 3 AE primarily related to 
MLN0128 
Dose reduce to next lower dose 
level
No change
Grade 3 AE primarily related to 
MLN1117
No change
Dose reduce to next lower dose 
level
Grade 3 AE related to 
MLN0128  and MLN1117a
No change
Dose reduce to next lower dose 
level
Abbreviations:  AE = adverse event.
a If the initial dose adjustment does not provide sufficient relief, either MLN1117 or MLN0128  can be 
subsequently reduced.
If the initial dose adjustment does not provide sufficient relief, either MLN1117 or 
MLN0128 can be subsequently reduced.  If MLN0128 + MLN1117 dosing is delayed for 
> 14 days for MLN0128 and/or MLN1117-related toxicities despite supportive treatment per 
standard clinical practice or despite more than 2 dose reductions of MLN0128  and 2 dose 
reductions of MLN1117, following discussions between the sponsor and the investigator, 
combination therapy must be stopped, the patient discontinued from the study, and the End-
of-Study (EOS) visit completed within 30 (+10) days of the last administration of MLN0128 
+ MLN1117.


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The sponsor’s clinician should be contacted before any dose modification in MLN0128  or 
MLN1117 for any patient in the study.
6.6.4   
Criteria for Beginning or Delaying a Subsequent Treatment Cycle
+ MLN1117 is administered in continuous cycles, and study drug should be administered 
continuously unless a Grade 3 or higher MLN0128 and/or MLN1117-related event occurs 
(See Section 6.6.3).
6.6.5   
Causality Assessment Guidance of Adverse Events for MLN0128 and 
MLN1117
A decision regarding which study drug requires dose reduction will depend on the toxicity, 
its onset, and time course as well as its potential relatedness to either MLN0128 or 
MLN1117.  Alternative dose modifications may be recommended after discussion with the 
investigator and sponsor’s clinician to maximize exposure of study treatment while 
protecting patient safety.  The assessment of a potential causal relationship of AEs to either 
MLN0128 and/or MLN1117 should be guided by the underlying single agent clinical 
experience.  A summary of Grade 3 or higher treatment-related AEs occurring in 5% or 
more of patients in the single-agent data can be used for this guidance and is presented in 
Table 6-3.
Table 6-3   
Guidelines for Assessment of a Potential Causal Relationship Based on 
Grade 3 or Higher Treatment-Related AEs Occurring in 5% or More 
of Patients in Each Single-Agent Clinical Program, Respectively
Adverse Event
MLN0128
MLN1117
Stomatitis/Mucosal Inflammation
Yes
No
Rash
Yes
No
Lymphopenia
Yes
No
Hyperglycemia
Yes
No
LFTs (AST/ALT elevation)
No
Yes
Fatigue/Asthenia
Yes
Yes
Abbreviations:  AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
LFTs = liver function tests.
6.6.6   
Criteria for Dose Interruption During a Cycle
If a patient experiences a DLT during Cycle 1 in the Escalation Stage, then treatment should 
be interrupted and the event will be counted toward the assessment of MTD for the given 
cohort.  Once the toxicity resolves and if the investigator believes the patient will benefit 


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from treatment, then the patient may continue study drug with dose reduction to an 
established safe dose of MLN0128 + MLN1117.  A patient who dose-reduces will not be 
allowed to re-escalate.  Patients who experience an AE that meets the definition for a DLT 
during the Escalation Stage after Cycle 1 or during the Expansion Stage should have their 
study drug treatment interrupted as outlined in Section 6.6.3.
6.6.7   
Criteria for Dose Reduction
See Section 6.6.3 for general dose modification guidelines.
6.6.8   
Criteria for Discontinuation of MLN0128 + MLN1117
See Section 6.9 for criteria resulting in discontinuation of MLN0128 + MLN1117.
6.7   
Excluded Concomitant Medications and Procedures
Recently completed in vitro metabolism experiments in human hepatocytes using 
14C-labeled MLN0128 suggest that the risk of a drug-drug interaction between MLN1117 
and MLN0128 is considered to be low (see Section 1.5.1.1). 
Strong CYP1A2 inhibitors and CYP inducers should be administered with caution and at the 
discretion of the investigator.  See Appendix 14.4 for a list of these agents.  Alternative 
treatments, if available, should be considered.
MLN1117 is a poorly soluble drug with inverse pH-dependent solubility (low solubility at 
higher pH).  Due to the potential alteration in MLN1117 absorption by agents that modify 
gastric pH, the following exclusions or restrictions apply:

Concomitant administration of any PPI is not permitted during the study.  Patients 
receiving PPI therapy before enrollment must stop using the PPI for 7 days before their 
first dose of MLN1117.  Examples of PPIs include omeprazole, esomeprazole, 
pantoprazole, lansoprazole, and rabeprazole.

Histamine H2 receptor antagonists are prohibited during Cycle 1 up to the point of 
completion of all protocol-specified PK sampling; however, beyond this point of time, 
histamine H2 receptor antagonists may be allowed, if needed, provided that the 
histamine H2 receptor antagonist is not taken within 12 hours before MLN1117 dosing 
and within 6 hours after MLN1117 dosing.  Patients receiving histamine H2 receptor 
antagonists before enrollment must stop using these medications for at least 24 hours 
before their first dose of MLN1117. Examples of histamine H2 receptor antagonists 


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include ranitidine, famotidine, and nizatidine.  Cimetidine, a moderate CYP1A2 
inhibitor, is not recommended as a first choice H2 receptor antagonist (see 
Appendix 14.4).

Neutralizing antacid preparations (acid neutralizers) and calcium supplements are not 
permitted during Cycle 1 on MLN1117 dosing days but may be taken as needed on 
non-MLN1117 dosing days; however, for all other cycles, administration of both of 
these agents is permitted except from 2 hours before until 2 hours after MLN1117 
dosing.  Some antigas preparations may also have antacid properties and should also 
not be permitted from 2 hours before until 2 hours after MLN1117 administration.
There is potential for MLN1117 to affect the PK of BCRP substrates (eg, methotrexate, 
imatinib, topotecan, lapatinib, rosuvastatin) as well as OCT1 or OCT2 substrates (eg, 
metformin, cimetidine, amantadine, famotidine, pindolol; see Section 14.5).  Thus, if 
patients require treatment with medications that are known substrates of these transporters, 
these agents should be administered with caution or alternate treatment options should be 
considered.  It is recommended that patients requiring metformin for hyperglycemia 
resulting from MLN0128 + MLN1117 administration begin treatment with the lowest 
effective dose of metformin and have glycemic levels closely monitored.
6.8   
Precautions and Restrictions
No dietary restrictions will be imposed on study patients.
Patients who show evidence of hyperglycemia during the study should be encouraged to 
follow a low carbohydrate diet.
It is not known what effects the administration of MLN0128 + MLN1117 has on human 
pregnancy or development of the embryo or fetus.  Therefore, female patients participating 
in this study should avoid becoming pregnant, and male patients should avoid impregnating 
a female partner.  Nonsterilized female patients of reproductive age group and male patients 
should use effective methods of contraception through defined periods during and after 
study treatment as specified below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or


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
If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the ICF through 90 days after the last dose 
of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of 
contraception.)
Male patients, even if surgically sterilized (ie, status postvasectomy), must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 90 days after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of 
contraception.)
6.9   
Management of Clinical Events
6.9.1.1   
Management of Hyperglycemia
All patients developing hyperglycemia during the study should have their glucose closely 
monitored by study staff.  The investigator may choose to continue close monitoring of 
patients who develop Grade 1 hyperglycemia (fasting glucose > ULN ≤ 160 mg/dL) or, 
alternatively, consider initiating treatment with an oral hypoglycemic agent, such as 
metformin.  All patients with ≥ Grade 2 hyperglycemia (fasting glucose > 160 mg/dL) must 
be treated aggressively with oral hypoglycemic agents and/or insulin as clinically indicated.  
The investigator should consult an endocrinologist, if needed, to aid in optimizing the 
patient’s hyperglycemia treatment plan.
It is recommended that patients be initially treated with a fast acting insulin sensitizer such 
as metformin at 500 mg orally QD and titrate up to a maximum of 1000 mg orally BID as 
needed.  Concurrent addition to metformin of dipeptidyl peptidase 4 (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 patients.  The dose of oral hypoglycemic agents should be adjusted in 


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patients with renal insufficiency.  In addition, patients should be encouraged to follow a low 
carbohydrate diet once hyperglycemia is first observed.
Guidance on study drug dose modification for patients with hyperglycemia is provided in 
Table 6-4.
Table 6-4   
Management of Hyperglycemia
Grade
Description
Treatment
Dose Modification
1
Fasting blood sugar 
> ULN - 160 mg/dL

Continue close monitoring of 
blood sugars

Initiate oral hypoglycemic agent
None
2
> 160 - 250 mg/dL

Initiate oral hypoglycemic agent 
and/or insulin if not well 
controlled on oral agent
None
≥3
> 250 mg/dL

Initiate oral hypoglycemic agent 
and/or insulin
Hold both MLN0128 and 
MLN1117 until ≤ Grade 2
Resume MLN0128 + 
MLN1117 based on timing of 
recovery after maximal 
treatment:

≤ 1 week:  resume both 
drugs at same dose and 
schedule

> 1 but ≤ 2 weeks:  reduce 
MLN0128 by 1 dose lower 
and maintain MLN1117 
unchanged

> 2 weeks:  discontinue 
subject from the study
Prevention/Prophylaxis:

Follow fasting glucose levels during clinic visits.

Monitor home glucometer test results.

Check HbA1c levels every 3 months during therapy.

Most episodes of Grade 1 or 2 hyperglycemia respond quickly to oral metformin.  Early initiation of 
therapy at the lowest therapeutic dose is recommended to prevent higher grade hyperglycemia.

Fasting blood glucose levels ≥ 140 mg/dL by glucometer should be followed by closer monitoring of 
serum glucose and possible intervention.  
Abbreviations:  HbA1c = glycosylated hemoglobin; ULN = upper limit of normal.
6.9.1.2   
Management of Hyperlipidemia
Guidance on study drug dose modification for patients with hyperlipidemia is provided in 
Table 6-5.


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Table 6-5   
Management of Hyperlipidemia
Grade
Description
Treatment
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 + MLN1117 
dosing until recovery to 
≤Grade 1.  Restart at 
same dose
3
Cholesterol > 400 - 500 mg/dL
Triglycerides > 500 - 1000 mg/dL
Same as for Grade 2
Hold MLN0128 + 
MLN1117 dose until 
recovery to ≤ Grade 1, then 
restart MLN0128 with a 
reduction of 1 dose lower 
while MLN1117 remains 
unchanged
4
Cholesterol > 500 mg/dL
Triglycerides > 1000 mg/dL
Same as for Grade 2
Discontinue treatment
Prevention/Prophylaxis:
Lifestyle modifications, as appropriate (balanced diet, limit alcohol consumption, increase physical activity)
Abbreviations:  ULN = upper limit of normal.
6.9.1.3   
Management of Oral Mucositis
Guidance on study drug dose modification for patients with oral mucositis is provided in 
Table 6-6.
Table 6-6   
Management of Oral Mucositis
Grade
Description
Treatment
Dose Modification
1
Asymptomatic or mild 
symptoms

Nonalcoholic mouth wash, or 
0.9% salt water rinse

Consider topical 
corticosteroids at earliest signs 
of mucositis
None
2
Moderate pain, not 
interfering with oral intake
Modified diet indicated

Topical analgesic mouth 
treatments

Topical corticosteroids

Initiate antiviral or antifungal 
therapy, if indicated

Maintain MLN0128 dose 
if tolerable

Hold only MLN0128 
dose if intolerable until 
recovery to ≤ Grade 1, 
then restart at same dose


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Table 6-6   
Management of Oral Mucositis
Grade
Description
Treatment
Dose Modification
3
Severe pain, interfering 
with oral intake

Same as for Grade 2

Consider intralesional 
corticosteroids

Hold only MLN0128 
dose until recovery to 
≤Grade 1, then restart 
with a reduction of 1 dose 
lower of MLN0128
4
Life-threatening 
consequences

Same as for Grade 2

Consider intralesional 
corticosteroids

Stop MLN0128 + 
MLN1117and 
discontinue patient from 
the study
Prevention/Prophylaxis:

Initiation of a nonalcoholic mouth wash, or 0.9% salt water rinses 4-6 times daily is strongly 
recommended at the start of therapy before signs of mucositis develop.

Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis as they may worsen mouth ulcers.
6.9.1.4   
Management of Rash
Guidance on study drug dose modification for patients with rash is provided in Table 6-7.
Table 6-7   
Management of Rash
Grade
Description
Treatment
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 or 
antibiotics
None
≥ 3
Macules/papules covering 
30% body surface area 
with or without symptoms
Consider treatment with topical 
steroid cream/ointment, oral 
anti-histamines, oral antibiotics, 
and/or pulsed steroids
Hold MLN0128 + MLN1117 until 
≤ Grade 2
Resume MLN0128 + MLN1117 
based on timing of recovery:

≤ 2 weeks:  reduce MLN0128 
dose by 1 dose; maintain 
MLN1117 unchanged

> 2 weeks:  stop MLN0128  + 
MLN1117and discontinue 
patient from the study
Prevention/Prophylaxis:

Rash should be managed aggressively.  The investigator should consider consulting a dermatologist or 
other specialist if needed.

A skin biopsy at the site of rash should be considered as soon as possible after the initial episode.


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6.9.1.5   
Management of Nausea/Vomiting
Guidance for patients with nausea and/or vomiting is provided in Table 6-8.
Table 6-8   
Management of Nausea/Vomiting
Grade
Description
Treatment
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 MLN0128 + 
MLN1117 until ≤ Grade 1

Resume MLN0128 + 
MLN1117 without dose 
modification
Prevention/Prophylaxis:
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications are encouraged and may be used 
before each MLN0128  + MLN1117 dosing as needed throughout the study.
Abbreviations:  IV = intravenous; IVF = intravenous fluids; TPN = total parental nutrition.
6.9.1.6   
Management of Cardiac Abnormalities
Management of Patients With Possible Cardiac Instability
For patients showing signs of cardiac instability after MLN0128 + MLN1117 dosing, 
additional monitoring onsite before clinic discharge should be considered.
Management of Patients With Left Ventricular Dysfunction
Guidance for MLN0128 + MLN1117 dose adjustment for patients with left ventricular 
dysfunction is provided in Table 6-9.
Table 6-9   
Management of Left Ventricular Dysfunction
Grade
Description
Dose Modification
1
Asymptomatic decline in
LVEF > 15% from baseline values OR;
LVEF > 10%-15% from baseline values and is 
below institution’s LLN
No change; continue MLN0128 + MLN1117 
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.


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Management of Patients with QTc Prolongation
Guidance for MLN0128 + MLN1117 dose adjustment for patients exhibiting a prolonged 
QTc is provided in Table 6-10.
Table 6-10   Management of QTc Prolongation
Grade
Description
Treatment
Dose Modification
2
480 msec 
QTc 501 
msec
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication, etc.)
None; continue MLN0128  + 
MLN1117 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 + MLN1117 should be 
interrupted.
The decision whether to reinitiate 
study drug 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 
study drug, and appear to have
benefitted from 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; msec = milliseconds; QTc = QT interval corrected for heart rate.
a A list of medications known to prolong QTc can be found at torsades.org and QTdrugs.org.
The procedures for acquiring and reviewing 12-lead ECGs are given in Section 7.4.12.
6.9.1.7   
Management of AST/ALT Elevations
Guidance on dose adjustment for patients with AST/ALT elevations is provided in 
Table 6-11.


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Table 6-11   Management of AST/ALT elevations
Grade
Description
Treatment
Dose Modification
1
> ULN - 3 ULN
None
None
2
Asymptomatic with levels 
3 - 5 ULN; > 3 ULN 
with the appearance of 
worsening fatigue, nausea, 
vomiting, right upper 
quadrant pain or tenderness, 
fever, rash, or eosinophilia

Closely monitor LFTs at 
least weekly or more 
frequently as indicated

Assess patient for other 
causes of transaminitis (eg, 
past medical history, 
concomitant medications)
None
3
> 5 - 20 ULN; > 5 ULN 
for > 2 weeks
Same as for Grade 2
Hold MLN0128 and MLN1117 
until ≤ Grade 1; Restart 
MLN0128 at the same dose; 
Restart MLN1117 at a 50% 
dose reduction
4
> 20 ULN
Same as for Grade 2
Stop MLN0128 + MLN1117 
and discontinue patient from the 
study
Prevention/Prophylaxis:
Ensure proper screening of patients for study participation.
Abbreviations:  LFTs = liver function tests; ULN = upper limit of normal.
6.9.1.8   
Management of Other Nonhematologic Toxicities
Guidance on dose adjustment for patients with other nonhematologic toxicities is provided 
in Table 6-12.


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Table 6-12   Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue)
Grade
Description
Treatment
Dose Modification
1
Mild; asymptomatic or mild 
symptoms; clinical or 
diagnostic observations only; 
intervention not indicated
Initiate appropriate medical 
therapy and monitor.
If tolerable, then no adjustment is 
required.
2
Moderate; minimal, local or 
noninvasive intervention 
indicated
Initiate appropriate medical 
therapy and monitor.

If tolerable, no adjustment 
required.

If toxicity becomes 
intolerable (or ≥ Grade 3), 
interrupt MLN0128 
+ MLN1117 dosing until 
recovery to ≤ Grade 1.  
Reinitiate combination with a 
≥ 1 dose level reduction of 
MLN1117.  If this dose 
adjustment does not provide 
sufficient relief, either 
MLN1117 or MLN0128 can 
be subsequently reduced.
≥ 3
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of 
hospitalization indicated
Interrupt MLN0128 +MLN1117 
dosing until recovery to 
≤Grade 1.  Reinitiate combination 
with a ≥1 dose level reduction of 
MLN1117.  If this dose 
adjustment does not provide 
sufficient relief, either MLN1117 
or MLN0128 can be subsequently 
reduced.
6.10   
Blinding and Unblinding
Not applicable.  This is an open-label study.
6.11   
Description of Investigational Agents
MLN0128 is available in 1 mg, 3 mg, and 5 mg capsules.  MLN1117 is available in 100 mg 
capsules.  See the MLN0128 + MLN1117 IB for full details.
6.12   
Preparation, Reconstitution, and Dispensation
MLN0128 and MLN1117 dosage forms will be provided in labeled bottles or blisters in 
accordance with all applicable regulations.  Materials provided by the sponsor should be 
dispensed to patients with clear administration instructions from the investigator.


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MLN0128 and MLN1117 are anticancer drugs, and, as with other potentially toxic 
compounds, caution should be exercised when handling MLN0128 and MLN1117.
6.13   
Packaging and Labeling
MLN0128 and MLN1117 are packaged in accordance with all applicable regulations.
6.14   
Storage, Handling, and Accountability
All investigational supplies will be kept in a secure area with controlled access and will be 
stored in their original packaging at labeled conditions.  All temperature excursions will be 
reported to the sponsor.  Containers will be kept closed during storage and will be used 
before the re-test date.
A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the patients, will be provided and kept at the study site.  Storage area 
temperature conditions must be monitored and recorded daily.  A daily temperature log will 
also be kept at the study site.
7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, good clinical practice (GCP), 
applicable regulatory requirements, and ICH guidelines.
7.1   
Study Personnel and Organizations
The contact information for the Millennium project clinician for this study, the central 
laboratory and any additional clinical laboratories, the coordinating investigator for each 
member state/country (where applicable), the Interactive Web Response System provider, 
and the contract research organization team may be found in the Study Manual.  A full list 
of investigators is available in the sponsor’s investigator database.
7.2   
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians.  If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  It is not envisioned that prisoners (or other 


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populations that might be vulnerable to coercion or exploitation) will be enrolled into this 
study.
7.3   
Treatment Group Assignments
In the Escalation Stage, patients will be divided into treatment arms that differ in 
combination dosing schedules to determine the MTDs and/or RP2Ds of MLN0128 + 
MLN1117 in each treatment arm.
Patients in the Expansion Stage will be enrolled into a single treatment arm, the dose and 
schedule of which will be specified prior to patient enrollment, to examine mutual DDI PK 
of MLN0128  and MLN1117.
7.4   
Study Procedures
Patients will be evaluated at scheduled visits over the following study periods:  screening, 
treatment, and EOS.  Evaluations during the screening period are to be conducted within 
28 days before administration of the first dose of study drug.  Procedures conducted during 
the screening period that are performed within 3 days of Cycle 1, Day 1 may also be used as 
the predose evaluation and do not need to be repeated, unless otherwise specified.  Unless 
otherwise noted, evaluations during the treatment period must occur before study drug 
administration.  Tests and procedures should be performed on schedule for all visits.  The 
timing of PK/pharmacodynamic assessments is specified in the Schedule of Events and is 
not flexible.  Laboratory assessments may occur 3 days of the scheduled day.  All EOS 
evaluations should occur within 30 (+10) days after the last dose of study drug, or before the 
start of subsequent antineoplastic therapy.
Refer to the Schedule of Events for timing of assessments.  Additional details are provided 
as necessary in the sections that follow.
7.4.1   
Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care.
7.4.2   
Patient Demographics
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7.4.3   
Medical History
During the screening period, a complete medical history will be compiled for each patient.  
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for it.  In addition, concomitant medications will be 
recorded as specified in Section 7.4.9.
7.4.4   
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.
7.4.5   
Patient Height and Weight
Height will be measured only during screening (within 28 days before the first dose of 
MLN0128 + MLN1117).
Weight will be measured during the times specified in the Schedule of Events.
7.4.6   
Vital Signs
Vital sign measurements include diastolic and systolic blood pressure, heart rate, and 
temperature.
7.4.7   
ECOG Performance Status
ECOG performance status is to be assessed at the times specified in the Schedule of Events.
7.4.8   
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening.  
A urine pregnancy test will be performed predose on Cycle 1, Day 1, and negative results 
must be available before the first dose may be administered.  A serum pregnancy test may 
also be performed within 3 days of dosing in place of the Cycle 1, Day 1 urine test.
7.4.9   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the electronic case report form (eCRF) from the first dose through 30 days after 
the last dose.  See Section 6.7 for a list of medications and therapies that are prohibited 
and/or allowed during the study.


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7.4.10   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events.  Refer to Section 9 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.
7.4.11   
Enrollment
A patient is considered to be enrolled in the study when the first dose of MLN0128 + 
MLN1117 has been administered
Procedures for completion of the enrollment information are described in the Study Manual.
7.4.12   
Electrocardiogram
ECGs will be performed locally.  A 12-lead ECG will be administered at the time points 
specified in the Schedule of Events.  All scheduled ECGs should be performed after the 
patient has rested quietly for at least 5 minutes in a supine position.  When the timing of a 
PK or safety laboratory blood sample coincides with the timing of ECG measurements, the 
ECG will be completed before the collection of the blood sample.  In some cases, it may be 
appropriate to repeat an abnormal ECG to rule out improper lead placement as contributing 
to the ECG abnormality.
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).  A list of medications 
known to prolong QTc can be found at torsades.org and QTdrugs.org.  If completed before 
study enrollment and if a repeat ECG meets eligibility requirements, the patient may enroll 
in the study upon review and agreement by the sponsor’s clinician.
If a QTc value is confirmed by a qualified reader as ≥ 501 msec for any ECG, the following 
will occur:

The sponsor’s clinician will be promptly notified.

MLN0128 + MLN1117 should be interrupted and an evaluation should be conducted to 
correct other possible causes (eg, electrolyte disturbance, concomitant medication).


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
A formal consultation by a cardiologist should be considered.  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.
The decision whether to reinitiate MLN0128  treatment with or without dose reduction and 
additional monitoring in those patients who had asymptomatic prolonged QTc ≥ 501 msec 
(Grade 3) that has reverted to an acceptable interval, have previously tolerated MLN0128, 
and appear to have benefitted from MLN0128  treatment with either disease control or 
response will be agreed to by the investigator and the sponsor’s clinician on a case-by-case 
basis.  See also Section 6.9.1.6.
7.4.13   
Echocardiogram or Multiple Gated Acquisition Scan
A MUGA scan or ECHO will be administered at the time points specified in the Schedule of 
Events.
7.4.14   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed locally.  Handling and shipment of clinical 
laboratory samples will be outlined in the Study Manual.  Clinical laboratory evaluations 
will be performed as outlined below:
Clinical Chemistry, Hematology, and Urinalysis
Blood samples for analysis of HbA1c and the following clinical chemistry and 
hematological parameters will be obtained along with urine samples for urinalysis as 
specified in the Schedule of Events.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (ANC)


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Chemistry

Blood urea nitrogen

Creatinine

Bilirubin (total)

Urate

Lactate 
dehydrogenase

Phosphate

Albumin

Alkaline phosphatase

AST

ALT

Glucose 

Sodium

Potassium

Calcium

Chloride

Carbon dioxide

Magnesium

Amylase
Urinalysis

Turbidity and Color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult Blood

Nitrite

Urobilinogen

Glucose

Leukocytes
Coagulation

Prothrombin time (PT)

International Normalized 
Ratio

Activated partial thromboplastin time 
(aPTT)
Blood sampling for coagulation assessments will be required within 24 hours before 
performing any skin biopsy or fresh tumor biopsy.
Fasting Glucose

Patients are required to fast overnight (nothing except water and/or medications after 
midnight) or for 8 hours minimum.

On Cycle 1, Day 1 and Cycle 1, Day 8, patients will be required to fast for 2 hours 
after dosing, until the completion of the 2 hour postdose fasting glucose sample.  On 
all other dosing days, the patient is only required to fast for 1 hour postdose.

Samples for fasting glucose will be obtained at the times specified in the Schedule of 
Events.
Fasting Insulin and Insulin C-Peptide Level

Patients are required to fast overnight (nothing except water and/or medications after 
midnight) or for 8 hours minimum.

On Cycle 1, Day 1 and Cycle 1, Day 8, patients in the Escalation Stage will be 
required to fast for 2 hours after dosing, until the completion of the 2-hour postdose 
fasting insulin and insulin C-peptide samples.  (The 4-hour and 8-hour postdose 
blood samples are non-fasting.)


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
Samples for fasting insulin and insulin C-peptide levels will be obtained at the times 
specified in the Schedule of Events.
Fasting Lipid Profile

Total cholesterol

Triglycerides

High density lipoprotein

Low density lipoprotein
Sampling for the fasting lipid profile will be obtained at the times specified in Schedule of 
Events.
In-Home Daily Fasting Glucose

In addition to obtaining fasting glucose levels at the clinic visits as outlined in the 
Schedule of Events, all patients will be given a glucometer to monitor their daily 
predose fasting blood glucose levels at home.

On Cycle 1, Day 2 (Escalation Stage) or Cycle 1, Day 3 (Expansion Stage), the 
patient will be provided an in-home glucometer.  Patients will be trained on proper 
use of the glucometer and instructed to collect a daily predose fasting glucose level 
every morning.  Patients will be instructed to bring the glucometer with them to each 
study visit so that the data collected can be reviewed and recorded in the source 
documents.  Investigators will be responsible for reviewing the home glucose 
monitoring logs for hyperglycemia.

The patient will be instructed to contact the site immediately if the value is abnormal 
(ie, 140 mg/dL, based on local ULN) for further instructions on the management 
of their hyperglycemia.  Hyperglycemia observed during home glucose monitoring 
should be confirmed in the clinic.

If no 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 140 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.

See also Section 6.9.1.1.
7.4.15   
Disease Assessment
Patients will undergo computed tomography (CT) with contrast as appropriate, magnetic 
resonance imaging (MRI), X-ray, and/or bone scanning to monitor and assess disease 
progression, using RECIST criteria (Version 1.1).(2)  Contrast CT scans of the chest, 
abdomen, and pelvis will be obtained at screening.  Specific disease sites that cannot be 
adequately imaged by CT may be documented by MRI.  Anatomical measurements 
(summed across target lesions) will be collected at baseline and each subsequent evaluation 


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using an imaging modality consistent with that used at screening.  Objective assessments 
will be performed at each time point as described in the Schedule of Events.  When possible, 
the same qualified physician will interpret results to reduce variability.  Radiographic 
images will be maintained at the site, and test results and physician’s findings will be filed in 
patient source documents.  Exceptions will be made for ovarian or prostate cancer patients 
with elevated tumor markers in the absence of measurable disease eligible to enroll in the 
Escalation Stage.  Such patients may be evaluated on the basis of CA-125 or prostate-
specific antigen, respectively.
7.4.16   
Biopsy Samples
During screening, a tumor pathology block (ie, tumor tissue obtained at the time of the 
patient’s original diagnosis and/or at the time of subsequent procedures conducted as part of 
the patient’s standard care) or freshly cut unstained slides, as described in the Study Manual, 
is required for patients in the Escalation Stage only.  If a paraffin-embedded tumor block or 
unstained slides are not available, the patient will be required to undergo a fresh tumor 
biopsy at screening as indicated in the Schedule of Events.  Patients who undergo biopsy of 
tumor tissue must have platelet counts greater than or equal to 75,000/mm3 and normal PT 
and aPTT within 24 hours before the biopsy and no history of excessive bleeding or of 
antiplatelet or anticoagulant therapy in the prior 7 days (eg, clopidogrel [Plavix®] or 
salicylates [aspirin]).  The tumor biopsy procedure will be performed by core needle, under 
radiological guidance if indicated, or surgically if the site of disease is superficial and 
palpable or visible.  If fresh tumor biopsy collection is unsuccessful, enrollment is 
contingent upon discussion with the sponsor.
Skin punch biopsies (approximately 2 mm in diameter) will be obtained as specified in 
Table A:  PK and Pharmacodynamic Assessment Schedule (Escalation Stage) in the 
Schedule of Events to detect the effect of MLN0128 + MLN1117 on pharmacodynamic 
markers in the epidermis.  On the day of the skin punch biopsy procedure, aPTT and PT 
must be within the normal range and the platelet count must be ≥20,000/mm3.  For skin 
biopsies on Day 25 of Cycle 1 of the Escalation Stage, aPTT and PT values obtained on 
Day 24 of Cycle 1 can be used.
The analysis methods of skin and tumor samples are described in Sections 7.4.18 and 7.4.20, 
respectively.  Detailed instructions for collection, processing, and shipment of the skin and 
fresh tumor biopsy samples are provided in the Study Manual.


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7.4.17   
PK Assessments
7.4.17.1   Escalation Stage Assessments
In the Escalation Stage, serial PK sampling to characterize the PK of MLN0128  and 
MLN1117 will occur on the following days in Cycle 1:  Day 1 (after first study drug dose) 
and Day 24 (after study drug dose).  Blood sampling will be performed at the times 
indicated in Table A:  PK and Pharmacodynamic Assessment Schedule (Escalation Stage).  
When the timing of a PK blood sample coincides with vital sign or ECG measurements, the 
vital sign or ECG measurement should be obtained before the PK blood sample.
The PK sampling schedules are presented to account for the possibility of either 
combination dosing schedule (ie, Treatment Arm A, Arm B, or Arm C) being selected in the 
Expansion Stage.
In addition to the PK sample collections specified, a blood sample to measure MLN0128  
and MLN1117 concentrations should be obtained, if clinically feasible, at the time of a 
serious or unusual AE that is judged by the investigator to be treatment-related, irrespective 
of the cycle, day, or stage of occurrence of the AE.  The date and exact time of the 
unscheduled sample collection should be recorded.  Details on the collection, storage, 
processing, handling, and shipping of PK samples are in the Study Manual.
7.4.17.2   Expansion Stage Assessments
In addition, patients in the Expansion Stage will provide urine samples for PK analysis 
during Cycle 1 at the time points specified in Table B:  PK Assessment Schedule (Expansion 
Stage:  Treatment Arm A) and Table C:  PK Assessment Schedule (Expansion Stage:  
Treatment Arm B and Arm C).  Samples will be collected as single predose voids and single 
cumulative 0- to 8-hour postdose duration samples on prespecified days during Cycle 1.
Timing for plasma and urine PK and skin pharmacodynamic assessments is found in 
Table B:  PK Assessment Schedule (Expansion Stage:  Treatment Arm A) and Table C:  PK 
Assessment Schedule (Expansion Stage:  Treatment Arm B and Arm C).  Investigators will 
be notified as to which treatment arm schedule to follow before the Expansion Stage begins.
Treatment Arm A:  MLN0128 QD and MLN1117 MWF QW
PK samples collected on Cycle 1, Day 5 will only be analyzed for MLN0128.  MLN1117 
plasma concentrations will not be measured in these samples.


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PK samples collected on Cycle 1, Day 12 will be analyzed for MLN0128 and MLN1117.
PK samples collected on Cycle 1, Day 19 will only be analyzed for MLN1117.  MLN0128 
plasma concentrations will not be measured in these samples.
Treatment Arm B and Arm C:  MLN1117 and MLN0128 Both Dosed MTuW QW
PK samples collected on Cycle 1, Day 3 will only be analyzed for MLN0128.  MLN1117 
plasma concentrations will not be measured in these samples.
PK samples collected on Cycle 1, Day 10 will be analyzed for MLN0128 and MLN1117.
PK samples collected on Cycle 1, Day 17 will only be analyzed for MLN1117.  MLN0128 
plasma concentrations will not be measured in these samples.
The PK sampling and bioanalysis plan will allow for assessment of any DDIs between 
MLN0128  and MLN1117.  Sampling on specified days, when both agents are 
coadministered, will be used to compare against the single-agent PK when each drug is 
administered alone in either treatment arm.
7.4.18   
Pharmacodynamic Assessments
Skin samples (punch biopsy) are to be collected in the Escalation Stage at the prespecified 
time points in the Schedule of Events and Table A:  PK and Pharmacodynamic Assessment 
Schedule (Escalation Stage).  Techniques used to evaluate the pharmacodynamic effect of 
MLN0128  + MLN1117 include, but are not limited to, monitoring of phosphorylation of 
molecules in the PI3K pathway, such as ribosomal protein S6 and AKT, in pre-and postdose 
samples.
7.4.19   
Pharmacogenomic Assessments
DNA extracted from blood samples obtained from all patients at screening will be evaluated 
for germline polymorphisms in CYP2C9 and CYP2C19 genes and may also be used to 
assess the impact of genetic polymorphisms on clinically important drug transporters, such 
as BCRP, organic anion-transporting polypeptide (OATP) 1B1, or OATP1B3, if either 
MLN0128 or MLN1117 is determined to be substrates of these transporters in future studies.  
Data from this study may be combined with data from previous and/or future studies to 
explore the relationship between MLN0128  and MLN1117 PK and the CYP2C9 and 
CYP2C19 genotypes.  DNA samples may be used as a comparator and evaluated for 
mutations detected in tumor samples.


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These analyses are not necessary for study closeout.  Detailed instructions for the collection, 
processing, and shipment of the blood samples are provided in the Laboratory Manual.
7.4.20   
Banked (Archived) Tumor Specimen Measurements
Banked formalin-fixed, paraffin-embedded tumor tissue (or fresh tumor biopsy as described 
in Section 7.4.16) should be obtained from patients in the Escalation Stage at screening for 
assessment of candidate biomarkers predictive of response, including, but not limited to 
somatic gene alterations and expression of tumor suppressor genes such as PTEN, tumor 
proliferation markers such as Ki-67, or diagnostic markers such as estrogen and 
progesterone receptors.  It is anticipated that developing these potential biomarkers of 
antitumor activity mediated by the combination of MLN0128 and MLN1117 will require 
analysis of the data from this study in combination with data from other clinical studies of 
this combination as well as each single agent.
7.5   
Completion of Study
Patients will be considered to have completed the study if they (1) complete 1 cycle of 
treatment with MLN0128 + MLN1117, (2) experience unacceptable toxicity during Cycle 1, 
or (3) experience progressive disease.
Patients who are withdrawn from treatment during Cycle 1 for reasons other than DLTs will 
be replaced.
In the absence of progressive disease or unacceptable toxicity, patients will be treated for a 
maximum of 12 months.  If beneficial for the patient, then further treatment with MLN0128 
+ MLN1117 may be permitted upon discussion with the sponsor.
7.6   
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up

Adverse event

Protocol violation

Symptomatic deterioration

Unsatisfactory therapeutic response


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
Study terminated by sponsor

Withdrawal by patient

Other

Progressive disease
Within 30 (10) days of the date of study drug discontinuation, all study procedures outlined 
for the EOS visit will be completed.  The primary reason for study drug discontinuation will 
be recorded in the eCRF.
Patients who are withdrawn from study during Cycle 1 for reasons other than a DLT will be 
replaced.
7.7   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing.  Patients will receive a sufficient 
quantity of MLN0128 and MLN1117 for each treatment cycle and a diary in which to record 
their dosing.  The study center staff will check the patient’s diary versus the patient’s supply 
of remaining MLN0128 and MLN1117 capsules at each study visit to ensure proper 
compliance with dosing.  Patients who are not compliant with the dosing schedule may be 
withdrawn from the study.
8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
Statistical analyses will be primarily descriptive and graphical in nature.  No formal 
statistical hypothesis testing will be performed.  The incidence of DLTs will be tabulated for 
each dose cohort.  Demographic and baseline characteristics will be summarized as 
appropriate.  Analysis of efficacy measures will be descriptive.  Disease response of 
MLN0128 + MLN1117 will be based on the best overall response defined using 
RECIST 1.1, when feasible.  A formal statistical analysis plan will be developed and 
finalized before database lock.


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8.1.1   
Determination of Sample Size
To estimate the number of patients for this study, it is assumed that 15% of enrolled patients 
will be non-evaluable.  Approximately 101 patients will be enrolled into this study.
Of the 101 evaluable patients estimated to be enrolled, approximately 81 will be enrolled 
into the Escalation Stage.  These patients will be divided into treatment arms which differ in 
combination dosing schedules to determine the MTDs and/or RP2Ds of MLN0128 + 
MLN1117 in each treatment arm.  The number of patients enrolled in the Escalation Stage 
was determined by estimating the number of dose combinations to be evaluated and the 
number of potential evaluable patients not experiencing a DLT.  It is estimated that 3 to 
6 patients will be evaluated at each dose level per treatment arm.
After the final doses and schedules have been selected, approximately 20 evaluable patients 
will be enrolled in the Expansion Stage to evaluate the mutual DDI PK for MLN0128 and 
MLN1117.
In the Expansion Stage, data from approximately16 of the 20 treated patients must satisfy 
specific criteria to be included in statistical analysis of the effect of MLN0128 
co-administration on MLN1117 PK and the effect of MLN1117 co-administration on 
MLN0128 PK.  If fewer than 16 patients meet these criteria, additional patients will be 
enrolled in the Expansion Stage to reach a minimum sample size of 16 patients.  Specific 
criteria for inclusion in the statistical analysis are provided in Section 8.1.7.1.
8.1.2   
Randomization and Stratification
For the Escalation Stage of the study, patients will be enrolled in successive dose cohorts as 
described in Section 6.4.  No randomization is planned for this study.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:

Safety population:  Patients who receive at least 1 dose of study drug will be used for 
all safety analyses as well as efficacy analyses as data allow.

PK DDI-evaluable population:  Patients from the Expansion Stage with sufficient 
dosing and concentration-time PK data to reliably estimate PK parameters for 
statistical analyses of the effect of MLN0128 on MLN1117 PK and the effect of 
MLN1117 on MLN0128 PK.


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
Pharmacodynamics population:  Patients with sufficient dosing data in Cycle 1 and 
sufficient skin or tumor data (collected within the protocol-specified window of 
sampling time) to reliably measure PD parameters.

Response-evaluable population:  Patients, who receive at least 1 dose of study drug, 
have measurable disease at baseline, and 1 postbaseline disease assessment will be 
used for analyses of response.

DLT-evaluable population:  Patients who either experience DLT during Cycle 1, or 
receive all scheduled doses and complete all study procedures in Cycle 1 without 
experiencing a DLT.
8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available efficacy and safety data will be included in data listings and tabulations.  No 
imputation of values for missing data will be performed.  The relevance of missing sample 
data will be assessed.
Data that are potentially spurious or erroneous will be examined according to standard data 
management operating procedures.
8.1.5   
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized, including gender, age, race, 
weight, height, body surface area, primary diagnosis, and other parameters as appropriate.  
No inferential statistics will be conducted.
8.1.6   
Efficacy Analysis
Patients will be assessed, if feasible, according to RECIST guidelines.  Analysis of efficacy 
measures will be descriptive.  Antitumor activity of MLN0128 + MLN1117 will be based on 
the best overall response.  Investigators will assess response using RECIST guidelines 
Version 1.1(2) at each time point.  The best overall response for each patient will be derived 
programmatically from among the reported responses.  Data listings will present the tumor 
measurements from CT or MRI (including changes from baseline), disease response 
category (eg, complete response, partial response, stable disease, duration of response and, 
as appropriate, tumor marker measurements).


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8.1.7   
PK/Pharmacodynamics/Biomarkers
8.1.7.1   
PK Analysis
The following analyses will be performed for patients in the PK population as data allow:

Plasma concentrations of MLN0128 and MLN1117 will be summarized by time 
postdose, and grouped by dose group, dosing cycle, and day.  Mean and individual 
plasma concentration-time profiles will be plotted by dose group and dosing cycle 
and day.

PK parameters will be calculated for MLN0128 and MLN1117 by 
noncompartmental analysis as permitted by the data.  These parameters will include, 
but will not be limited to, Cmax, Tmax, single-dose end of dosing interval (trough) 
concentration, AUClast, area under the plasma concentration versus time curve from 
zero to next dose (AUCτ), t1/2, apparent oral clearance, peak-to-trough ratio, renal 
clearance, and accumulation ratio.  As appropriate, these parameters will be 
summarized by dose group and dosing cycle and day.  Dose proportionality of Cmax 
and AUCτ may be assessed graphically and by regression analysis using a power 
model.
Expansion Stage
The following statistical analysis will be performed on PK data acquired in the Expansion 
Stage.  An analysis of variance will be performed with log-transformed Cmax and AUCτ as 
the dependent variables, treatment as the fixed effect, and patient as the random effect.  
Least-square mean ratios between the treatment states (MLN0128+ MLN1117 [Test]) versus 
MLN0128 or MLN1117 alone [Reference]) will be calculated along with 90% confidence 
intervals.  The comparisons made will depend on the combination dosing schedule that is 
eventually selected for the Expansion Stage following the determination of the combination 
MTDs in each treatment arm during the Escalation Stage.  Provided below are the options:
MLN0128 QD and MLN1117 MWF QW:  Cycle 1, Day 12 (MLN0128 + MLN1117) versus 
Cycle 1, Day 5 (MLN0128 only) or Cycle 1, Day 19 (MLN1117 only)
MLN1117 and MLN0128 both Administered MTuW QW:  Cycle 1, Day 10 (MLN0128 + 
MLN1117) versus Cycle 1, Day 3 (MLN0128 only) or Cycle 1, Day 17 (MLN1117 only)
A minimum of 16 patients must complete the protocol-specified dosing with both agents and 
PK assessments to provide sufficient plasma concentration-time data to determine the 


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MLN0128 and MLN1117 Cmax and AUClast to be included in statistical analyses of the effect 
of MLN0128 co-administration on MLN1117 PK and the effect of MLN1117 
co-administration on MLN0128 PK.
8.1.7.2   
Pharmacodynamic Analysis
Descriptive statistics, graphical methods, and statistical modeling, as appropriate, will be 
used to explore the relationship between response and the levels of various biomarkers.
As permitted by the data, the relationship between MLN0128 and MLN1117 plasma 
exposures and levels of skin and tumor pharmacodynamic markers measured by 
immunohistochemistry may be evaluated graphically to guide understanding of 
exposure-response relationships.
8.1.7.3   
Pharmacogenomic Analysis
Descriptive statistics and graphical methods may be used to explore the relationship between 
genotypes in drug metabolizing enzymes (and possibly transporters) that contribute to 
MLN0128 and MLN1117 disposition and selected PK parameters of MLN0128 and 
MLN1117.  Descriptive, statistical, and graphical methods, as appropriate, may also be used 
to explore the relationship between drug response to the combination and tumor genotype.
8.1.8   
Safety Analysis
The incidence of DLT will be tabulated for each dose group.  In addition, to assess the 
relationship between toxicities and MLN0128 + MLN1117 dose levels, the preferred term of 
individual toxicities will be summarized by their frequency and intensity for each dose 
group.  The DLT-evaluable population will be used for the analysis of DLT.
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baseline in the patient’s vital signs, weight, ECGs, and clinical laboratory results using 
the safety population.  Exposure to study drug and reasons for discontinuation will be 
tabulated.
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of study drug will be tabulated.


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AEs will be tabulated according to the Medical Dictionary for Regulatory Activities and will 
include the following categories: 

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

The most commonly reported treatment-emergent AEs (ie, those events reported by 
10% of all patients)

SAEs
A listing of treatment-emergent AEs resulting in study drug discontinuation will be 
provided.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change 
from baseline in clinical laboratory parameters) will be presented for all scheduled 
measurements over time.  Mean laboratory values over time will be plotted for key 
laboratory parameters.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs 
and weight over time will be tabulated by scheduled time point.
Shift tables for laboratory parameters will be generated based on changes in NCI CTCAE 
grade from baseline to the worst postbaseline value.  Graphical displays of key safety 
parameters, such as scatter plots of baseline versus worst postbaseline values, may be used 
to understand the MLN0128 + MLN1117 safety profile.
All concomitant medications collected from screening through the study period will be 
classified to preferred terms according to the World Health Organization drug dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities 
and to further define the safety profile of the MLN0128 + MLN1117 combination.


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8.1.9   
Interim Analysis
No formal interim analysis is planned.
8.2   
PK Modeling
MLN0128 and MLN1117 PK data collected in this study, together with PK data collected 
from previous and future studies, may contribute to population PK analysis.  The objectives 
of this analysis are to understand potential sources of PK variation, including 
patient-specific covariates (eg, age, gender, and renal and hepatic function) and to enable 
exploratory analysis of the relationships between PK and drug effects, including 
pharmacodynamics, clinical response, and safety.  If population PK analysis is considered 
feasible, the specifics of the modeling approaches will be described separately in a 
population PK analysis plan.  Results will be reported separately.
9.   
ADVERSE EVENTS
9.1   
Definitions
9.1.1   
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or patient 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 means any untoward medical occurrence in a patient or patient administered a 
pharmaceutical product; the untoward medical occurrence does not necessarily have a causal 
relationship with this treatment.  An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product whether or not it is related to the 
medicinal product.  This includes any newly occurring event, or a previous condition that 
has increased in severity or frequency since the administration of study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.


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9.1.3   
Serious Adverse Event Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.  
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or nonpathogenic, is 
considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using 
the NCI CTCAE, Version 4.03, effective date 14 June 2010.(1)  Clarification should be made 
between an 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 


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severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  For example, a 
white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 (severe) but 
may not be considered serious.  Seriousness (not intensity) serves as a guide for defining 
regulatory reporting obligations.
9.2   
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF (see Section 9.3 for the 
period of observation).  Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE.  When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs, and serious pretreatment events (as defined in Section 9.1) 
must be reported (see Section 9.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below).  This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event.  The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site.  A sample of the SAE Form may be found in the Study Manual.  
Follow-up information on the SAE or serious pretreatment event may be requested by 
Millennium.  SAE report information must be consistent with the data provided on the 
eCRF.
SAE Reporting Contact Information
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient 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).
Company Confidential Information


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For both serious and nonserious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010.(1)  The criteria are provided in the 
Study Manual.
Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question:  Is there a reasonable possibility that the AE is associated with the 
study drug?
9.3   
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:

AEs will be reported from start of dosing on Day 1 of Cycle 1 through 30 days after 
administration of the last dose of study drug and recorded in the eCRFs.

Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first 
dose of study drug, but will not be recorded in the eCRF.

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from the first dose of study drug through 30 days 
after administration of the last dose of study drug and recorded in the eCRF.  After 
this period, only related SAEs must be reported to the Millennium Department of 
Pharmacovigilance or designee.  SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).
9.4  
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug. The sponsor must also be contacted immediately by faxing a completed Pregnancy 
Form to the Millennium Department of Pharmacovigilance or designee (see Section 9.2).  
The pregnancy must be followed for the final pregnancy outcome.


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If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 9.2).  Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.
10.   
ADMINISTRATIVE REQUIREMENTS
10.1   
Good Clinical Practice
The study will be conducted in accordance with the ICH-GCP and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
study drug as described in the protocol and the IB.
10.2   
Data Quality Assurance
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the study for each study 
patient.  Study data will be entered into an eCRF by site personnel using a secure, validated, 
web-based electronic data capture (EDC) application.  Millennium will have access to all 
data upon entry in the EDC application.
Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution.  Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
10.3   
Electronic Case Report Form Completion 
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.


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


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10.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
10.8   
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies).  Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium.  Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients.  Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 
circumstances permit, to discuss the planned course of action.  Any departures from the 
protocol must be documented.
10.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
10.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator.  
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site.  Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.


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10.11   Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals
who identify a potential product complaint situation should immediately contact MedComm 
Solutions (see below) and report the event.  Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance 
from a Millennium Quality representative.
For Product Complaints,
call MedComm Solutions at
1-877-674-3784 (877 MPI DRUG) (for United States and Canada sites)
1-510-740-1273 (international number)
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed according to the procedures outlined in Section 9.2.
10.12   Closure of the Study
Within 90 days of the end of the study, the sponsor will notify the competent authorities and 
the IECs in all member states where the study is being carried out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical trial results will be 
submitted to the competent authorities and IECs in all member states involved in the study.
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause.  
Written notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:

Determination of unexpected, significant, or unacceptable risk to patients

Failure to enter patients at an acceptable rate

Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on interim analysis


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
Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
event that any access devices for the EDC application have been provided, these will be 
returned to Millennium once the site’s participation in the study has concluded.
Within 15 days of premature closure, Millennium must notify the competent authorities and 
IECs of any member state where the study is being conducted, providing the reasons for 
study closure. 
10.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.
11.   
USE OF INFORMATION
All information regarding MLN0128 + MLN1117 supplied by Millennium to the 
investigator is privileged and confidential information.  The investigator agrees to use this 
information to accomplish the study and will not use it for other purposes without consent 
from Millennium.  It is understood that there is an obligation to provide Millennium with 
complete data obtained during the study.  The information obtained from the clinical study 
will be used toward the development of MLN0128 + MLN1117 and may be disclosed to 
regulatory authority(ies), other investigators, corporate partners, or consultants as required.
Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.


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It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer-reviewed scientific or medical journal.  A Publications Group 
comprising Millennium employees and study investigators will be formed to oversee the 
publication of the study results, which will reflect the experience of all participating study 
centers.  Subsequently, individual investigators may publish results from the study in 
compliance with their agreements with Millennium.
A prepublication manuscript or abstract is to be provided to Millennium a minimum of 
30 days before the intended submission date of the manuscript or abstract to a publisher.  
Within 30 days after receipt by Millennium of the notification, Millennium shall inform the 
study centers whether it has objections to the publication for reasons including, but not 
limited to, those defined below:

If patentable patient matter is disclosed, the publication shall be delayed for a period 
not to exceed 90 days from Millennium’s receipt of the proposed publication to 
allow time for the filing of patent applications covering patentable patient matter.

If confidential information is contained in any proposed publication or public 
disclosure, such confidential information will be removed at Millennium’s request.
The overall principal investigator will be the last author on abstracts and publications of the 
data generated from this study.  Other authors will be listed according to number of patients 
enrolled to the study.  If the principal investigator has the highest enrollment, he/she may 
choose to be either first or last author.  This policy may be changed with the agreement of 
both the investigators and Millennium.


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12.   
INVESTIGATOR AGREEMENT
I have read Protocol C32001 Amendment 6:  A Multicenter, Open-label, Phase 1b Study of 
MLN0128 (an Oral mTORC1/2 Inhibitor) in Combination With MLN1117 (an Oral PI3Kα 
Inhibitor) in Adult Patients With Advanced Nonhematologic Malignancies
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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Kompier LC, Lurkin I, van der Aa MN, van Rhijn BW, van der Kwast TH, 
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[Electronic Resource] 2010;5(11):e13821.


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13.
Janku F, Tsimberidou AM, Garrido-Laguna I, Wang X, Luthra R, Hong DS, et al. 
PIK3CA mutations in patients with advanced cancers treated with PI3K/AKT/mTOR 
axis inhibitors. Molecular Cancer Therapeutics 2011;10(3):558-65.
14.
Laplante M, Sabatini, DM. mTOR Signaling in Growth Control and Disease. Cell 
2012;149(2):274-93.
15.
Jessen K, et al. INK128 Is a Potent and Selective TORC1/2 Inhibitor With Broad 
Oral Antitumor Activity. Mol. Cancer Therapy 2009;8(12):Abstract B148.
16.
Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, 
Moskatel E, et al. mTOR kinase inhibition causes feedback-dependent biphasic 
regulation of AKT signaling. Cancer Discov 2011;1(3):248-59.
17.
Burris HA, 3rd. Overcoming acquired resistance to anticancer therapy: focus on the 
PI3K/AKT/mTOR pathway. Cancer Chemother Pharmacol 2013.
18.
Tabernero J, Rojo F, Calvo E, Burris H, Judson I, Hazell K, et al. Dose- and 
schedule-dependent inhibition of the mammalian target of rapamycin pathway with 
everolimus: a phase I tumor pharmacodynamic study in patients with advanced solid 
tumors. J Clin Oncol 2008;26(10):1603-10.
19.
Le Tourneau C, Lee JJ, Siu LL. Dose escalation methods in phase I cancer clinical 
trials. Journal of the National Cancer Institute 2009;101(10):708-20.
20.
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.
21.
The Criteria Committee of New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, 
Brown & Co; 1994.


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14.   
APPENDICES
14.1   
Cockcroft-Gault Equation
Creatinine Clearance  =
0.85 (140 - age [years]) weight [kg]
72 (serum creatinine [mg/dL])
OR
0.85 (140 - age [years]) weight [kg]
0.81 (serum creatinine [µmol/L])
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.
14.2   
Eastern Cooperative Oncology Group Scale for Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours.
3
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair
5
Dead
Source:  Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.(20)


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14.3   
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations 
of physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or 
anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort.  Symptoms of heart 
failure or the anginal syndrome may be present even at rest.  
If any physical activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels.  9th Ed.  Boston, MA:  Little, Brown & Co; 1994:253-256.(21)


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14.4   
List of Relevant Cytochrome P450 Inhibitors and Inducers
Moderate CYP1A2 Inhibitors
cimetidine
methoxsalen 
Strong CYP1A2 Inhibitors
fluvoxamine
ciprofloxacin
Clinically Significant Enzyme Inducers
carbamazepine
rifabutin
St. John’s wort
phenobarbital
rifampin
phenytoin
rifapentine 
Source: fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm.
Note that these lists are not exhaustive.
14.5   
List of Breast Cancer Resistance Protein, Organic Cation Transporter 
Proteins 1 and 2 Substrates
BCRP, OCT1, and OCT2 Substrates
BCRP Substrates
OCT1 and OCT2 Substrates
Methotrexate
metformin
Imatinib
cimetidine
Topotecan
amantadine
Lapatinib
famotidine
Rosuvastatin
pindolol


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14.6   
Amendment 1 Rationale and Purposes
Rationale for Amendment 1
The MLN0128 in Combination with MLN1117 C32001 protocol was amended to provide 
further guidance on use of certain concomitant medications and clarification on the analysis 
of PK samples in the Mutual DDI PK Expansion Cohort.
Purposes for Amendment 1
The purposes of this amendment were to:

Provide further guidance on the use of concomitant medications that are substrates of 
BCRP, OCT1, and OCT2

Provide clarification on the PK sample analysis in the Mutual DDI PK Expansion 
Cohort

Improve the order of assessments in the Schedule of Events table

Correct an error regarding dose escalation

Delete a repeated sentence regarding biopsy samples

Correct typographical errors, punctuation, grammar, and formatting
14.7   
Amendment 2 Rationale and Purposes
Rationale for Amendment 2
The primary purpose of this amendment was to adjust the dose escalation schedule on the 
basis of tolerability data from the initial cohorts (Treatment Arm A, Cohorts 1A and 2A).  
Dose escalation and the initiation of additional cohorts were stopped because the study drug 
combination in Cohort 2A was not tolerable.  A third treatment arm was added, and the dose 
escalation plan was updated.  On the basis of PK profiles and operational considerations, a 
third skin biopsy was added.  Additionally, cardiac- and pulmonary-related exclusion criteria 
were updated.  The definition of blood glucose (serum versus plasma) and Cycle 1 fasting 
requirements after study drug administration were clarified.  SAE and product complaint 
reporting information was aligned with current procedures.
Purposes for Amendment 2
The purposes of this amendment were to:

Add a skin biopsy sample on Cycle 1, Day 24 at 8 hours postdose (Treatment Arm B 
and Arm C); add a PK sample and skin biopsy (Treatment Arm A) at 2 hours postdose 
on Cycle 1, Day 25; and specify a window for PK samples when obtained at the same 
time as skin biopsy samples

Update data for clinical Study INK1117-001

Update physiochemical properties of MLN1117


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
Add a description of the initial clinical experience with MLN0128 in combination with 
MLN1117

Simplify the description of the study rationale, incorporate the protocol amendment 
rationale on the basis of initial clinical experience with MLN0128 in combination with 
MLN1117, and incorporate an additional treatment arm (Treatment Arm C)

Align the primary safety endpoint with corresponding statistical analyses

Specify the process for selection of the dose and schedule for the Mutual Drug-Drug 
Interaction PK cohort and the tumor-specific cohorts

Clarify the number of patients to be enrolled in the study, and remove redundant 
references to patient numbers throughout the protocol

Update cardiac- and pulmonary-related exclusion criteria

Create a separate section for study drug administration instructions for the Mutual 
Drug-Drug Interaction PK cohort and add links to Table B and Table C in the Schedule 
of Events

Adjust the dose escalation plan and dosing group assignments on the basis of initial 
safety and tolerability data from Treatment Arm A (Cohorts 1A and 2A) and to reflect 
the addition of Treatment Arm C

Update dose modification guidelines to align with available capsule strengths

Clarify the use of concomitant neutralizing antacids on days when study drug is not 
administered

Specify the availability of 100 mg capsules only and remove reference to 50 mg 
capsules of MLN1117

Remove reference to patients continuing in the study with written permission from the 
sponsor

Clarify that on Cycle 1, Day 1 and Cycle 1, Day 8, patients will be required to fast for 
2 hours after dosing, until the completion of the 2-hour postdose fasting glucose, 
insulin, and insulin C-peptide samples

Specify that the 4-hour and 8-hour postdose blood samples for insulin and insulin C-
peptide are nonfasting

Clarify the definition of blood glucose (serum vs plasma)

Remove the specification for a minimum of 10 slides of tumor tissue at study entry 

Replace the specification that the consequence of study withdrawal is that no new 
information will be collected and specify that within 30 days (+ 10 days) of study drug 
discontinuation, the EOS visit will be completed

Update SAE reporting information to align with current Millennium standards

Update product complaints information to align with current Millennium standards

Add an appendix to specify the Cockcroft-Gault formula for calculated creatinine 
clearance

Correct typographical errors, abbreviations, punctuation, grammar, and formatting


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14.8   
Amendment 3 Rationale and Purposes
Rationale for Amendment 3
The primary purpose of this amendment was to extend the period of contraception duration, 
based on teratogenic and abortive effects identified during preclinical embryofetal studies in 
rats.  Additionally, SAE and product complaint reporting information was aligned with 
current procedures.  Language referencing the efficacy of MLN0128 compared to approved 
rapalogs was also removed.  When referencing Cohort 2A, the dose evaluated under 
Protocol Amendment 1, at which the study drug combination was not tolerable, was 
specified.
Purposes for Amendment 3
The purposes of this amendment were to:

Delete reference to the efficacy of MLN0128 compared to approved rapalogs

Specify the dose evaluated in Cohort 2A, under Protocol Amendment 1, at which the 
study drug combination was not tolerable

Extend the period of contraception duration from 30 days to 90 days after the last dose 
of study drug, based on teratogenic and abortive effects identified during preclinical 
embryofetal studies in rats

Update SAE reporting information to align with current Millennium standards

Correct typographical errors, punctuation, grammar, and formatting


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14.9   
Amendment 4 Rationale and Purposes
Rationale for Amendment 4
The purpose of this amendment was to add an inclusion criterion for LVEF that must be 
within 5 absolute percentage points of the institutional standard of normal as measured by 
ECHO or MUGA scan within 4 weeks before the first study drug administration.  
Additionally, the time before patients must be discontinued from the study for MLN0128-
and/or MLN1117-related toxicities was reduced, and the criteria for dose interruption during 
Cycle 1 of the Escalation Stage was aligned with the general dose modification guidelines.  
Additionally, assessment windows and values in Section 7.4, Study Procedures, were 
aligned with the Schedule of Events.
Purposes for Amendment 4
The purposes of this amendment were to:

Add an inclusion criterion for LVEF within 4 weeks before the first study drug 
administration and simplify the corresponding study design procedure

Reduce the time before patients must be discontinued from the study for MLN0128-
and/or MLN1117-related toxicities to > 14 days

Align the criteria for dose interruption during Cycle 1 of the Escalation Stage with 
general dose modification guidelines such that if a patient experiences a DLT, 
treatment should be interrupted

Align ECG rate QTc value with that provided in Table 6-10, Management of QTc 
Prolongation

Align the window for EOS assessments in Section 7.4, Study Procedures, with the 
Schedule of Events

Specify that if a QTc value 501 is confirmed, both MLN0128 + MLN1117 should be 
interrupted 

Align the value that platelet count must be ≥20,000/mm3 for skin biopsies in 
Section 7.4.16, Biopsy Samples, with the Schedule of Events

Correct typographical errors, punctuation, grammar, and formatting


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14.10   Amendment 5 Rationale and Purposes
Rationale for Amendment 5
The primary purpose of this amendment was to modify the design and assessments for the 
expansion stage of Study C32001.  Design modifications included elimination of the tumor-
specific cohorts from the Expansion Stage and reduction of the study’s planned sample size 
to account for this change.  Assessment modifications for the Expansion Stage included
reduction of 12-lead electrocardiogram (ECG) and glycosylated hemoglobin (HbA1c) 
frequency, removal of fasting insulin and insulin c-peptide monitoring, and rescheduling of 
assessments originally planned for Cycle 1, Day 2 to Cycle 1, Day 3.
Purposes for Amendment 5
The specific purposes of this amendment were as follows:

Remove the tumor-specific cohorts from the expansion stage, update relevant text 
references and the planned study sample size accordingly, and simplify references to 
the “mutual drug-drug interaction expansion cohort” to “expansion stage”.

Remove fasting insulin and insulin c-peptide level monitoring during the Expansion 
Stage.

Modify the schedule of ECG assessments so that ECGs are conducted only on 
Days 1, 8, 15, and 22 during the Expansion Stage.  Additionally, ECGs scheduled for 
4 hours postdose were removed from the planned assessments for the Expansion Stage.

Reschedule procedures planned for Cycle 1, Day 2 during the Expansion Stage (ie, 
clinical chemistry assessment, fasting glucose assessment, and distribution of a 
glucometer for in-home daily fasting glucose monitoring) to Cycle 1, Day 3.

Clarify that patients participating in the Expansion Stage do not need to provide tumor 
tissue at screening or skin biopsies for pharmacodynamic assessment.

Remove HbA1c assessment as part of the chemistry laboratory panel to allow for 
reduced assessment frequency (ie, at baseline and every 3 cycles thereafter).

Update the discussions of clinical experience with MLN0128 and MLN1117.

Correct typographical errors, punctuation, grammar, and formatting.


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14.11   Amendment 6 Detailed Summary of Changes
The primary sections of the protocol affected by the changes in Amendment 6 are indicated. 
The corresponding text has been revised throughout the protocol.
Change 1: Remove the exclusion criterion relating to treatment with strong CYP inhibitors 
or inducers.
The primary change occurs in Section 5.2 Exclusion Criteria #16:
Deleted 
text:
16. Patients who are taking strong or moderate CYP3A4 inhibitors, strong 
CYP2C9 or CYP2C19 inhibitors or clinically significant inducers of CYPs 3A4, 
2C9, or 2C19 within 14 days of the first dose of MLN0128 + MLN1117, or 
patients who require treatment with these agents during the trial (See Section 6.7
for a list of these drugs.)
Rationale for Change:
This change, which removes enrollment restrictions for patients taking CYP3A4, CYP2C9, 
or CYP2C19 inhibitors and/or inducers in this study, was made to allow for more flexibility 
in patient enrollment based on updated data on MLN0128 metabolism by specific CYP 
isoforms.


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Change 2: Update the list of concomitant medications prohibited during the study.
The primary change occurs in Section 6.7 Excluded Concomitant Medications and 
Procedures:
Initial wording:
MLN1117 is primarily metabolized by CYP3A4 (72%), with 
minor contributions from CYPs 1A2 (12%), 2C9 (9%), and 2C8 
(6%); whereas, MLN0128 is metabolized by enzymes 
CYP2C19 (35%), CYP3A4 (28%), and 2C9 (28%).  
Consequently, induction of CYP3A, 2C19, and 2C9 enzymes by 
co-administered drugs can potentially result in decreased 
MLN1117 and MLN0128 exposures with the associated risk of 
decreased efficacy of MLN1117 and MLN0128.  Conversely, 
inhibition of these enzymes can potentially result in increased 
MLN1117 and MLN0128 exposures and thus increase the risk 
for toxicity.  Therefore, use of strong and moderate inhibitors of 
CYP3A, strong inhibitors of CYP2C9, strong inhibitors of 
CYP2C19, and clinically significant inducers of CYP3A/2C 
enzymes are not permitted during the study.  Accordingly, the 
following concomitant medications are excluded:

CYP3A, 2C9, and 2C19 inducers:  rifampin, rifapentine, 
rifabutin, phenytoin, carbamazepine, oxcarbazepine, 
phenobarbital, primidone, St. John’s Wort, bosentan, 
nafcillin, and modafinilCYP3A, 2C9, and 2C19 
inhibitors:  ketoconazole, itraconazole, voriconazole, 
posaconazole, boceprevir, telaprevir, fluconazole, 
clarithromycin, telithromycin, troleandomycin, 
erythromycin, nefazodone, mibefradil, conivaptan, 
diltiazem, verapamil, dronedarone, aprepitant, 
casopitant, tofisopam, ciprofloxacin, amiodarone, 
fluvoxamine, and ticlopidine
….

[…]Examples of histamine H2 receptor antagonists 
include ranitidine, famotidine, nizatidine, and 
cimetidine.


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Amended 
or new 
wording:
MLN1117 is primarily metabolized by CYP3A4 (72%), with minor 
contributions from CYPs 1A2 (12%), 2C9 (9%), and 2C8 (6%); whereas, 
MLN0128 is metabolized by enzymes CYP2C19 (35%), CYP3A4 (28%), and 
2C9 (28%).  Consequently, induction of CYP3A, 2C19, and 2C9 enzymes by co-
administered drugs can potentially result in decreased MLN1117 and MLN0128 
exposures with the associated risk of decreased efficacy of MLN1117 and 
MLN0128.  Conversely, inhibition of these enzymes can potentially result in 
increased MLN1117 and MLN0128 exposures and thus increase the risk for 
toxicity.  Recently completed in vitro metabolism experiments in human 
hepatocytes using 14C-labeled MLN0128 suggest that the risk of a drug-drug 
interaction between MLN1117 and MLN0128 is considered to be low (see 
Section 1.5.1.1).
Therefore, use of Strong and moderate CYP1A2 inhibitors of CYP3A, strong 
inhibitors of CYP2C9, strong inhibitors of CYP2C19, and clinically significant
and CYP inducers should be administered with caution and at the discretion 
of the investigator.  See Appendix 14.4 for a list of these agents. Alternative 
treatments, if available, should be considered. CYP3A/2C enzymes are not 
permitted during the study.  Accordingly, the following concomitant medications 
are excluded:

CYP3A, 2C9, and 2C19 inducers:  rifampin, rifapentine, rifabutin, 
phenytoin, carbamazepine, oxcarbazepine, phenobarbital, primidone, St. 
John’s Wort, bosentan, nafcillin, and modafinil

CYP3A, 2C9, and 2C19 inhibitors:  ketoconazole, itraconazole, 
voriconazole, posaconazole, boceprevir, telaprevir, fluconazole, 
clarithromycin, telithromycin, troleandomycin, erythromycin, 
nefazodone, mibefradil, conivaptan, diltiazem, verapamil, dronedarone, 
aprepitant, casopitant, tofisopam, ciprofloxacin, amiodarone, 
fluvoxamine, and ticlopidine
[…]

[…]Examples of histamine H2 receptor antagonists include ranitidine, 
famotidine, and nizatidine, and cimetidine.  Cimetidine, a moderate 
CYP1A2 inhibitor, is not recommended as a first choice H2 receptor 
antagonist (see Appendix 14.4).


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Rationale for Change:
This change was made to update the recommendations on concomitant medication use 
during the study based on MLN0128 metabolism by specific CYP isoforms.
Change 3: Update the list of relevant CYP inhibitors and inducers.
The primary change occurs in Appendix 14.4 List of Relevant Cytochrome P450 Inhibitors 
and Inducers:
Description 
of the 
change:
The list of relevant CYP inhibitors and inducers was updated to remove sections 
listing strong CYP2C19 inhibitors and strong CYP3A4 inhibitors; to add a 
section listing strong and moderate CYP1A2 inhibitors; and update the section 
listing clinically significant enzyme inducers.
Rationale for Change:
This change was made for consistency with updated data on MLN0128 metabolism by 
specific CYP isoforms.


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Change 4: Update the description of potential drug-drug interactions.. 
The primary change occurs in Section 1.5.1.1 Drug Interaction Risk With :
Initial 
wording:
In vitro metabolism experiments using recombinant CYP isoforms have 
shown that MLN1117 is metabolized by CYPs 3A4, 1A2, 2C8, and 2C9 
with relative contributions of 72%, 12%, 6%, and 9%, respectively.  
Therefore, it is possible that clinically significant inhibitors (eg, strong, 
moderate inhibitors) or inducers of CYP3A4 may produce increases or 
decreases in MLN1117 systemic exposures, respectively.  Accordingly, 
concomitant use of strong or moderate CYP3A4 inhibitors/inducers is not 
permitted in this study.
Amended or 
new wording:
In vitro metabolism experiments using recombinant CYP isoforms have 
shown that MLN1117 is metabolized by CYPs 3A4, 1A2, 2C8, and 2C9 
with relative contributions of 72%, 12%, 6%, and 9%, respectively.  
Recently completed in vitro metabolism experiments in human 
hepatocytes using 14C-labeled MLN0128 suggest that MLN0128 is 
metabolized primarily via CYP1A2 (approximately 31% to 40%), with 
a minor contribution from CYP3A4 (approximately 11% to 22%). 
These data suggest that MLN0128 is also metabolized by direct 
glucuronidation (approximately 22%) and an unidentified non-uridine 
diphosphate glucuronosyltransferase pathway (approximately 18%). 
The new data differ from the previous in vitro CYP phenotyping data 
obtained using recombinant CYP enzymes, which suggested the 
involvement of CYP2C9 (approximately 35%), CYP2C19 
(approximately 28%), and CYP3A4 (approximately 28%) in MLN0128 
metabolism. 
In addition, physiologically based PK modeling and simulation using 
the new metabolism data for MLN0128 suggest that the risk for a 
metabolism-based drug-drug interaction with MLN0128 appears to be 
low. Therefore, it is possible that clinically significant inhibitors (eg, strong, 
moderate CYP1A2inhibitors) or and CYP inducers of CYP3A4 may 
produce increases or decreases in MLN1117 systemic exposures, 
respectively (see Appendix 14.4) should only be administered with 
caution and at the discretion of the investigator during the study.  
Alternative treatments, if available, should be considered. Accordingly, 
concomitant use of strong or moderate CYP3A4 inhibitors/inducers is not 
permitted in this study.
Rationale for Change:
This paragraph was amended to describe updated data on MLN0128 metabolism by specific 
CYP isoforms.
The following sections also include this change:

Section 1.5.1.2 Drug Interaction Risk With MLN1117.

Section 6.7 Excluded Concomitant Medications and Procedures.


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Change 5: Remove dietary restrictions related to CYP inhibitors and inducers.
The primary change occurs in Section 6.7 Excluded Concomitant Medications and 
Procedures: 
Deleted 
text:

In addition to the above medications, consumption of grapefruit or 
grapefruit juice is not permitted during the study.  Patients should not 
consume food or beverages containing the fruit or juice of grapefruits or 
Seville oranges within 7 days before the first dose of study drug and 
throughout the study.
Rationale for Change:
This change was made for consistency with new data that removes the necessity for 
restrictions concerning CYP2C9 and 2C19.
The following sections also contain this change:

Section 6.8 Precautions and Restrictions.

Appendix 14.4 List of Relevant Cytochrome P450 Inhibitors and Inducers.
Change 6: Insert language to reduce the required frequency of radiographic disease 
assessments for patients who have received at least 1 year of continuous MLN0128 
treatment per protocol.
The primary change occurs in footnote “u” the Schedule of Events.
Added text:
For long term patients, defined as study participation ≥1 year, a CT 
(with contrast)/MRI of chest, abdomen, and pelvis will be obtained at 
intervals of up to every 4 cycles (plus or minus 7 days) as clinically 
indicated.
Rationale for Change:
The change was made to reduce the burden for long-term patients.


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Protected Personal 
Data

SAP_000.pdf: 


• Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title:  Multicenter, Open-label, Phase 1b Study of MLN0128 (an Oral mTORC1/2 Inhibitor) in 
Combination With MLN1117 (an Oral PI3Kα Inhibitor) in Adult Patients With Advanced 
Nonhematologic Malignancies
NCT Number: NCT01899053
SAP Approve Date: 18 Aug 2016
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 information or 
company confidential information. 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
ORRDORTITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: C32001
A Multicenter, Open-label, Phase 1b Study of MLN0128 (an Oral mTORC1/2 Inhibitor) in 
Combination With MLN1117 (an Oral PI3Kα Inhibitor) in Adult Patients With Advanced 
Nonhematologic Malignancies
PHASE 1
Version: FINAL
Date: 18 Aug 2016
Prepared by:
Based on:
Protocol Version:  Amendment 4
Protocol Date: 02 April 2014
CONFIDENTIAL PROPERTY OF TAKEDA
This document is a confidential communication of Takeda. Acceptance of this document 
constitutes the agreement by the recipient that no information contained herein will be published 
or disclosed without written authorization from Takeda.
Protected Personal Data


Protected Personal Data


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2.0
TABLE OF CONTENTS
1.0
ORRDORTITLE PAGE ..................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................3
3.0
LIST OF ABBREVIATIONS..........................................................................................5
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Exploratory Objectives ..............................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS.............................................................................................10
5.1
Primary Endpoints ...................................................................................................10
5.2
Secondary Endpoints ...............................................................................................10
5.3
Exploratory Endpoints .............................................................................................10
6.0
DETERMINATION OF SAMPLE SIZE.......................................................................11
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................12
7.1
General Principles....................................................................................................12
7.1.1
Conventions for Missing Adverse Event Dates...................................................12
7.2
Analysis Sets ...........................................................................................................13
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................14
7.6
Medication History and Concomitant Medications...................................................14
7.7
Study Drug Exposure and Compliance.....................................................................14
7.8
Efficacy Analysis.....................................................................................................15
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................16
7.9.1
Pharmacokinetic Analysis ..................................................................................16
7.9.2
Pharmacodynamic Analysis ...............................................................................18
7.10
Other Outcomes.......................................................................................................19
7.10.1 Pharmacogenomic Analysis ...............................................................................19
7.11
Safety Analysis........................................................................................................19
7.11.1 Adverse Events ..................................................................................................20
7.11.2 Clinical Laboratory Evaluations .........................................................................22
7.11.3 Vital Signs .........................................................................................................23
7.11.4 12-Lead ECGs ...................................................................................................24


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7.11.5 Other Observations Related to Safety.................................................................24
7.12
Interim Analysis ......................................................................................................24
7.13
Changes in the Statistical Analysis Plan...................................................................24
8.0
OTHER.........................................................................................................................26


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3.0
LIST OF ABBREVIATIONS
4EBP1
4E-binding protein
AE
adverse event
AKT
protein kinase B (PKB)
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration versus time curve
AUC24h
area under the plasma concentration versus time curve from zero to 
24 hours
AUCinf
area under the plasma concentration versus time curve from zero to 
infinity
AUClast
area under the concentration-time curve from time 0 to the end of the 
dosing interval
AUCτ
area under the plasma concentration versus time curve from zero to 
next dose
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
Cmax
single-dose maximum (peak) concentration  
CR
complete response 
CRF
case report form
DDI
drug-drug interaction
DLT
dose limiting toxicity 
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
EOS
End of Study (visit)
LDH
lactate dehydrogenase
LLN
lower limit of normal
MedDRA
Medical Dictionary for Regulatory Activities
MTuW
Monday, Tuesday, Wednesday (dosing schedule)
MWF
Monday, Wednesday, Friday (dosing schedule)
MTD
maximum tolerated dose
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse
Events
ORR
Overall response rate


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PD
pharmacodynamics
PI3K
phosphoinositol-3-kinase
PK
pharmacokinetics
PR
partial response
QD
quaque die; each day; once daily
QT
QT interval (millisec) of electrocardiograph
QTc
rate-corrected QT interval (millisec) of electrocardiograph
QW
once weekly
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
stable disease
S6
ribosomal protein S6 kinase
t1/2
terminal disposition half-life
ULN
upper limit of normal
WHO
World Health Organization
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4.0
OBJECTIVES
4.1
Primary Objectives
!
To evaluate the safety profile and to determine DLTs, MTDs and/or RP2Ds, and dosing 
schedules of oral MLN0128 + MLN1117 in patients with advanced nonhematologic 
malignancies
!
To characterize the single- and multiple-dose plasma PK of MLN0128 + MLN1117 in 
patients with advanced nonhematologic malignancies
4.2
Secondary Objectives
!
To evaluate evidence of antitumor activity of MLN0128 + MLN1117
4.3
Exploratory Objectives
!
!
!
4.4
Study Design
This study is a multicenter, open-label, phase 1b trial of MLN0128 (an oral mTORC1/2 
inhibitor) in combination with MLN1117 (an oral inhibitor of the PI3K∀isoform) when 
administered to adult patients with advanced nonhematological malignancies for whom standard, 
curative, or life-prolonging anticancer treatment does not exist or is no longer effective.  The 
study will consist of 2 stages:  a (dose) Escalation Stage followed by an Expansion Stage.  In the 
Escalation Stage, 2 dosing regimens for the combination will be evaluated in separate treatment 
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Statistical Analysis Plan
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arms.  The phrase “study drug” or “MLN0128 + MLN1117” refers to combination dosing of 
MLN0128 + MLN1117.
In the Escalation Stage, patients will be enrolled into dose escalation cohorts at different 
combination doses and schedules of MLN0128 and MLN1117 using a standard 3 + 3 approach 
to determine the maximum tolerated doses (MTDs) and/or recommended phase 2 doses (RP2Ds) 
in each treatment arm and optimal dosing schedules to be implemented in the Expansion Stage.  
Study drug will be administered in 28-day cycles.  In Treatment Arm A, MLN0128 will be 
administered once daily every day (QD) and MLN1117 will be administered once daily on 
Monday, Wednesday, and Friday (MWF) of each week.  In Treatment Arm B and Arm C, both 
MLN0128 and MLN1117 will be administered QD on Monday, Tuesday, and Wednesday 
(MTuW) of each week.
Patients will be enrolled in the Expansion Stage to further characterize the safety, tolerability, 
PK, and pharmacodynamics of MLN0128 in combination with MLN1117.  This stage will 
consist of a Mutual DDI PK Expansion Cohort and tumor-specific cohorts.  The combination 
dose and schedule from 1 of the treatment arms evaluated in the Escalation Stage will be 
implemented in the Mutual DDI PK Expansion Cohort.  The combination of doses and schedules 
from any of the treatment arms evaluated in the Escalation Stage may be implemented in each 
individual tumor-specific expansion cohort.  The tumor types selected for evaluation in the 
Expansion Stage will be based on safety and antitumor activity observed during Study C32001, 
by the emerging results of other MLN0128 and/or MLN1117 clinical studies, and by emerging 
data from nonclinical experiments.  Likewise, the schedules for combination dosing in an 
individual tumor-specific cohort of the Expansion Stage will be based on clinical observations 
made during the Escalation Stage.  The dose, schedule, and selection of tumor types for the 
tumor-specific cohorts will be identified in a protocol amendment.  
Toxicity will be evaluated according to National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010.  AEs will be 
assessed, and laboratory values, vital signs, physical exam findings, and electrocardiograms 
(ECGs) will be obtained to evaluate the safety and tolerability of MLN0128 + MLN1117.
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5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoints
!
AEs, SAEs, assessments of clinical laboratory values, physical exam findings, 
electrocardiograms (ECGs), and vital sign measurements
!
MLN0128 and MLN1117 plasma PK parameters including, but not limited to, Cmax, Tmax, 
area under the concentration-time curve from time 0 to the end of the dosing interval 
(AUClast), t1/2, apparent oral clearance (CL/F), peak-to-trough ratio, and accumulation 
ratio
5.2
Secondary Endpoints
!
Measures of disease response including objective response rate and duration of response, 
based on investigator’s assessment and using if feasible, the Response Evaluation Criteria 
in Solid Tumors (RECIST) guideline (version 1.1)
5.3
Exploratory Endpoints
!
!
!
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6.0
DETERMINATION OF SAMPLE SIZE
To estimate the number of patients for this study, it is assumed that 15% of enrolled patients will 
be non-evaluable.  Approximately 152 patients will be enrolled into this study.
Of the 152 patient estimated to be enrolled, approximately 72 will be enrolled into the Escalation 
Stage.  These patients will be divided into treatment arms which differ in combination dosing 
schedules to determine the MTDs and/or RP2Ds of MLN0128 + MLN1117 in each treatment 
arm.  The number of patients enrolled in the Escalation Stage was determined by estimating the 
number of dose combinations to be evaluated and the number of potential evaluable patients not 
experiencing a DLT.  It is estimated that 3 to 6 patients will be evaluated at each dose level per 
treatment arm.
After the final doses and schedules have been selected, approximately 80 patients will be 
enrolled in the Expansion Stage.  This stage will consist of a Mutual DDI PK Expansion Cohort 
and tumor-specific cohorts.  
In the Mutual DDI PK Expansion Cohort of the Expansion Stage, data from approximately 16 of 
the 20 treated patients must satisfy specific criteria to be included in statistical analysis of the 
effect of MLN0128 co-administration on MLN1117 PK and the effect of MLN1117 co-
administration on MLN0128 PK.  If fewer than 16 patients meet these criteria, additional patients 
will be enrolled in the Mutual DDI PK Expansion Cohort to reach a minimum sample size of 16 
patients. 


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7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
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 non-missing) per category for categorical data, unless specified 
otherwise.  
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Unless otherwise specified, summary tabulations will be presented for each 
MLN0128/MLN1117 dose level within each of the treatment arms, total for each treatment arm, 
total for the dose escalation cohort, and for the mutual DDI PK expansion cohort.
Unless otherwise specified, the baseline value is defined as the value collected at the time closest 
to, but prior to, the start of study drug administration. Cycle 1 day 1 values are considered pre-
dose.   Screening values are considered baseline values if a cycle 1 day value is unavailable. 
All statistical analyses will be conducted using SAS® Version 9.4.
7.1.1
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If the start date has a month and year but the day is missing, the event will be considered
treatment emergent if the month and year of the start date of the event are:
o
On or after the month and year of the date of the first dose of study drug
and
o
On or before the month and year of the date of the last dose of study drug plus 30
days

If the start date has a year, but the day and month are missing, the event will be
considered treatment emergent if the year of the start date of the event is:


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o
On or after the year of the date of the first dose of study drug
and 
o
On or before the year of the date of the last dose of study drug plus 30 days

If the start date of an event is completely missing then the event is assumed to be 
treatment emergent.
However, if the end date is complete or partially missing but it is clear that the end date is before 
the first dose of study drug, the event will not be considered treatment emergent.
7.2
Analysis Sets
The Safety Population consists of all enrolled patients who have received at least 1 dose of any 
study drug.  All safety analyses will be based on the safety population.
The Pharmacokinetic DDI-evaluable population consists of all patients from the Mutual DDI PK 
Expansion Cohort with sufficient dosing and concentration-time PK data to reliably estimate PK 
parameters for statistical analyses of the effect of MLN0128 on MLN1117 PK and the effect of 
MLN1117 on MLN0128 PK.  The PK DDI analyses will be performed using the PK DDI-
evaluable population.
The pharmacodynamics population consists of patients with at least one pre and post baseline 
skin biopsy.  The PD analyses will be performed using the pharmacodynamics population.
The Response-Evaluable Population consists of all patients who receive at least 1 dose of study 
drug, and have at least 1 post baseline disease assessment will be used for analyses of response.  
Response analyses will be performed using the response-evaluable population.   
The DLT-evaluable population is defined as all patients who experience a DLT during Cycle 1, 
or receive all scheduled doses and complete all study procedures in Cycle 1 without experiencing 
a DLT.
7.3
Disposition of Subjects
The number and percentage of patients in each population will be presented by 
MLN0128/MLN1117 dose level within each of the treatment arms, total for each treatment arm, 
total for the dose escalation cohort, and for the mutual DDI PK expansion cohort.


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The number and percentage of patients who have discontinued study drug, the primary reason for 
discontinuing study drug, and still ongoing at the time of the data cutoff for the clinical study 
report will be summarized similarly.   All percentages will be based on the number of patients in 
the safety population.
7.4
Demographic and Other Baseline Characteristics
Baseline demographic data (gender, age, race, ethnicity, weight, height, and body mass index) 
will be summarized for each of the treatment arms in the dose escalation stage, for the dose 
escalation stage total, and for the mutual DDI PK expansion cohort.  Age will be calculated from 
the date of informed consent.
7.5
Medical History and Concurrent Medical Conditions
Baseline disease type (primary diagnosis), time since initial diagnosis (months), disease stage at 
study entry, and Eastern Cooperative Oncology Group (ECOG) performance status will be 
summarized for each of the treatment arms in the dose escalation stage, for the dose escalation 
stage total, and for the mutual DDI PK expansion cohort.  The time since initial diagnosis in 
months is calculated as:  (first dose date - date of initial diagnosis +1) /30.4375.
7.6
Medication History and Concomitant Medications
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary.  The number and percentage of patients taking concomitant medications will be 
tabulated by WHO drug generic term for the safety population by MLN0128/MLN1117 dose 
level within each of the treatment arms, total for each treatment arm, total for the dose escalation 
cohort, and for the mutual DDI PK expansion cohort. 
7.7
Study Drug Exposure and Compliance
The exposure to MLN0128/MLN1117 will be characterized by the cumulative dose (mg), 
planned dose (mg) and relative dose intensity (%) for each study drug.  In addition, the number 
of treated cycles, number and percent of patients who had ≥1, ≥2, …, and ≥6 treated cycles, and 
the duration of treatment in weeks will be summarized.  
A treated cycle is defined as a cycle in which the patient received any amount of study drug
(MLN0128 or MLN1117). 


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Relative dose intensity (%) is defined as 100 * (cumulative dose received in mg) / (planned dose
in mg). Planned dose is assigned dose level at study start * planned doses per cycle * maximum 
number of cycles.
Action on each study drug (MLN0128 and MLN1117) will be summarized for each cycle 
(Cycles 1 to 6), for patients who go beyond 6 cycles, and for all patients.   
The extent of exposure and action on each study drug will be summarized by
MLN0128/MLN1117 dose level within each of the treatment arms, total for each treatment arm, 
total for the dose escalation cohort, and for the mutual DDI PK expansion cohort based on the 
safety population.   
7.8
Efficacy Analysis
Efficacy is not the primary endpoint of the study. The secondary efficacy endpoints are overall 
response rate (ORR) and duration of response (DOR) based on investigator’s assessment and 
using if feasible, the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 
1.1).  
The best overall response for each patient will be derived programmatically from among the 
reported responses based on the investigator assessment.  The ORR is the percent of patients in 
the response evaluable population with a best response of CR or PR.  
Summaries of the number and percentage of patients falling into each response category (eg, CR, 
PR, Stable Disease (SD), Progressive Disease), with ORR (CR + PR), and with CR + PR of any 
duration or SD > 6 months will be summarized by MLN0128/MLN1117 dose level within each 
of the treatment arms, total for each treatment arm, total for the dose escalation cohort, and for 
the mutual DDI PK expansion cohort based on the response evaluable population.   
The duration of SD will calculated for the patients with a best response of SD.  Duration of SD is 
defined as the number of days from cycle 1 day 1 until progressive disease or until the last 
response assessment if there is no progressive disease. 
The duration of response (DOR) will be calculated for patients with a best response of CR or PR.  
The DOR is defined as the time from the date of first documented response of CR/PR to the first 


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documented PD, or censored at the last response assessment date that is SD or better for a patient 
that has not progressed. 
The investigator assessment of response (eg, CR, PR, stable disease [SD]) and whether 
symptomatic deterioration occurred at each visit will be provided in a data listing.  In addition, 
the duration of SD, DOR, and the best overall response will be included in a data listing.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
7.9.1
Pharmacokinetic Analysis
The pharmacokinetics population will be used for the description of the concentration-time 
profiles and for the estimation of the PK parameters.  
7.9.1.1
Pharmacokinetic Concentrations
Descriptive statistics (number of patients, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of variation, geometric mean, median, minimum, and maximum) will be 
used to summarize the plasma concentrations of MLN0128 and MLN1117 on Cycle 1 Day 1 and 
Cycle 1 Day 24 for each MLN0128/MLN117 dose level within each arm in the dose escalation 
cohort, and on cycle 1 day 3, day 10, and day 17 for the mutual DDI PK expansion cohort.
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 on Cycle 1 Day 1 and Cycle 1 Day 24 for each MLN0128/MLN117 dose 
level within each arm in the dose escalation cohort and on cycle 1 day 3, day 10, and day 17 for 
the mutual DDI PK expansion cohort (overlay onto one plot).  
Linear and semi-logarithmic plots of individual plasma concentration versus actual sampling 
time will be provided (overlay Cycle 1 Day 1 and Cycle 1 Day 24 profiles for each individual for 
the dose escalation cohort, and Cycle 1 Days 3, 10, and 17 for the mutual DDI PK expansion 
cohort). All individual patient plasma concentration data will be in a data listing.
7.9.1.2
Pharmacokinetic Parameters
PK parameters will be estimated using non-compartmental methods with 
Professional Version 6.1 or higher (
).  The plasma PK 
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parameters will be estimated from the concentration-time profiles for all PK population patients. 
In estimating the PK parameters, BQL values at the beginning of the profile will be set to zero. 
BQL values that occur after the first quantifiable point will be considered missing. Values that 
are embedded between BQLs, or quantifiable values occurring after two or more BQLs, will be 
set to missing at the discretion of the pharmacokineticist.  Actual sampling times, rather than 
scheduled sampling times, will be used in all computations involving sampling times.
Descriptive statistics (number of patients, arithmetic mean, arithmetic standard deviation, 
arithmetic coefficient of deviation, geometric mean, median, minimum value, and maximum 
value) will be used to summarize the calculated PK parameters.  For Tmax, only median, 
minimum value, and maximum value will be presented.  All individual patient PK parameter 
data will be in a data listing.
Data permitting, the following PK parameters will be calculated for MLN0128 and MLN1117: 

Area under the plasma concentration-time curve from time 0 to time of last measurable 
concentration (AUC0-last )

Area under the plasma concentration-time curve from time 0 to infinity (AUC0-inf)

Area under the plasma concentration-time curve from time 0 to 24 hr (AUC24hr)

Observed maximum plasma concentration (Cmax)

Time to observed maximum plasma concentration (Tmax)

Terminal disposition phase rate constant (lambdaz)

Terminal phase phase half-life (t1/2)

Apparent oral clearance (CL/F)

Apparent terminal phase volume of distribution (Vz/F)

Accumulation ratio


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For PK data acquired in the Mutual DDI PK Expansion Cohort an analysis of variance will be 
performed with log-transformed Cmax and AUCτ as the dependent variables, treatment as the 
fixed effect, and patient as the random effect.  Least-square mean ratios between the treatment 
states (MLN0128+ MLN1117 [Test]) versus MLN0128 or MLN1117 alone [Reference]) will be 
calculated along with 90% confidence intervals (CIs).  The chosen schedule for the mutual DDI 
PK expansion cohort was MLN1117 and MLN0128 both Administered MTuW (cohort B).  A 
comparison will be made of MLN0128 (C1D3) alone versus MLN0128+MLN1117 (C1D10) and 
MLN1117 alone (C1D17) versus MLN0128+MLN1117 (C1D10).
In the Mutual DDI PK Expansion Cohort the amount of MLN0128 and MLN1117 excreted in 
urine will be determined based upon urine concentration of each agent and the cumulative 
volume of urine collected during the 0-8h collection duration, as specified in the protocol.
The renal clearance of MLN0128 and MLN1117 will be determined by the taking the ratio of 
amount of MLN0128 and MLN1117 excreted in urine from 0-8h post-dose to the plasma AUC0-
8h. These parameters will be listed and summarized for the mutual DDI PK expansion cohort.
7.9.2
Pharmacodynamic Analysis
7.9.2.1
Pharmacodynamic Parameter Determination
Non-compartmental analysis will be used to determine the pharmacodynamic parameters using 
 for all pharmacodynamic evaluable subjects in arms B and C 
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only.  The analysis will be based on the percent change from baseline in the H- score and the 
actual sampling times.  
The following parameters will be calculated for each marker:

Emax: Maximum observed effect

TEmax: Time of maximum observed effect (hours)

AUEC0-t:  Area under the effect (inhibition)-time curve over the dosing interval (t=8 or 
24 hrs based on available data), calculated using the linear trapezoidal rule
The pharmacodynamic parameters will be summarized by MLN0128/MLN1117 schedule for 
each arm (B and C only).  Scatter plots of individual and median values of AUEC0-t vs. 
MLN0128/MLN1117 schedule will be generated for each arm (B and C only) and for each 
marker.
7.10
Other Outcomes
7.10.1 Pharmacogenomic Analysis
DNA extracted from blood samples obtained from all patients at screening may be evaluated for 
germline polymorphisms in CYP2C9 and CYP2C19 genes and may also be used to assess the 
impact of genetic polymorphisms on clinically important drug transporters, such as BCRP, 
OATP1B1, or OATP1B3, if either MLN0128 or MLN1117 is determined to be substrates of 
these transporters in future studies. Data from this study may be combined with data from 
previous and/or future studies to explore the relationship between MLN0128 and MLN1117 PK 
and the CYP2C9 and CYP2C19 genotypes. DNA samples may be used as a comparator and 
evaluated for mutations detected in tumor samples.
The results of such analysis will not be presented in the CSR but as a standalone report.
7.11
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, weight, and clinical laboratory results.  
These analyses will be performed using the safety population.


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7.11.1 Adverse Events
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
Version 19.0. Treatment-emergent AEs are defined as any AE that occurs after administration of 
the first dose of study treatment and up through 30 days after the last dose of study medication. 
Treatment-emergent AEs will be tabulated by MedDRA system organ class and preferred term
and will include the following categories

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs.

The most commonly reported treatment-emergent AEs [by preferred term – at least 10% 
of patients in each treatment arm in the dose escalation cohort, and for at least 10% of 
patients in the DDI expansion cohort.]
TEAEs will be summarized by by MLN0128/MLN1117 dose level within each of the treatment 
arms, total for each treatment arm, total for the dose escalation cohort, and for the mutual DDI 
PK expansion cohort. 
Patients with the same AE more than once will have the maximum intensity of that event 
counted within each body system, and once within each preferred term.
Adverse events of interest will be tabulated for the following:
Adverse event of 
interest
MedDRA Preferred Term
Rash
Fixed eruption,  Mucocutaneous rash,  Rash, Rash generalized, 
Rash macular, Rash maculo-papular,  Rash maculovesicular, 
Rash morbilliform,  Rash rubelliform,  Rash scarlatiniform, 
Rash vesicular,  Dermatitis exfoliative,  Drug eruption,  Drug 
hypersensitivity,  Drug rash with eosinophilia and systemic 
symptoms, Reaction to drug excipients, Toxic skin eruption, 
Administration related reaction,  Erythema,  Generalised 
erythema,  Rash erythematous,  Rash popular,  Rash 
papulosquamous


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Adverse event of 
interest
MedDRA Preferred Term
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
7.11.1.1    
Serious Adverse Events
The number and percentage of subjects experiencing at least 1 treatment emergent serious AE
(SAE) will be summarized by MedDRA system organ class, and preferred term.  Drug-related 
SAEs will be summarized similarly.


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7.11.1.2    
Deaths
A by-subject listing of the deaths will be presented.  An on-study death is defined as a death that 
occurs between the first dose of study drug and within 30 days of the last dose of study drug.
7.11.1.3    
Adverse Events Resulting in Discontinuation of Study Drug
The number and percentage of subjects experiencing treatment emergent AEs resulting in 
discontinuation of study drug will be summarized by MedDRA system organ class, and preferred 
term.  
A by-subject listing of treatment-emergent AEs resulting in discontinuation of study drug will be 
presented.  All AEs resulting in discontinuation of study drug will be displayed (regardless of 
treatment emergent AE status).
7.11.1.4
Dose Limiting Toxicities (DLTs)
A by-subject listing of DLTs in Cycle 1 will be presented for patients in the DLT-evaluable 
population.
7.11.2 Clinical Laboratory Evaluations
For the purposes of summarization, all laboratory values will be converted to standardized units.  
Whenever available, laboratory values will be assigned toxicity grades using the NCI CTCAE 
version 4.0.  
The number and percent of patients with shifts in the worst post-baseline NCI CTCAE toxicity 
grade relative to the baseline toxicity grade will be summarized:
Chemistry
Hematology
Alanine aminotransferase (ALT) increased
Hemoglobin
Alkaline phosphatase increased
Activated partial thromboplastin time 
(aPTT) prolonged
Aspartate aminotransferase (AST) increased
INR increased
Bilirubin (total) increased
Lymphocyte count decreased
Cholesterol high
Lymphocyte count increased
Creatinine increased
Neutrophil count decreased
Calcium decreased
Platelet count decreased
Calcium increased
White blood cell count decreased


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Chemistry
Hematology
Gamma glutamyl transferase (GGT) increased
Glucose decreased
Glucose increased
Potassium decreased
Potassium increased
Magnesium decreased
Magnesium increased
Sodium decreased
Sodium increased
Triglycerides increased
Albumin increased
Phosphate increased
For those laboratory tests not assigned NCI-CTCAE toxicity grades the number and proportion 
of patients with shifts in laboratory values to outside the laboratory normal range relative to the 
baseline value will be summarized. 
Laboratory data will be summarized by MLN0128/MLN1117 dose level within each of the 
treatment arms, total for each treatment arm, total for the dose escalation cohort, and for the 
mutual DDI PK expansion cohort. 
7.11.3 Vital Signs
Vital sign results (diastolic and systolic blood pressure) and body weight will be summarized as 
follows:

Baseline value

Minimum post-baseline value

Change to Minimum post-baseline value

Maximum post-baseline value

Change to Maximum post-baseline value
Vital signs data will be summarized by MLN0128/MLN1117 dose level within each of the 
treatment arms, total for each treatment arm, total for the dose escalation cohort, and for the 
mutual DDI PK expansion cohort. 


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7.11.4 12-Lead ECGs
Selected ECG parameters (ventricular rate, PR, QRS, QT, and QTc (Fridericia) will be 
summarized as follows:

Baseline value

Minimum post-baseline value

Change to Minimum post-baseline value

Maximum post-baseline value

Change to Maximum post-baseline value   
All QT values will be converted to QTcF using Fridericia’s correction:
(sec)
[Note: RR = 60 seconds/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.   
ECG data will be summarized by MLN0128/MLN1117 dose level within each of the treatment 
arms, total for each treatment arm, total for the dose escalation cohort, and for the mutual DDI 
PK expansion cohort. 
7.11.5 Other Observations Related to Safety
Not applicable.
7.12
Interim Analysis
No formal interim analysis is planned.  In the Expansion Stage, the first stage of Simon Two 
Stage Design will be used to make a go-no go decision.
7.13
Changes in the Statistical Analysis Plan 
The planned interim analysis was not performed as patients were not enrolled in the tumor-
specific cohorts in the Expansion Stage planned in the protocol.


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Mean laboratory values over time were not plotted for key lab parameters as specified in the 
statistical methods section of the protocol. 


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8.0
OTHER
The below subject-level listings will be generated:
–
Disposition
–
Populations
–
Demographics
–
Baseline Characteristics
–
Prior Therapy
–
Prior Radiation
–
Exposure to study drug
–
All Adverse events
–
TEAEs leading to study drug discontinuation 
–
Serious AEs 
–
On-study deaths 
–
DLTs during Cycle 1
–
Pharmacokinetic concentrations 
–
Pharmacokinetic parameters 
–
Pharmacodynamic data
–
Efficacy