Clinical trial NCT02393209
Conditions: Non-small Cell Lung Cancer
Keywords: Drug therapy
Sponsor: Millennium Pharmaceuticals, Inc.
Start date: 2015-06-03; Completion date: 2017-01-20
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine the recommended phase 2 dose (RP2D) of TAK-117 when administered in combination with docetaxel in participants with non-small cell lung cancer (NSCLC) and to evaluate efficacy, safety, and tolerability of TAK-117 administered alone and in combination with docetaxel at the RP2D in participants with locally advanced or metastatic non-small cell lung cancer.

Detailed description:
The drug being evaluated in this study is called TAK-117. TAK-117 is tested in combination with docetaxel versus docetaxel alone for the treatment of non-small cell lung cancer (NSCLC).

This study consisted of 2 phases:

* Phase 1b - dose escalation phase
* Phase 2 - expansion phase.

The study enrolled 14 patients with NSCLC who have been treated with multiple prior lines of therapies will be enrolled for Phase 1b. The participants will receive docetaxel (36 mg/m\^2) intravenous (IV) and TAK-117 tablets, orally administered, once daily in 21-day dosing cycles. The TAK-117 dose will be escalated until recommended Phase 2 dose (RP2D) is determined.

Each part of the adaptive Phase 2 portion of the study is designed as a stand-alone, randomized study evaluating PFS as the primary efficacy measure in a total of 60 participants between the 2 treatment arms: TAK-117 plus docetaxel versus docetaxel alone. An event-driven analysis of PFS will be performed after each part of Phase 2. On the basis of the PFS analysis of the preceding part of the study, the study may be stopped for efficacy or futility, or proceed to the next part. However, Phase 2 of the study was cancelled.

Study drug will be administered in 21-day dosing cycles. During each phase of the study, participants will be treated with a maximum of 9 cycles of either docetaxel alone or docetaxel plus TAK-117. Subsequently, participants treated with docetaxel plus TAK-117 may continue to receive TAK-117 monotherapy until progression of disease, occurrence of unacceptable toxicities or death.

The maximum duration of treatment for participants will be 12 months unless it is determined that a participant would derive benefit from continued treatment beyond 12 months. Participants will continue to be followed after discontinuation of study drug to collect PFS and OS data. Participants may withdraw from therapy at any time.

This multicenter trial will be conducted in North America. The overall time to participate in this study is up to 24 months.

Arms: arm 1: TAK-117 200 mg, tablets, orally on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 of the 21-day cycle and docetaxel 36 mg/m\^2, intravenous (IV) infusion, on Days 1 and 8 of the 21-day cycle up ro Cycle 9 (approximately 189 days). arm 2: TAK-117 200 mg, tablets, orally on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 of the 21-day cycle and docetaxel 36 mg/m\^2, IV infusion, on Days 1 and 8 of the 21-day cycle up to 6 cycles (approximately 126 days). arm 3: TAK-117 tablets, at the dose determined in the dose escalation phase, on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 of a 21-day cycle plus Docetaxel 36 mg/m\^2 IV infusion on Days 1 and 8 of a 21-day cycle. arm 4: Docetaxel 75 mg/m\^2, IV infusion once every 3 weeks (per approved prescribing information) with dosing on Day 1 of each 21-day cycle.
Interventions: intervention 1: Docetaxel intervention 2: TAK-117
Intervention descriptions: intervention 1: Docetaxel intravenous infusion intervention 2: TAK-117 Tablets

Protocol documents:
Prot_001.pdf: 
Certain information within this clinical study report has been redacted (ie, specific content is masked 
irreversibly from view with a black 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.

Patient identifiers within the text, tables, or figures or in by-patient data listings.

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.
If needed, certain appendices that contain a large volume of personally identifiable information or 
company confidential information may be removed in their entirety if it is considered that they do not add 
substantially to the interpretation of the data (eg, appendix of investigator’s curriculum vitae). 


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
Confidential
1
CLINICAL STUDY PROTOCOL MLN1117-1501 AMENDMENT 3
MLN1117
A Phase 1b/Adaptive Phase 2 Study of Docetaxel With or Without MLN1117 in Patients 
With Locally Advanced or Metastatic Non-small Cell Lung Cancer
Protocol Number:
MLN1117-1501
Indication:
Non-small cell lung cancer
Phase:
1b/2
Sponsor:
Millennium Pharmaceuticals, Inc.
EudraCT Number:
2014-004281-25
Therapeutic Area:
Oncology
Protocol History
Original
15 December 2014
Amendment 1
27 April 2015
Amendment 2
29 June 2015
Amendment 3
20 October 2015
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA  USA  02139
Telephone:  
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may be found at the 
end of the document.
(or designee)
Signature
Date DD Month YYYY
 (or designee)
Signature
Date DD Month YYYY
, Clinical 
Pharmacology (or designee)
Signature
Date DD Month YYYY
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior written 
authorization of Millennium Pharmaceuticals is expressly prohibited.


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Rationale for Amendment 3
This amendment is being instituted to expand the Phase 2 eligibility criteria to allow for
specific prior therapies, in response to the recent regulatory approval of immune checkpoint 
inhibitors in the relevant setting. 
The amendment also allows for the exploration of alternative dosing regimens of study drug 
if needed based on emerging study data and consensus between the sponsor and the 
investigators. Additionally, clarifications to the following are needed: definitions for
analysis populations (intent-to-treat [ITT] and response evaluable); stratification factors to 
be utilized in the randomization scheme for Phase 2 portion of the study; selected statistical 
methods that will be used for efficacy analyses; and instructions for the centralized storage 
of copies of Phase 2 radiographic images taken for disease assessment. A restriction for 
female patients regarding the donation of eggs has been incorporated for consistency with 
male restrictions.  Administrative updates include correction of the estimated number of 
participating clinical study sites, incorporation of a development code alias for MLN1117
(TAK-117), and updates to the list of sponsor signatories.
Purposes for Amendment 3
The purposes are to:

Allow for administration of alternative dosing regimens for MLN1117 and for 
docetaxel under certain circumstances.

Expand Phase 2 eligibility criteria to allow enrollment of patients who received prior 
therapy with nivolumab, pembrolizumab, or other immune-checkpoint inhibitors under 
specific circumstances.

Define stratification factors to be applied during randomization of Phase 2 enrollment.

Clarify that during Phase 2 of the study, a copy of all radiographic images taken for the 
purpose of disease assessment must be sent to the central imaging vendor, and confirm 
that disease-response evaluations conducted during the study will be based solely on 
investigator assessment.

Clarify the ITT population definition.

Clarify the definition of the Response-Evaluable population and specify the efficacy 
analyses for which the population will be utilized.

Clarify the statistical methods to be used in the analyses of primary efficacy endpoints.

Incorporate a censoring rule for the analysis of overall survival (OS).

Incorporate a restriction for female patients regarding the donation of eggs.

Incorporate the development code TAK-117 as a synonym for MLN1117.

Update the list of sponsor signatories and the estimated number of participating clinical 
study sites.

Correct typographical errors, punctuation, grammar, and formatting.
For specific examples and locations of these changes, see Section 14.8.  


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PROTOCOL SUMMARY
Study Title:  A Phase 1b/Adaptive Phase 2 Study of Docetaxel With or Without MLN1117 in Patients 
With Locally Advanced or Metastatic Non-small Cell Lung Cancer
Number of Patients:  Approximately 75 to 155 total; approximately 15 patients will be enrolled in 
Phase 1b (dose escalation), and 60 to 140 patients may be enrolled in Phase 2 (dose expansion) based 
on a sequential, adaptive design.
Study Objectives
Primary
Phase 1b (Dose Escalation)
To determine the dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and 
recommended phase 2 dose (RP2D) of MLN1117 when administered orally in combination with 
docetaxel in patients with non-small cell lung cancer (NSCLC)
Phase 2 (Dose Expansion) 
To evaluate progression-free survival (PFS) as the primary efficacy measure of MLN1117 plus 
docetaxel versus docetaxel alone in patients with advanced NSCLC
Secondary
To evaluate the safety and tolerability of MLN1117 plus docetaxel administered to patients with 
NSCLC (Phase 1b and Phase 2)
To evaluate the pharmacokinetics (PK) of MLN1117 when administered with docetaxel (Phase 
1b and Phase 2)
To evaluate additional efficacy measures, such as response rate, disease control rate, response 
duration, time to progression, and overall survival (OS), of MLN1117 plus docetaxel versus 
docetaxel alone in patients with NSCLC (Phase 2 only)
To evaluate PFS and additional efficacy measures of MLN1117 plus docetaxel versus docetaxel 
alone in different populations of patients with NSCLC, such as patients with squamous NSCLC 
versus nonsquamous NSCLC, and patients with squamous NSCLC with or without PIK3CA
mutation and/or amplification (MUT/AMP) (Phase 2 only)
Exploratory

 

 
 



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Overview of Study Design:  This is an open-label, phase 1b/adaptive phase 2 study of MLN1117 in 
combination with docetaxel versus docetaxel alone in adult patients with NSCLC. This study consists 
of a Phase 1b dose escalation phase, and an adaptive, randomized Phase 2 expansion phase.  
In Phase 1b of the study, the DLTs, MTD, and RP2D of MLN1117 plus docetaxel will be determined 
using a 3 + 3 dose escalation scheme with a fixed dose of docetaxel and varying dose levels of 
MLN1117.  During a 21-day cycle of treatment, docetaxel (36 mg/m2) will be administered 
intravenously (IV) on Days 1 and 8, and MLN1117 tablets (planned doses 300, 600, and 900 mg) will 
be administered orally on a weekly schedule that includes 3 consecutive dosing days per week (eg, on 
Days 2, 3, 4, 9, 10, 11, 16, 17, and 18).  If MTD or RP2D is not achieved by 900 mg, higher dose levels 
at 300 mg increments may be evaluated.  More conservative dose escalation, evaluation of intermediate 
doses, and expansion of an existing dose level 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 or exposure of MLN1117 plus docetaxel.  Additionally 
during Phase 1b, if MLN1117 de-escalation is warranted, the daily MLN1117 dose may be reduced, or 
the number of treatment days per week may be reduced (eg, from 3 days to 2 days, or further to 1◦day) 
while maintaining the same weekly MLN1117 dose. Subsequent escalation may be permitted based on 
observed safety and tolerability data. These decisions will be made jointly by investigators and the 
Millennium project clinician. The alternative MLN1117 regimen may be carried forward into Phase 2 
of the study if deemed appropriate by the sponsor, in consultation with the investigators.
Testing of escalating MLN1117 doses in combination with a fixed docetaxel dose and schedule is 
planned. However, if frequent docetaxel dose modifications are necessary when administered in 
combination with MLN1117, the fixed dose of docetaxel may be decreased (eg, –1 dose level) based on 
discussion and agreement between investigators and the Millennium project clinician. If decreased, the 
lower docetaxel dose may be carried forward into Phase 2 of the study if deemed appropriate by the 
sponsor, in consultation with the investigators.
Patients will be enrolled in the adaptive, randomized Phase 2 portion of the study to evaluate the 
efficacy of MLN1117 plus docetaxel versus docetaxel alone. The safety and tolerability of MLN1117 
administered in combination with docetaxel at the RP2D determined during Phase 1b will also be 
further characterized. Phase 2 of the study will use a sequential, multistage Bayesian adaptive design 
and will consist of up to 3 parts evaluating the following patients: 
Part 1:  NSCLC (inclusive of both squamous and nonsquamous histology and all PIK3CA
genotypes)
Part 2:  Histology-specific NSCLC (either squamous or nonsquamous)
Part 3:  Histology- and genotype-specific NSCLC (PIK3CA MUT/AMP positive squamous 
NSCLC if squamous histology is selected in Part 2) 
Each part of the adaptive Phase 2 study is designed as a stand-alone, randomized study evaluating PFS 
as the primary efficacy measure in a distinct population of NSCLC between the 2 treatment arms: 
MLN1117 plus docetaxel versus docetaxel alone.  There will be a primary, event-driven analysis of 
PFS after each part of Phase 2.  Phase 2 will start with Part 1 in NSCLC patients inclusive of all 
histological types and all PIK3CA genotypes (PIK3CA mutation, amplification, or wild-type).  On the 
basis of the primary PFS analysis of Part 1, the study may be stopped for efficacy or futility.  If neither 
the efficacy nor the futility boundary is met, a subgroup analysis of PFS based on histology will be 
performed.  The study will proceed to Part 2 if a differential level of efficacy is observed between 
squamous and nonsquamous and a preferred histology (squamous or nonsquamous) is determined.  The 
primary PFS analysis of Part 2 will in turn determine whether the study should proceed to Part 3, which 
will evaluate patients with a specific histology and genotype, namely, squamous NSCLC patients with 


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PIK3CA MUT/AMP if squamous histology is selected for Part 2.  Patients will be randomized 1:1 to 
one of the following treatment arms in Parts 1, 2, and 3 of Phase 2 of the study:
Arm A: docetaxel 36 mg/m2 IV on Days 1 and 8 of a 21-day cycle plus MLN1117 tablets, at 
the dose determined in Phase 1b, on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 of a 21-day cycle. 
(An alternative combination dosing regimen may be used based on the RP2D decision in 
Phase 1b.)  
Arm B: docetaxel 75 mg/m2 IV once every 3 weeks (per approved prescribing information) 
with dosing on Day 1 of each 21-day cycle
The treatment duration for all patients in Phase 1b and Phase 2 may be up to 9 cycles of either 
docetaxel alone or docetaxel in combination with MLN1117.  Patients receiving docetaxel plus 
MLN1117 may continue treatment with MLN1117 monotherapy beyond 9 cycles.  Patients may 
continue to receive treatment until either disease progression, occurrence of unacceptable toxicities, or 
death.  The maximum duration of treatment will be 9 cycles (approximately 6 months) for patients 
receiving docetaxel alone or12 months for patients receiving MLN117 plus docetaxel (ie, 9 cycles of 
MLN1117 plus docetaxel followed by MLN1117 alone) unless, after discussion between the 
investigator and sponsor, it is determined that a patient would derive benefit from continued treatment 
beyond 9 cycles or12 months, respectively.  Patients may discontinue study treatment at any time.  
Patients will attend the End-of-Treatment visit 30 to 40 days after receiving their last dose of study 
drug.
Patients will continue to be followed after discontinuation of study treatment to collect OS data for a 
period of up to 12 months (after last dose of study treatment). In addition, for patients who discontinue 
treatment due to reasons other than disease progression, PFS data will be collected during the 
posttreatment follow-up period of up to 6 months after the last dose of study drug, and OS data 
collection will continue until death, withdrawal of consent for further follow-up, or 12 months 
following the last dose of study drug.  
Throughout the study, adverse events will be assessed and laboratory values, vital signs, and 
electrocardiograms will be obtained to evaluate the safety and tolerability of MLN1117 alone or in 
combination with docetaxel.  Toxicity will be evaluated according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events, Version 4.03, effective date 14 June 2010. 
Radiological tumor evaluations (computed tomography [CT] scan with IV contrast or magnetic 
resonance imaging [MRI] as clinically indicated of the chest, abdomen, and pelvis) will be used to 
evaluate disease response according to the modified Response Evaluation Criteria in Solid Tumors 
(RECIST) guidelines, Version 1.1. Radiographic tumor evaluations and disease assessment will be 
performed by the investigator throughout the study.  During the Phase 2 portion of the study, copies of 
all radiographic images with measurements will be sent to a central imaging vendor for the purpose of 
retrospective review by the sponsor.  However, central radiologic evaluation is not planned for 
response assessment during the study.
 
 
 
Blood samples for analysis of circulating tumor DNA will be collected at baseline from all patients.  
Subsequent samples will be obtained during the study and analyzed for the presence and clone 
frequency of somatic mutations frequently reported in solid tumors including PIK3CA mutations.  
Correlative studies will be performed to compare the mutation data generated from circulating tumor 
DNA versus tumor tissue DNA.  Dynamic changes in mutant clone frequency measured in circulating 
tumor DNA over the course of treatment will be evaluated in relation to objective response and disease 


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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status.
In addition, archived or fresh biopsy tumor tissue samples collected during screening will be analyzed 
for somatic alterations and other biomarkers that may relate to sensitivity or resistance to MLN1117 
plus docetaxel. 
Pharmacokinetic samples will be collected to characterize the PK of MLN1117 when administered in 
combination with docetaxel.  
Study Population:  The patient population will consist of adults 18 years of age or older with locally 
advanced or metastatic NSCLC refractory or resistant to 1 prior line of platinum-based, non-docetaxel-
containing systemic chemotherapy (Phase 2).  Also eligible for Phase 2 are patients who, after 
front-line, platinum-based, non-docetaxel-containing chemotherapy, received 1 line of nivolumab or 
other immune-checkpoint inhibitors but progressed on or after that therapy. Patients with NSCLC who 
have been treated with multiple prior lines of therapies are eligible for Phase 1b. Patients must have a 
histologically or cytologically confirmed diagnosis of NSCLC (squamous or nonsquamous).  In Phase 
2 of the study, patients with squamous NSCLC with a diagnosis of mixed squamous and nonsquamous 
(or adenosquamous) NSCLC are acceptable; patients with nonsquamous NSCLC with known driver 
mutations (EGFR and ALK) indicated for front-line targeted therapy are excluded as are patients with 
known KRAS gene mutations.  Patients must have locally advanced or metastatic disease (Stage IIIb or 
Stage IV) with radiographically or clinically evaluable lesions per modified RECIST criteria 
(Version 1.1). Measurable disease by radiographic techniques (CT or MRI) is required only for Phase 
2 of the study.  Patients enrolled in Phase 2 must have archived or fresh tumor biopsy samples obtained 
during screening sufficient for genotyping; enrollment will be contingent on the local or central 
laboratory confirming receipt of an adequate amount of tissue including sufficient DNA for analysis.  
Patients must have adequate organ function and an Eastern Cooperative Oncology Group Performance 
Status of 0 or 1.  Patients must have recovered (ie, Grade 1 toxicity or eligibility per this protocol is 
met) from the reversible effects of prior anticancer therapy.  Patients who have been previously treated 
with a phosphoinositide 3-kinase or AKT inhibitor are not to be enrolled. No patients will have 
exposure to strong inhibitors or inducers of cytochrome P450 3A within 14 days, proton pump 
inhibitors within 7 days, or histamine-H2 receptor antagonists or neutralizing antacids within 24 hours
before the first dose of study drug.  Patients with poorly controlled diabetes mellitus and clinically 
significant co-morbidities will not be enrolled.
Duration of Study:  Approximately 24 to 36 months based on the sequential and adaptive design of 
Phase 2 of the study


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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STUDY DESIGN DIAGRAM
Screening
Within 28 days 
of first dose
Docetaxel (36 mg/m2)* IV once 
weekly, 2 weeks on, 1 week off, 
with dosing on Day 1 and Day 8
plus
MLN1117 po tablets (planned dose 
escalation of 300, 600, and 900 mg) 
dosed 3 days on and 4 days off, in 
3-week cycles.*
End-of-Treatment
Posttreatment  follow-up
OS for 12 months after 
last study drug dose; PFS 
for 6 months after last 
study drug dose only for 
patients who discontinue 
for reasons other than PD
EOT Visit 
30 to 40 
days after 
last dose of 
study drug
21-day Cycles.
Docetaxel + MLN1117 for 
up to 9 cycles followed by 
MLN1117 monotherapy 
until PD or discontinuation 
due to any other reason.
PHASE 1b
3 + 3 Dose Escalation: see Section 6.4 for dose escalation rules
Abbreviations:  EOT = end of treatment; IV = intravenous; OS = overall survival; PD = progressive disease; PFS = progression-free survival; po = by mouth. 
*Alternative dosing schedule(s) may be investigated in Phase 1b and may be carried forward into Phase 2 of the study.


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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Screening
Randomization
Within 
28 days 
of first 
dose
ARM A: Docetaxel (36 mg/m2)* 
IV once weekly, 2 weeks on, 
1 week off, with dosing days on 
Day 1 and 8 
plus
MLN1117 po tablets using dosing 
regimen determined in Phase 1b
End-of-Treatment
ARM B: Docetaxel (75 mg/m2) 
IV once every 3 weeks on Day 1
Posttreatment  follow-up
OS for 12 months 
after last study drug 
dose; 
PFS for 6 months 
after last study drug 
dose only for 
patients who 
discontinue for 
reasons other than 
PD
EOT Visit
30 to 40 
days after 
last study 
drug dose 
21-day Cycles.
Docetaxel or docetaxel + 
MLN1117 for up to 9 cycles. 
Beyond 9 cycles, patients treated 
with docetaxel + MLN1117 will 
receive MLN1117 monotherapy 
using the same MLN1117 dosing 
regimen until PD or 
discontinuation due to any other 
reason.
PHASE 2
Abbreviations:  EOT= end of treatment; IV = intravenous; MUT/AMP = mutation and/or amplification; OS = overall survival; PD= progressive 
disease; PFS = progression-free survival; po = by mouth; WT = wildtype. 
Balanced between histological 
type of NSCLC confirmed at 
screening (squamous and 
nonsquamous). Prior therapy 
(1 vs. >1) and PIK3CA   
(MUT/AMP versus WT) 
genotype will be used as 
stratification factors.
*Alternative dosing schedule(s) may be carried forward from Phase 1b.


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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SCHEDULES OF EVENTS
Screeninga
Within 28 
Days
TREATMENT CYCLE 1
EOTd
PFSFUP/ 
OSFUP
Day 1 
Predosea
Day 
2
Day 
3b
Day 8
Day 9c
Day 16
Informed consente
X
Inclusion/exclusion criteria
X
Demographics
X
Medical history
X
Physical examinationf
X
X
X
X
X
X
X
X
Height
X
Weight
X
X
X
Vital signsg
X
X
X
X
X
X
ECOG Performance Status
X
X
X
Patient diary review
X
X
X
X
X
X
X
X
X
X
12-lead ECGi
X
X
X
X
X
Concomitant medications 
and proceduresj
Recorded from the first dose through 30 days after the last dose
AE collection
Recorded from the first dose through 30 days after the last dose
SAE collectionk
Recorded from the time the informed consent is signed through 30 days after the last dose of study drug
Pregnancy testl
X
X
Hematologym
X
X
X
X
X
X
X
Chemistrym
X
X
X
X
X
X
X
Urinalysis
X
X
X
Fasting serum glucosen
X
X
X
X
X
Fasting lipid profileo
X
X


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Screeninga
Within 28 
Days
TREATMENT CYCLE 1
EOTd
PFSFUP/ 
OSFUP
Day 1 
Predosea
Day 
2
Day 
3b
Day 8
Day 9c
Day 16
HbA1c
X
In-home daily fasting 
glucose monitoring
See footnote p
Blood samples for PK
For Phase 1b, see the Plasma Pharmacokinetic Sampling Schedule During Phase 1b.
For Phase 2, see the Plasma Pharmacokinetic Sampling Schedule During Phase 2, 
Arm A Only.
Blood germline DNA 
X
Plasma ctDNA
X
Tumor tissue (banked) or 
fresh biopsy sampleq
X
Disease evaluation by  
RECIST 1.1 (CT/MRI)r
X
Disease assessment to be conducted during Days 18-21 at the end of Cycles 2, 4, and
6 and then every 3 cycles thereafter
X
Q2 mo
OS follow-up (OS and 
subsequent anticancer 
therapy)s
X
Q3 mo
Dosing
Phase 1b t, u, v
Docetaxel (36 mg/m2) IV once weekly, 2 weeks on, 1 week off, in combination with 
MLN1117, 3 days on and 4 days off, for 3-week cycles for up to 9 cycles
Phase 2 – Arm At, u, v
Docetaxel (36 mg/m2) IV once weekly, 2 weeks on, 1 week off, in combination with 
MLN1117 (dose TBD from dose escalation), 3 days on and 4 days off, for 3-week 
cycles for up to 9 cycles
Phase 2 – Arm B v
Docetaxel (75 mg/m2) IV once every 3 weeks
Abbreviations: AE = adverse event; CT = computed tomography; ctDNA = circulating tumor DNA; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; 
 EOT = end of treatment; 
HbA1c  = hemoglobin A1c; IV = intravenous(ly); mo = month(s); MRI = magnetic resonance imaging; OS = overall survival; OSFUP = overall survival 
follow-up; PFSFUP = progression-free survival follow-up; PK = pharmacokinetic(s); RECIST = Response Evaluation Criteria in Solid Tumors; 
SAE = serious adverse event; TBD = to be determined.


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Screeninga
Within 28 
Days
TREATMENT CYCLE 1
EOTd
PFSFUP/ 
OSFUP
Day 1 
Predosea
Day 
2
Day 
3b
Day 8
Day 9c
Day 16
a Screening assessments are performed within 28 days before the Cycle 1 Day 1 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 Assessments on Day 3 will be done ONLY when patients are in the clinic for Phase 1b PK sampling, see Plasma Pharmacokinetic Sampling Schedule 
During Phase 1b.
c Phase 2, Arm B patients will not attend the Cycle 1 Day 9 visit.
d The EOT visit will occur 30-40 days after the last dose of study drug.
e Informed consent may be captured before the Screening period (28 days before Cycle 1 Day 1 dosing).
f
A standard-of-care physical exam, including neurological assessment, should be done at screening, predose on Days 1, 2, 8, and 9; on Day 16 postdose; and 
at EOT.  The physical exam on Days 2, 3, 8, 9, and 16 should be symptom directed.
g Vital signs should be obtained at screening, predose on Days 1 and 8; and on Day 16 postdose; and at EOT.  Vital signs include blood pressure, heart rate, 
and temperature.
h On Day 1 only of every cycle and at EOT (Phase 2, only).
i
Single 12-lead ECGs will be conducted at Screening, on Cycle 1 Day 1 predose; Cycle 1 Day 2 predose and at 4 hours (± 30 min) post MLN1117 dose; 
Cycle 1 Day 9 predose; and at EOT. 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.
j
See Section 6.6 for medications and procedures that are prohibited during the study and Section 6.8 for medications that should be used cautiously during 
the study.
k Only those SAEs that occur after the first dose of study drug will be collected in the electronic case report form; however, all SAEs occurring after consent 
will be reported.  See Section 9.
l
A serum pregnancy test will be performed for women of childbearing potential at screening.  A urine pregnancy test must be performed predose on Cycle 1
Day 1 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 Cycle 1 Day 1 urine test.
m Samples may be collected up to 3 days before the scheduled visit.  See Section 7.4.13 for the full hematology and chemistry panel.
n Phase 1b fasting serum glucose will be measured at screening; Cycle 1 Day 2 predose and at 0.5 hours (± 15 min), 1 hour (± 15 min), 2 hours (± 30 min), 
4 hours ([± 30 min] fasting not required), 8 hours ([± 30 min] fasting not required), and 24 hours (± 2 hours) after dosing; Cycle 1 Day 9 predose and 
2 hours (± 30 min) postdose; Cycle 1 Day 16 predose only; and at EOT. Phase 2 fasting serum glucose will be measured at screening; Cycle 1 Day 2
predose; Cycle 1 Day 9 predose; and at EOT.
o See Section 7.4.13 for the fasting lipid panel.
p Patients who experience on-study hyperglycemia will be given a glucometer to monitor their daily predose fasting blood glucose (FBG) levels at home and 
will be instructed to notify the investigator when the FBG 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 7.4.15 for further instruction.


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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Screeninga
Within 28 
Days
TREATMENT CYCLE 1
EOTd
PFSFUP/ 
OSFUP
Day 1 
Predosea
Day 
2
Day 
3b
Day 8
Day 9c
Day 16
q Tumor tissue (banked) will be required at screening as specified in Section 7.4.17.  For banked tissue, the sample can be from either paraffin-embedded 
tumor block or unstained slides.  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 7.4.17.  The sample must be collected during screening before the first dose of study drug.  Tumor tissue will be 
analyzed and will be tested retrospectively for genetic mutations and amplifications.
r
Response assessments will be performed on Days 18-21 at the end of treatment Cycles 2, 4, and 6 and then every 3 cycles thereafter starting at Cycle 9 until 
the patient discontinues study drug due to disease progression, unacceptable toxicity, or death. A CT scan with IV 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 Cycle 1 Day 1, the results of 
that scan may be used for tumor lesion measurements at screening. For patients who discontinue for reasons other than disease progression, PFS is to be 
assessed every 2 months up to 6 months after study treatment.
s OS is to be assessed every 3 months for up to 1 year after the patient’s last dose of study drug.
t
Patients will be treated for up to 9 cycles with either docetaxel alone or docetaxel plus MLN1117.  Patients receiving docetaxel plus MLN1117 will 
continue treatment with MLN1117 monotherapy beyond Cycle 9.
u During Phase 1b, if MLN1117 de-escalation is warranted, the daily dose of MLN1117 may be reduced or the number of treatment days per week may be 
reduced (eg, from 3 days to 2 days, or further to 1◦day); see Section 6.1 for details.
v Testing of escalating MLN1117 doses in combination with a fixed docetaxel dose and schedule is planned. However, if frequent docetaxel dose 
modifications are necessary when administered in combination with MLN1117, the fixed dose of docetaxel may be decreased (eg, –1 dose level) based on 
discussion and agreement between investigators and the Millennium project clinician; see Section 6.1. 


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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TREATMENT CYCLES 2-9
EOTa
PFSFUP/
OSFUP
Day 1
Day 8
Physical examinationb
X
Xb
X
Weight
X
X
Vital signsc
X
X
X
ECOG Performance Status
X
X
Patient Diary Review
X
X
X
X
X
X
X
12-lead ECGe
X
X
Concomitant medications and proceduresf
Recorded from the first dose through 30 days after the last dose
AE collection
Recorded from the first dose through 30 days after the last dose
SAE collectiong
Recorded from the time the informed consent is signed through 30 days after the last dose of study drug
Pregnancy testh
X
Hematologyi
X
X
X
Chemistryi
X
X
X
Urinalysis
X
X
Fasting serum glucosej
X
X
X
Fasting lipid profilek
X
In-home daily fasting glucose monitoring
See footnote l.
Plasma ctDNAm
X
Disease evaluation by RECIST 1.1 
(CT/MRI)n
Disease assessment to be conducted during Days 18-21 at the end of the end of 
Cycles 2, 4, and 6 and then every 3 cycles thereafter
X
Q2 mo
OS follow-up (OS and subsequent 
anticancer therapy) o
X
Q3 mo


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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TREATMENT CYCLES 2-9
EOTa
PFSFUP/
OSFUP
Day 1
Day 8
Dosing
Phase 1b p, q, r
Docetaxel (36 mg/m2) IV once weekly, 2 weeks on, 1 week off, in combination 
with MLN1117, 3 days on and 4 days off, for 3-week cycles for up to 9 cycles
Phase 2 – Arm Ap, q, r
Docetaxel (36 mg/m2) IV once weekly, 2 weeks on, 1 week off, in combination 
with MLN1117 (dose TBD from dose escalation), 3 days on and 4 days off, for 
3-week cycles for up to 9 cycles
Phase 2 – Arm B r
Docetaxel (75 mg/m2) IV once every 3 weeks
Abbreviations: AE = adverse event; CT = computed tomography; ctDNA = circulating tumor DNA; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; 
 
 EOT = end of treatment; 
IV = intravenous(ly); mo = month(s); MRI = magnetic resonance imaging; OS = overall survival; OSFUP = overall-survival follow-up; 
PFSFUP = progression-free survival follow-up; PK = pharmacokinetic; RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse 
event.
a The EOT visit will occur 30-40 days after the last dose of study drug.
b A standard-of-care physical exam, including neurological assessment, should be done predose on Day 1 and Day 8, and at EOT. The physical exam on Day
8 should be symptom directed.
c Vital signs should be obtained predose on Day 1 and Day 8 and at EOT. Vital signs include blood pressure, heart rate, and temperature.
d On Day 1 only of every cycle and at EOT (Phase 2 only).
e ECGs should be taken predose on Day 1 of every cycle and at EOT.  When the timing of a safety laboratory blood sample coincides with the timing of ECG 
measurements, then the ECG will be completed before the collection of the blood sample.
f
See Section 6.6 for medications and procedures that are prohibited during the study and Section 6.7 for medications that should be used cautiously during 
the study.
g Only those SAEs that occur after the first dose of study drug will be collected in the electronic case report form; however, all SAEs occurring after consent 
will be reported.  See Section 9.
h Urine pregnancy test must be performed before Day 1 of each cycle.
i
Samples may be collected up to 3 days before the scheduled visit.  See Section 7.4.13 for the full hematology and chemistry panel.
j
Fasting serum glucose (FSG) is required on Day 1 predose and Day 8 predose for Cycles 2-9 and at EOT.
k See Section 7.4.13 for the fasting lipid panel.
l
Patients who experience on-study hyperglycemia will be given a glucometer to monitor their daily predose fasting blood glucose (FBG) levels at home and 
will be instructed to notify the investigator when the FBG 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 7.4.15 for further instruction.


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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TREATMENT CYCLES 2-9
EOTa
PFSFUP/
OSFUP
Day 1
Day 8
m Samples to be taken on Day 1 every 2 cycles, starting at Cycle 3 Day 1, until EOT.
n Response assessments will be performed on Days 18-21 at the end of treatment Cycles 2, 4, and 6 and then every 3 cycles thereafter starting at Cycle 9 until 
the patient discontinues study drug due to disease progression, unacceptable toxicity, or death.  A CT scan with IV 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 Cycle 1 Day 1, the results of 
that scan may be used for tumor lesion measurements at screening. For patients who discontinue for reasons other than disease progression, PFS is to be 
assessed every 2 months up to 6 months after study treatment.
o OS is to be assessed every 3 months for up to 1 year after the patient’s last dose of study drug.
p Patients will be treated for up to 9 cycles with either docetaxel alone or docetaxel plus MLN1117.  Patients receiving docetaxel plus MLN1117 will 
continue treatment with MLN1117 monotherapy beyond Cycle 9.
q During Phase 1b, if MLN1117 de-escalation is warranted, the daily dose of MLN1117 may be reduced or the number of treatment days per week may be 
reduced (eg, from 3 days to 2 days, or further to 1◦day; see Section 6.1 for details.
r
Testing of escalating MLN1117 doses in combination with a fixed docetaxel dose and schedule is planned. However, if frequent docetaxel dose 
modifications are necessary when administered in combination with MLN1117, the fixed dose of docetaxel may be decreased (eg, –1 dose level) based on 
discussion and agreement between investigators and the Millennium project clinician; see Section 6.1.


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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TREATMENT CYCLES 10 AND BEYOND
(for Single-Agent MLN1117 ONLY)
EOTa
PFSFUP/
OSFUP
Predose Day 1 or 2
Physical examination
X
X
Weight
X
X
Vital signsb
X
X
ECOG Performance Status
X
X
Patient diary review
X
X
X
X
X
X
12-lead ECGd
Xd
X
Concomitant medications and 
procedurese
Recorded from the first dose through 30 days after the last dose
AE collection
Recorded from the first dose through 30 days after the last dose
SAE collectionf
Recorded from the time the informed consent is signed through 30 days after the last dose of study drug
Pregnancy testg
X
Hematologyh
X
X
Chemistryh
X
X
Urinalysis
X
X
Fasting serum glucose
X
X
Fasting lipid profilei
X
In-home daily fasting glucose 
monitoringj
See footnote j.
Plasma ctDNA k
X
Disease evaluation by RECIST 1.1 
(CT/MRI)l
Disease assessment to be conducted during Days 18-21 at the end of the end of Cycles 2, 4, and 6 
and then every 3 cycles thereafter
X
Q2mo
OS follow-up (OS and subsequent 
anticancer therapy)m
X
Q3mo


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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TREATMENT CYCLES 10 AND BEYOND
(for Single-Agent MLN1117 ONLY)
EOTa
PFSFUP/
OSFUP
Predose Day 1 or 2
Dosing
Phase 1b n
MLN1117 (dose TBD from dose escalation), 3 days on and 4 days off, for 3-week cycles 
Phase 2 – Arm A n
MLN1117 (dose TBD from dose escalation), 3 days on and 4 days off, for 3-week cycles 
Abbreviations: AE = adverse event; CT = computed tomography; ctDNA = circulating tumor DNA; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; 
 
; EOT = end of treatment; 
MRI = magnetic resonance imaging; OS = overall survival; OSFUP = overall-survival follow-up; PFSFUP = progression-free survival followup; 
RECIST = Response Evaluation Criteria in Solid Tumors; SAE = serious adverse event; TBD = to be determined.
a The EOT visit will occur 30-40 days after the last dose of study drug.
b Vital signs should be assessed predose on Day 1 or Day 2, and at EOT. Vital signs include blood pressure, heart rate, and temperature.
c On Day 1 or 2 of every cycle and at EOT (Phase 2 only).
d ECGs should be taken predose on Day 1 or Day 2 of every cycle and at EOT.  
e See Section 6.6 for medications and procedures that are prohibited during the study and Section 6.8 for medications that should be used cautiously during 
the study.
f
Only those SAEs that occur after the first dose of study drug will be collected in the electronic case report form; however, all SAEs occurring after consent 
will be reported.  See Section 9.
g Urine pregnancy test must be performed before Day 1 or Day 2 of each cycle.
h Samples may be collected 3 days before the scheduled visit.  See Section 7.4.13 for the full hematology and chemistry panel.
i
See Section 7.4.13 for the fasting lipid panel.
j
Patients who experience on-study hyperglycemia will be given a glucometer to monitor their daily predose fasting blood glucose (FBG) levels at home and 
will be instructed to notify the investigator when the FBG 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 7.4.15 for further instruction.
k Samples to be taken on Day 1 or Day 2 every 2 cycles, starting at Cycle 11 Day 1, until EOT.
l
Response assessments will be performed on Days 18-21 at the end of treatment Cycles 2, 4, and 6 and then every 3 cycles thereafter starting at Cycle 9 until 
the patient discontinues study drug due to disease progression, unacceptable toxicity, or death.  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 Cycle 1 Day 1, the results 
of that scan may be used for tumor lesion measurements at screening.  For patients who discontinue for reasons other than disease progression, PFS to be 
assessed every 2 months up to 6 months after study treatment.
m OS is to be assessed every 3 months for up to 1 year after the patient’s last dose of study drug.


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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TREATMENT CYCLES 10 AND BEYOND
(for Single-Agent MLN1117 ONLY)
EOTa
PFSFUP/
OSFUP
Predose Day 1 or 2
n During Phase 1b, if MLN1117 de-escalation is warranted, the daily dose of MLN1117 may be reduced or the number of treatment days per week may be 
reduced (eg, from 3 days to 2 days, or further to 1◦day). See Section 6.1 for details.


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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PHARMACOKINETIC SAMPLING SCHEDULES
Plasma Pharmacokinetic Sampling Schedule During Phase 1b
Time Point
Cycle 1
Day 2
Predose; within 30 min of dosing
X
0.5 hours postdose (± 5 min)
X
1 hour postdose (± 15 min)
X
2 hours postdose (± 15 min)
X
4 hours postdose (± 45 min)
X
6 hours postdose (± 45 min)
X
8 hours postdose (± 1 h)
X
24 hours postdose (± 1 h)
X
Total Samples 
8
Plasma Pharmacokinetic Sampling Schedule During Phase 2, Arm A Only
Time Point
Cycle 1
Cycle 1
Day 2
Day 16
At time of clinic visit (2-6 hours postdose)a
X
Approximately 1 hour after the last PK 
sample (3-7 hours postdose)a
X
Predose; within 30 min of dosing
X
0.5 hours postdose (± 5 min)
X
1 hour postdose (± 15 min)
X
2 hours postdose (± 15 min)
X
4 hours postdose (± 45 min)
X
Total Samples 
5
2
a On Cycle 1 Day 16 patients will take their MLN1117 dose at home and report to the clinical 
site 2-6 hours after dosing.


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................23
LIST OF FIGURES............................................................................................................23
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................23
1. BACKGROUND AND STUDY RATIONALE..............................................................27
1.1 Disease Under Treatment..........................................................................................27
1.2 MLN1117.................................................................................................................27
1.2.1 Nonclinical Experience ......................................................................................28
1.2.2 Clinical Experience............................................................................................29
1.3 Docetaxel .................................................................................................................31
1.4 Study Rationale ........................................................................................................32
1.4.1 Rationale for Combining MLN1117 With Docetaxel .........................................32
1.4.2 Rationale for MLN1117 Dose and Schedule Selection .......................................33
1.4.3 Rationale for Docetaxel Dose Selection .............................................................33
1.5 Potential Risks and Benefits .....................................................................................34
2. STUDY OBJECTIVES ..................................................................................................35
2.1 Primary Objectives ...................................................................................................35
2.2 Secondary Objectives ...............................................................................................36
2.3 Exploratory Objectives .............................................................................................36
3. STUDY ENDPOINTS....................................................................................................37
3.1 Primary Endpoints....................................................................................................37
3.2 Secondary Endpoints................................................................................................37
3.3 Exploratory Endpoints..............................................................................................38
4. STUDY DESIGN...........................................................................................................38
4.1 Overview of Study Design........................................................................................38
4.1.1 Phase 1b (Dose Escalation) ................................................................................40
4.1.2 Phase 2 (Dose Expansion)..................................................................................41
4.2 Number of Patients...................................................................................................44
4.3 Duration of Study.....................................................................................................44
5. STUDY POPULATION.................................................................................................45
5.1 Inclusion Criteria......................................................................................................45
5.2 Exclusion Criteria.....................................................................................................49
6. STUDY DRUG..............................................................................................................51
6.1 Study Drug Administration.......................................................................................51
6.1.1 MLN1117 Administration..................................................................................52
6.1.2 Reference/Control Therapy: Docetaxel Administration ......................................53
6.2 Definitions of Dose-Limiting Toxicity......................................................................53
6.3 Phase 1b Dose Escalation Rules................................................................................55
6.4 Maximum Tolerated Dose and Recommended Phase 2 Dose....................................57
6.5 Dose Modification Guidelines ..................................................................................57
6.5.1 Phase 1b Intrapatient Dose Escalation................................................................58
6.5.2 Phase 1b, Cycle 1, Intrapatient Dose Reduction .................................................59
6.6 Excluded Concomitant Medications and Procedures.................................................66
6.7 Permitted Concomitant Medications and Procedures.................................................66
6.8 Precautions and Restrictions .....................................................................................66


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6.9 Management of Clinical Events................................................................................68
6.10 Blinding and Unblinding ........................................................................................73
6.11 Description of Investigational Agents .....................................................................73
6.12 Preparation, Reconstitution, and Dispensation ........................................................74
6.13 Packaging and Labeling..........................................................................................74
6.14 Storage, Handling, and Accountability....................................................................74
7. STUDY CONDUCT ......................................................................................................75
7.1 Study Personnel and Organizations...........................................................................75
7.2 Arrangements for Recruitment of Patients ................................................................75
7.3 Treatment Group Assignments .................................................................................76
7.4 Study Procedures......................................................................................................76
7.4.1 Informed Consent ..............................................................................................76
7.4.2 Patient Demographics ........................................................................................76
7.4.3 Medical History.................................................................................................76
7.4.4 Physical Examination.........................................................................................76
7.4.5 Patient Height and Weight .................................................................................76
7.4.6 Vital Signs .........................................................................................................77
7.4.7 Pregnancy Test ..................................................................................................77
7.4.8 Eastern Cooperative Oncology Group Scale for Performance Status ..................77
7.4.9 Concomitant Medications and Procedures..........................................................77
7.4.10 Adverse Events ................................................................................................77
7.4.11 Enrollment .......................................................................................................77
7.4.12 Electrocardiogram............................................................................................78
7.4.13 Clinical Laboratory Evaluations.......................................................................78
7.4.14 Fasting Serum Glucose ....................................................................................79
7.4.15 In-Home Daily Glucose Monitoring.................................................................79
7.4.16 Disease Assessment .........................................................................................80
7.4.17 Archival Tumor Tissue and Tumor Biopsies ....................................................80
7.4.18 Pharmacokinetic Measurements.......................................................................81
7.4.19 DNA Measurements.........................................................................................81
7.4.20 Health-Related Quality of Life .........................................................................82
7.5 Completion of Treatment..........................................................................................82
7.6 Completion of Study.................................................................................................82
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement................83
7.8 Withdrawal of Patients From Study..........................................................................83
7.9 Study Compliance ....................................................................................................84
7.10 Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)...........................................................................................................84
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................85
8.1 Statistical Methods ...................................................................................................85
8.1.1 Determination of Sample Size............................................................................85
8.1.2 Randomization and Stratification .......................................................................89
8.1.3 Populations for Analysis ....................................................................................90
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................91
8.1.5 Demographic and Baseline Characteristics.........................................................91
8.1.6 Efficacy Analysis...............................................................................................91


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8.1.7 Exploratory Analysis .........................................................................................92
8.1.8
.........................92
8.1.9 Pharmacokinetics/Biomarkers............................................................................93
8.1.10 Safety Analysis ................................................................................................94
8.1.11 Interim Analysis...............................................................................................95
9. ADVERSE EVENTS .....................................................................................................96
9.1 Definitions................................................................................................................96
9.1.1 Adverse Event Definition...................................................................................96
9.1.2 Serious Adverse Event Definition ......................................................................97
9.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................98
9.3 Monitoring of Adverse Events and Period of Observation.........................................99
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........99
9.5 Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities .........100
10. ADMINISTRATIVE REQUIREMENTS ...................................................................100
10.1 Good Clinical Practice..........................................................................................100
10.2 Data Quality Assurance ........................................................................................100
10.3 Electronic Case Report Form Completion.............................................................101
10.4 Study Monitoring .................................................................................................101
10.5 Ethical Considerations..........................................................................................102
10.6 Patient Information and Informed Consent............................................................102
10.7 Patient Confidentiality..........................................................................................102
10.8 Investigator Compliance.......................................................................................102
10.9 On-site Audits ......................................................................................................103
10.10 Investigator and Site Responsibility for Drug Accountability..............................103
10.11 Product Complaints ............................................................................................103
10.12 Closure of the Study ...........................................................................................104
10.13 Record Retention................................................................................................104
11. USE OF INFORMATION..........................................................................................105
12. INVESTIGATOR AGREEMENT..............................................................................107
13. REFERENCES...........................................................................................................108
14. APPENDICES ...........................................................................................................110
14.1 Eastern Cooperative Oncology Group Scale for Performance Status.....................110
14.2 Cockcroft-Gault Estimate .....................................................................................110
14.3 List of Strong Inhibitors and Inducers of CYP3A4................................................110
14.4 New York Heart Association Classification of Cardiac Disease ............................111
14.5 Methods of Contraception Considered to be Effective ..........................................111
14.6 Amendment 1 Rationale and Purposes..................................................................113
14.7 Amendment 2 Rationale and Purposes..................................................................114
14.8 Amendment 3 Detailed Summary of Changes.......................................................115


TAK-117 (MLN1117)
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LIST OF TABLES
Table 1.a   
INK1117-001 Dosing Regimens .................................................................30
Table 6.a   
Guidelines for MLN1117 and Docetaxel Dose Modifications for 
Hematologic Toxicity..................................................................................61
Table 6.b   
Guidelines for MLN1117 and Docetaxel Dose Modifications for 
Nonhematologic Toxicity............................................................................62
Table 6.c   
Management of Hyperglycemia...................................................................69
LIST OF FIGURES
Figure 6.a   
Dose Escalation Algorithm..........................................................................56
Figure 8.a   
Phase 2, Sequential and Bayesian Design....................................................89
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
5-HT3
5-hydroxytryptamine
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
ASH
American Society of Hematology
AST
aspartate aminotransferase
ATP
adenosine 5’ triphosphate
AUC
area under the plasma concentration versus time curve
AUCinf
area under the plasma concentration versus time curve from zero to infinity
AUClast
area under the plasma concentration versus time curve from zero to the time of the 
last quantifiable concentration
AUCτ
area under the plasma concentration versus time curve from zero to next dose
BCRP
breast cancer resistance protein
BID
bis in die; twice daily
BUN
blood urea nitrogen
CI
confidence interval
CL/F
apparent total body clearance


TAK-117 (MLN1117)
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Abbreviation
Term
Cmax
single-dose maximum (peak) concentration  
CO2
carbon dioxide
CR
complete response
CT
computed tomography
ctDNA
circulating tumor DNA
CYP
cytochrome P450
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid
DOR
duration of response
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data capture
EGFR
epidermal growth factor receptor
EMA
European Medicines Agency
 
 
EOT
End of Treatment (visit)
FBG
fasting blood glucose
FSG
fasting serum glucose
GCP
Good Clinical Practice
G-CSF
granulocyte colony stimulating factor
GGT
gamma glutamyl transferase
GLP
Good Laboratory Practices
HbA1c
hemoglobin A1c
hCG
human chorionic gonadotropin
HDL
high-density lipoprotein
HDPE
high-density polyethylene
HER2 
human epidermal growth factor receptor 2
HRMUT/AMP
squamous PIK3CA mutation and/or amplification hazard ratio
HRnonsquamous
nonsquamous hazard ratio
HRoverall
overall hazard ratio


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Abbreviation
Term
HRsquamous
squamous hazard ratio
IB
Investigator’s Brochure
IC50
concentration producing 50% inhibition
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
IGFR
insulin-like growth factor receptor 
ITT
intent-to-treat
IV
intravenous; intravenously
IXRS
interactive voice/web response system
LDH
lactate dehydrogenase
LDL
low-density lipoprotein
LFT
liver function test(s)
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MLN1117
TAK-117
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
mTORr
serine/threonine kinase mechanistic target of rapamycin
MTW
Monday, Tuesday, and Wednesday
MUT/AMP
mutation and/or amplification
MWF
Monday, Wednesday, and Friday
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC
non-small cell lung cancer
OCT
organic cation transporter
OS
overall survival
PD
progressive disease (disease progression)
PFS
progression-free survival
Pgp
P-glycoprotein
PI3K
phosphoinositide 3-kinase
PI3K
phosphoinositide 3-kinase alpha isoform
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PTEN
phosphatase and tensin homolog


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Abbreviation
Term
PR
partial response
PRO
patient-reported outcome
Q3W
every 3 weeks
QD
quaque die; once daily
QW
weekly
RBC
red blood cell
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
RR
response rate
RTK
receptor tyrosine kinase
SAE
serious adverse event
SAP
statistical analysis plan
SCLC
small cell lung cancer
SD
stable disease
SmPC
Summary of Product Characteristics
SUSAR
suspected unexpected serious adverse reaction
t1/2
terminal disposition half-life
TAK-117
MLN1117
TEAE
treatment-emergent adverse event
Tmax
single-dose first time of occurrence of maximum (peak) concentration
TTP
time to progression
ULN
upper limit of the normal range
US
United States
USPI
United States Prescribing Information
WT
wild-type


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1.   
BACKGROUND AND STUDY RATIONALE
MLN1117 is an orally available, potent, and selective small molecule inhibitor of the class I 
phosphoinositide 3-kinase (PI3K) alpha isoform (PI3K).  It is being developed for the 
treatment of malignancies in which the PI3K pathway is believed to contribute significantly 
to the pathologic process and response to the standard therapies.  
MLN1117 is also being developed in combination with MLN0128 (a novel, highly selective, 
orally bioavailable adenosine 5’ triphosphate (ATP)-competitive inhibitor of the 
serine/threonine kinase referred to as the metabolic target of rapamycin [mTORr]) as a 
treatment for advanced nonhematologic malignancies.
1.1   
Disease Under Treatment
Lung cancer, classified into small cell lung cancer (SCLC) and non-small cell lung cancer 
(NSCLC), remains the leading cause of cancer-related mortality worldwide. Non-small cell 
lung cancer, including squamous cell carcinoma and nonsquamous cell carcinoma 
(adenocarcinoma, large cell carcinoma, and others), accounts for more than 80% of all lung 
cancer cases.  The majority of patients with NSCLC are diagnosed at an advanced stage with 
inoperable, locally advanced or metastatic disease.  Therefore, the standard treatment, which 
commonly includes a combination of chemotherapy and radiation therapy, focuses mainly 
on disease control and maintenance of quality of life. The overall survival (OS) for patients 
with NSCLC in the advanced setting is approximately 8 to 10 months, making it an area of 
highly unmet medical need that attracts extensive research and development efforts.(4)  
1.2   
MLN1117
Activating somatic missense mutations (eg, E542K, E545K, and H1047R) in the 
phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene 
encoding the p110catalytic subunit of PI3Khave been identified as a major mechanism 
for PI3K-dependent malignant transformation, proliferation, and survival.  PIK3CA
mutations have been reported to occur in various solid tumors with the highest rates in breast 
(27%), endometrial (24%), bladder (23%), colon (15%), and ovarian (10%) cancers.(5, 6, 7)  In 
addition to direct mutations of PI3K, the pathway may also be activated by mutations or 
overexpression of upstream effectors such as receptor tyrosine kinases (RTKs) including 
human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor
(EGFR), and insulin-like growth factor receptor (IGFR). PIK3CA is also amplified in 
several tumor types including the squamous type of NSCLC.(8)  MLN1117 is a selective,


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small molecule inhibitor of PI3K.  MLN1117 has demonstrated greatest antiproliferative 
activity in cell lines harboring PIK3CA activating mutations and/or HER2 overexpression.   
1.2.1   
Nonclinical Experience
In human tumor mouse xenograft models harboring activating mutations for PI3K, 
MLN1117 inhibited pharmacodynamic markers of the PI3K pathway that correlate with 
strong tumor growth inhibition in a specific and dose-dependent manner. 
Secondary pharmacology studies demonstrated no appreciable off-target activities and 
limited potential to affect metabolism or immune function at pharmacologically active doses 
and exposures.
MLN1117 displayed no effect on electrocardiograms (ECGs) obtained from monkeys and 
low potential concentration required for 50% inhibition effect (IC50) > 30 µM to affect the 
human ether-a-go-go-related potassium channel.
MLN1117 displayed consistent and predictable oral (PO) pharmacokinetic (PK) parameters 
across mice, rats, and monkeys, with rapid absorption first time to maximum plasma
concentration (Tmax) (ranging from 0.25-5.0 hours) and high PO bioavailability (ranging 
from 70%-98%).  Pharmacokinetic analysis displayed a dose-dependent increase in 
MLN1117 levels in plasma and tumor lysates in the MDA-MB-453 tumor xenograft model.  
MLN1117 is also an inhibitor of organic cation transporter (OCT)1, OCT2, and breast 
cancer resistance protein (BCRP), but not of P-glycoprotein (Pgp).  Multiple human 
cytochrome P450 (CYP) isozymes (CYP3A4/5, 1A2, 2C8, and 2C9) appear to contribute to 
MLN1117 metabolism, with CYP3A4 responsible for 72% of the metabolism, when 
normalized for liver content.  MLN1117 displayed low potential (IC50 100 µM) for 
inhibition of CYP3A4/5, CYP2D6, CYP2C19, CYP2C9, CYP2C8, and CYP1A2, and did 
not induce CYP1A2, 2B6, or 3A4/5 activity, except in 1 hepatocyte preparation, in which 
there was an increase in CYP3A4 mRNA; however, this was not associated with an increase 
in CYP3A4/5 activity.  The potential for MLN1117 to cause exposure changes to 
concomitantly administered CYP isozyme substrates is low; however, concomitantly 
administered inhibitors and inducers of CYP3A4 isozyme can affect the exposure to 
MLN1117.  
Toxicology studies were performed in rats and in monkeys.  After repeat PO administration 
in the rat, doses 100 mg/kg were well tolerated, and a dose of 300 mg/kg was considered 
severely toxic.  Twenty-eight days of repeat PO dosing in the monkey demonstrated that 


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doses 50 mg/kg were well tolerated, and a dose of 250 mg/kg produced dose-limiting and 
severe toxicities.  The observed toxicities were consistent between rats and monkeys with no 
apparent sex differences.  
The adverse effects observed in rats included decreases in body weight and test article-
related alterations primarily centered on minimal to mild lymphoid depletion that correlated 
with clinical pathology, organ weight, and microscopic observations including lower white 
blood cell and lymphocyte counts; decreased spleen and thymus weights, and lymphoid 
depletion in multiple lymph nodes, Peyer’s patches, spleen, and thymus; bone marrow 
depletion; and decreased incidence/severity of background mononuclear infiltrates in the 
liver.  In the monkey, test-article related alterations were limited to lymphoid depletion and 
included decreased thymus weights and minimal to mild microscopic lymphoid depletion in 
the thymus, spleen, and 1 or more lymph nodes.
On the basis of 28-day Good Laboratory Practice (GLP) toxicology studies, the severely 
toxic dose in 10% in rats was 100 mg/kg (600 mg/m2) and the highest nonseverely toxic 
dose in monkeys was 50 mg/kg (600 mg/m2).  
MLN1117 was evaluated in the bacterial reverse mutation (Ames) assay, and there was no 
evidence of mutagenicity.
Detailed information regarding the nonclinical pharmacology and toxicology of MLN1117
may be found in the Investigator’s Brochure (IB).
1.2.2   
Clinical Experience
Millennium is currently evaluating the safety, tolerability, and PK profile of single-agent 
MLN1117 in a first-in-human, dose-finding study in patients with advanced, 
nonhematologic malignancies (Study INK1117-001).  This ongoing phase 1 study is 
designed to determine the maximum tolerated dose (MTD) or the recommended phase 2 
dose (RP2D) and dose-limiting toxicities (DLTs) when MLN1117 is administered PO on 
21-day cycles of daily and intermittent dosing schedules.  Study INK1117-001 consists of a 
dose escalation phase and a dose-level expansion phase.  The escalation phase will enroll 
approximately 120 patients with any solid tumor.  The expansion phase will enroll 
approximately 70 patients who have breast cancer or non-small cell lung cancer. As of 23 
June 2014, a total of 78 patients had been enrolled into the escalation phase and had received 
at least 1 dose of MLN1117.  A tabular summary of the weekly dosing regimens
administered as of 23 June 2014 is presented in Table 1.a.


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Table 1.a   
INK1117-001 Dosing Regimens
Weekly Dosing Regimen/Dose (mg)
No. of Subjects
QD:  100, 150, 200, 300
QD on MWF QW:  200, 300, 400, 600, 900, 1200
QD on MTW QW:  200, 400, 600, 900
BID on MWF QW:  300
Enrolled:  78
Abbreviations:  BID = twice daily; MTW = Monday, Tuesday, and Wednesday; 
MWF = Monday, Wednesday, and Friday; QD = once daily; QW = each week.
In the PK analysis portion of this study, MLN1117 capsules were administered PO using 
3 different dosing schedules:  once daily (QD); 3 days each week (QW) of consecutive-day 
dosing (eg, Monday, Tuesday, and Wednesday [MTW] QW); and 3 days each week of 
every-other-day dosing (eg, Monday, Wednesday, and Friday [MWF] QW).  The plasma PK 
of MLN1117 was evaluated in Study INK1117-001 for 24 hours after dosing of MLN1117 
on Day 1 of Cycles 1 and 2, and during Week 2 of Cycle 1.  Preliminary PK data suggest 
fast PO absorption following MLN1117 dosing, with a mean plasma terminal disposition 
half-life (t½) of approximately 11 hours across cohorts.  The extent of accumulation 
following QD dosing was low (accumulation ratio of approximately 1.2).  Systemic 
exposures of MLN1117 increased with increasing dose over the 100- to 1200-mg dose 
range.  There was a 9-fold increase in plasma exposure (area under the plasma concentration 
versus time curve [AUC] from zero to infinity [AUCinf]) of MLN1117, with a 12-fold 
increase in dose from 100 to 1200 mg. 
Of the 78 patients treated in Study INK1117-001 for whom data had been entered into the 
clinical database as of the data cutoff, 75 (96%) had reported ≥1 treatment-emergent 
adverse event (TEAE), and 67 patients (86%) had experienced ≥1 TEAE that was 
considered to be study drug related.  The most commonly reported (≥15% of patients 
overall) study drug-related adverse events (AEs) included nausea (36 patients, 46%), 
hyperglycemia or vomiting (25 patients each, 32%), diarrhea (22 patients, 28%), fatigue 
(18 patients, 23%), aspartate aminotransferase (AST) increased or appetite decreased 
(15 patients each, 19%), and alanine aminotransferase (ALT) increased (12 patients, 15%).
Adverse events with severity ≥Grade 3 were reported in 38 of 78 patients (49%).  The most 
common (≥5% of patients) ≥Grade 3 AEs that were reported as being related to MLN1117 
were ALT increased (6 patients, 8%), hyperglycemia (5 patients, 6%), and AST increased 
(4 patients, 5%). 


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Of 23 patients treated with QD MLN1117 on [MTW] QW, the regimen of MLN1117 that 
will be used in this study, the most commonly reported (≥10% of patients) study drug-
related AEs were nausea (11 patients, 48%), hyperglycemia or vomiting (9 patients each, 
39%), diarrhea or fatigue (7 patients each, 30%), AST increased or asthenia (3 patients each, 
13%).  The ≥Grade 3 study drug-related AEs associated with the [MTW] QW schedule 
include hyperglycemia (3 patients, 13%) and ALT increased (1 patient, 4%). No ≥Grade 3 
drug-related AST increased was observed in the [MTW] QW cohort.
A total of 11 patients (14%) had discontinued from Study INK1117-001 because of 1 or 
more AEs as of the clinical data cutoff; most events were reported as severity Grade 3, and 
the majority were considered not related to study drug.  No events of severity Grade 4 were 
reported as resulting in study discontinuation, although 2 events (hypercalcemia, respiratory 
failure) resulted in fatal outcomes; neither of these events was considered related to study 
drug.
As of the clinical data cutoff, serious adverse events (SAEs) had occurred in 29 of the 78 
enrolled patients (37%) in Study INK1117-0001.  The majority of the SAEs were reported 
as unrelated to study drug and resolved without sequelae.  A total of 6 patients had died 
either during the treatment period or within 30 days of their last dose of study drug; none of 
the fatalities were considered related to study drug.
Millennium has also initiated a multicenter, open-label, phase 1b trial (C32001) of 
MLN1117 in combination with MLN0128 (a PO mTORC1/2 inhibitor) administered to 
adult patients with advanced nonhematologic malignancies.  The primary objective of this 
study is to evaluate the safety, tolerability, PK, and pharmacodynamics of MLN0128 in 
combination with MLN1117.  
Further details on these studies are provided in the IB.  
1.3   
Docetaxel
Docetaxel is an antimicrotubule agent that has demonstrated significant clinical activity both 
as single-agent therapy and in combination with other chemotherapeutic agents in a wide 
range of solid tumors.  In the United States (US) and Europe, docetaxel is approved as 
single-agent therapy for locally advanced or metastatic NSCLC after platinum therapy 
failure; and with cisplatin for unresectable, locally advanced or metastatic untreated 
NSCLC. Investigators are instructed to consult the most recent local prescribing information


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(eg, SmPC, USPI, etc) for complete details regarding the administration and management of 
docetaxel. 
1.4   
Study Rationale
The PI3K signaling pathway critical for many cellular processes, such as proliferation and 
survival, is frequently dysregulated in lung cancer in response to genetic alterations that 
affect one of its components: activating mutations or amplification of upstream receptor 
tyrosine kinase, amplification of PI3K, loss or inactivation of PTEN, over-activation of 
downstream kinase AKT, and mutational activation of the PIK3CA gene encoding the 
p110catalytic subunit of PI3K. Activating mutations of PIK3CA have been found in 
approximately 5% to 10% of NSCLC; however, genomic amplification of PIK3CA was 
identified in 30% to 50% of squamous cell carcinoma of lung. Chemotherapy is also known 
to cause activation of the PI3K pathway in cancer cells to sustain survival.(9) Nonclinical 
pharmacology data demonstrated significant antitumor activity in xenograft models of 
NSCLC, in particular, in combination with docetaxel. Therefore, targeting PI3K signaling, 
particularly by a PI3K-specific inhibitor such as MLN1117, may provide a potential 
treatment option for patients with advanced NSCLC in combination with standard care 
agents such as docetaxel.
1.4.1   
Rationale for Combining MLN1117 With Docetaxel
Preliminary nonclinical evaluation of MLN1117 in combination with docetaxel, a standard 
chemotherapy agent commonly used in both the front-line (in combination with other 
chemotherapy agents) and second-line (single agent) or later settings, demonstrated equal or 
better antitumor activity when MLN1117 was administered 24 hours after treatment with 
docetaxel compared with concomitant dosing of both compounds in a small cell lung
carcinoma model using NCI-H1048 (NCDS-02264:  Antitumor Activity of MLN1117 and 
Taxotere Alone or In Combination in NCI-H1048 Xenografts, and NCDS-02265:  
Scheduling Effect of MLN1117 in Combination with High Dose Taxotere on Tumor Growth 
Delay of NCI-H1048 Xenografts).  In addition, treatment with docetaxel activated the PI3K 
pathway, which could be suppressed by MLN1117 resulting in enhanced apoptosis (NCDS-
02263:  PD [Pharmacodynamic] Evaluation of the Combination of Docetaxel and MLN1117 
in NCI-H1048 Cells In Vitro).  The current study is designed to clinically evaluate the 
combination of MLN1117 and docetaxel for safety, tolerability, optimal dose/schedule, and 
preliminary efficacy in advanced NSCLC.


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1.4.2   
Rationale for MLN1117 Dose and Schedule Selection
MLN1117 has been studied in a number of doses/schedules in Study INK1117-001 
including QD, QD continuously on 3 days with 4 days off each week (ie, once-daily on 
MTW of each week), QD on 3 days with dosing on every other day of each week (ie, MWF 
of each week), and twice-daily (BID) on MWF of each week. Currently the highest 
tolerated dose of single-agent MLN1117 is 900 mg in both the MTW and MWF dosing 
schedules.  Safety findings of these 2 schedules across dose levels that have been evaluated 
were comparable.  Both schedules, at a given dose, deliver the same total weekly dose and 
comparable total weekly AUC of MLN1117. Because MLN1117 exhibits AUC-dependent 
efficacy in nonclinical efficacy studies, either MTW or MWF schedules are expected to
provide comparable effect at similar doses of MLN1117. In this study, the MTW dosing 
schedule of 3 days continuous dosing with 4 days off each week will be selected to be 
combined with docetaxel. On the basis of nonclinical observations indicating better 
antitumor activity using sequential dosing of MLN1117 following docetaxel treatment, 
MLN1117 will be dosed 24 hours after docetaxel (see Section 1.4.1). Thus, MLN1117 will 
be dosed QD on Days 2 through 4, 9 through 11, and 16 through 18 of each dosing cycle.
However, during Phase 1b, if MLN1117 de-escalation is warranted, the daily dose of 
MLN1117 may be reduced, or the number of treatment days per week may be reduced 
(eg, from 3 days to 2 days, or further to 1◦day); see Section 6.1. These decisions will be
made jointly by investigators and the Millennium project clinician. The alternative 
MLN1117 regimen may be carried forward into Phase 2 of the study if deemed appropriate 
by the sponsor in consultation with the investigators.
The Phase 1b portion of the study is a dose escalation of MLN1117 in combination with 
docetaxel.  This portion of the study will evaluate the safety, tolerability, and PK of 
MLN1117 administration at ascending dose levels (dose levels of 300, 600, and 900 mg are 
planned).  MLN1117 doses will be administered 24 hours after docetaxel.  The highest dose 
of MLN1117 that can be safely combined with docetaxel will be selected for the Phase 2 
portion of the study.
1.4.3   
Rationale for Docetaxel Dose Selection
For treatment after failure of prior platinum-based chemotherapy, the standard dose of 
docetaxel as monotherapy is 75 mg/m2 administered intravenously (IV) over 1 hour every 3 
weeks (Q3W).  In this study, the docetaxel alone control arm will use this standard Q3W
regimen.  In the MLN1117 plus docetaxel arm, docetaxel will be administered on a weekly 
schedule at a dose of 36 mg/m2 (2 weeks on, 1 week off) in combination with MLN1117. If, 


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however, during the dose-escalation phase, frequent docetaxel dose modifications are 
necessary, the fixed dose of docetaxel may be decreased (eg, –1 dose level) based on 
discussion and agreement between investigators and the Millennium project clinician. If 
decreased, the lower docetaxel dose may be carried forward into Phase 2 of the study if 
deemed appropriate by the sponsor in consultation with the investigators.
Administering docetaxel weekly has shown similar efficacy but better tolerability in a 
meta-analysis of 5 randomized trials comparing the weekly versus the Q3W regimen of 
docetaxel.(10)  The weekly rather than the Q3W schedule of docetaxel has been selected in 
this study as it is best suited to combine with the 3-on/4-off weekly intermittent dosing 
regimen of MLN1117. Such a combination will provide 3 instances of combined dosing 
within a treatment cycle, where a 3-day pulse of MLN1117 would be administered 24 hours
after each docetaxel dose to maximize the expected benefits from the combination 
anticipated from the previously described mechanistic studies and nonclinical data.  The 
total docetaxel dose per cycle planned for the MLN1117 plus docetaxel arm (2 × 36 mg/m2) 
is similar to that of the docetaxel alone control arm (75 mg/m2).  
This study is designed to clinically evaluate the combination of MLN1117 and docetaxel for 
safety, tolerability, optimal dose/schedule, and preliminary efficacy in advanced NSCLC. 
1.5   
Potential Risks and Benefits
MLN1117 is a selective inhibitor of PI3Kthat might provide a better tolerability profile 
than pan-PI3K inhibitors.  
Grade 1 through 3 increases in ALT and/or AST have been observed in patients receiving 
MLN1117 in Study INK1117-001.  The elevations were reported primarily in connection 
with the 200- and 300-mg QD doses.  Most were nonserious and reversible.  Patients in the 
current study will have frequent monitoring of liver function tests (LFTs) as outlined in the 
Schedules of Events.
Grade 1 through 3 hyperglycemia events have been reported in patients receiving MLN1117 
in Study INK1117-001.  Elevations were minimized with antihyperglycemic agents or no 
intervention. In addition to obtaining fasting serum glucose (FSG) levels at the study site 
(see Schedules of Events), patients in this study who experience hyperglycemia will be 
given a glucometer to monitor their daily predose fasting blood glucose (FBG) levels at 
home.  Patients will be instructed to notify the study staff immediately of any abnormal 
readings for further instructions on the management of their hyperglycemia.


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Nausea and vomiting have been reported among the most frequent drug-related AEs in 
patients receiving MLN1117 in Study INK1117-001.  Use of anti-emetics (such as PO 
compazine or ondanestron) per local standard care, if needed to control nausea or vomiting, 
is permitted. 
Further details regarding TEAEs observed in patients receiving MLN1117 in Study
INK1117-001 are presented in the MLN1117 IB.
Please refer to Section 6.9 for instructions regarding the management of these AEs.
Patients treated with docetaxel commonly experience bone marrow suppression, 
gastrointestinal events, fatigue, and hair loss.  While these events are generally reversible 
and manageable, they can lead to serious outcomes or hospitalization.  Cumulative toxicities 
of docetaxel include edema or other forms of fluid retention and neuropathy, which can limit 
tolerability to extended treatment cycles, and thus reduce the opportunity for durable disease 
control.  Refer to the docetaxel prescribing information for further details regarding the 
anticipated risks and benefits of docetaxel.
Taken together, the safety data of MLN1117 and docetaxel as single agents indicate that the 
combination of these 2 agents may lead to increased gastrointestinal toxicities that should be 
generally reversible (see Section 6.9).  The combination of MLN1117 and docetaxel may 
lead to exacerbation of non-overlapping toxicities and the occurrence of new toxicities that 
have not been identified with the single agents.
2.
STUDY OBJECTIVES
2.1   
Primary Objectives
The primary objectives are:
Phase 1b

To determine the DLTs, MTD, and RP2D of MLN1117 when administered PO in
combination with docetaxel in patients with NSCLC
Phase 2

To evaluate progression-free survival (PFS) as the primary efficacy measure of
MLN1117 plus docetaxel versus docetaxel alone in patients with advanced NSCLC


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2.2   
Secondary Objectives
The secondary objectives are:

To evaluate the safety and tolerability of MLN1117 plus docetaxel administered to
patients with NSCLC (Phase 1b and Phase 2)

To evaluate the PK of MLN1117 when administered with docetaxel (Phase 1b and
Phase 2)

To evaluate additional efficacy measures, such as response rate (RR), disease control
rate, response duration, time to progression (TTP), and OS, of MLN1117 plus
docetaxel versus docetaxel alone in patients with NSCLC (Phase 2 only)

To evaluate PFS and additional efficacy measures of MLN1117 plus docetaxel
versus docetaxel alone in different populations of patients with NSCLC, such as
patients with squamous NSCLC versus nonsquamous NSCLC, and patients with
squamous NSCLC with or without PIK3CA mutation and/or amplification
(MUT/AMP) (Phase 2 only)
2.3   
Exploratory Objectives
The exploratory objectives are:





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3.
STUDY ENDPOINTS
3.1   
Primary Endpoints
The primary endpoints are:
Phase 1b

DLTs, MTD, and RP2D
Phase 2

PFS
3.2   
Secondary Endpoints
The secondary endpoints are:

Safety (Phase 1b and Phase 2)
o
Vital signs
o
Physical examination findings
o
12-lead ECG
o
Clinical laboratory test results
o
AEs and SAEs

Response rate (complete response [CR] + partial response [PR]), disease control rate
(CR + PR + stable disease [SD]), duration of response (DOR), and TTP (Phase 2
only)

OS (Phase 2 only)

PK parameters for MLN1117 including, but not limited to, single-dose maximum
(peak) concentration (Cmax), Tmax, AUC from zero to next dose (AUCτ) and from
time zero to last the time of the last quantifiable concentration (AUClast), t1/2, and
apparent total body clearance (CL/F), as permitted by the data (Phase 1b only)

MLN1117 plasma concentrations when administered 1 day after docetaxel (Phase 2
only)


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3.3   
Exploratory Endpoints 
The exploratory endpoints are:




4.
STUDY DESIGN
4.1   
Overview of Study Design
This is an open-label, phase 1b/adaptive phase 2 study of MLN1117 in combination with 
docetaxel versus docetaxel alone in adult patients with NSCLC.  
This study consists of a Phase 1b dose escalation phase and an adaptive, randomized Phase 2 
expansion phase. The patient population will consist of adults with locally advanced or 
metastatic NSCLC refractory or resistant to 1 prior line platinum-based, non-docetaxel-
containing systemic chemotherapy (Phase 2). Patients who, after front-line, platinum-based, 
non-docetaxel-containing chemotherapy, have also been treated with 1 line of nivolumab or 
other immune-checkpoint inhibitors but progressed on or after that therapy, would also be 
eligible for Phase 2. Patients with NSCLC who have been treated with multiple prior lines 
of therapies are eligible for Phase 1b.
Eligibility will be determined during the Screening period, which may last for up to 28 days 
before the Cycle 1 Day 1 visit. Patients who meet all eligibility criteria and provide written 


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informed consent will be enrolled in this study.  For each phase of the study, study drug will 
be administered in cycles of 21 days (see Section 6.1).
Docetaxel will be administered IV, and MLN1117 will be administered PO throughout the 
study. 
The treatment duration for all patients in Phase 1b and Phase 2 may be up to 9 cycles of 
either docetaxel alone or docetaxel in combination with MLN1117.  Patients receiving 
docetaxel plus MLN1117 may continue treatment with MLN1117 monotherapy beyond 
9 cycles.  Patients may continue to receive treatment until either disease progression (PD), 
occurrence of unacceptable toxicities, or death.  The maximum duration of treatment will be 
9 cycles (approximately 6 months) for patients receiving docetaxel alone or 12 months for 
patients receiving MLN1117 plus docetaxel (ie, 9 cycles of MLN1117 plus docetaxel 
followed by MLN1117 alone) unless, after discussion between the investigator and sponsor, 
it is determined that a patient would derive benefit from continued treatment beyond 
9 cycles or12 months, respectively.  Patients may discontinue study treatment at any time.  
Patients will attend the End-of-Treatment (EOT) visit 30 to 40 days after receiving their last 
dose of study drug.   
Patients will continue to be followed after discontinuation of study treatment to collect OS 
data for a period of up to 12 months (after last dose of study treatment).  In addition, for 
patients who discontinue treatment due to reasons other than PD, PFS data will be collected 
during the posttreatment follow-up period of up to 6 months after the last dose of study drug,
and OS data collection will continue until death, withdrawal of consent for further follow-
up, or 12 months following the last dose of study drug.  
Throughout the study, AEs will be assessed, and laboratory values, vital signs, and ECGs 
will be obtained per the Schedules of Events to evaluate the safety and tolerability of 
MLN1117 alone or in combination with docetaxel.   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.(11)  Dose-limiting toxicities are defined in 
Section 6.2.  
Radiological tumor evaluations (computed tomography [CT] scan with IV contrast or 
magnetic resonance imaging [MRI] as clinically indicated of the chest, abdomen, and pelvis)
will be used to evaluate disease response according to modified Response Evaluation 
Criteria in Solid Tumors (RECIST) guidelines, Version 1.1).(12)  Radiographic tumor 
evaluations and disease assessment will be performed by the investigator at the time points 


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specified in the Schedules of Events.  In the Phase 2 portion of the study, a copy of all 
radiographic images with measurements will be sent to a central imaging vendor for the 
purpose of retrospective review by the sponsor; however, central radiologic evaluation is not 
planned for response assessment during the conduct of the study.
In addition to objective response assessment per modified RECIST guidelines, in Phase 2 of 
the study, 
 
 
  
 
 and treatment on physical, role, emotional, cognitive, and social 
functioning.
Blood samples for analysis of circulating tumor DNA will be collected at baseline in all 
patients.  Subsequent samples will be obtained at the time points specified in the Schedules
of Events and analyzed for the presence and clone frequency of somatic mutations 
frequently reported in solid tumors including PIK3CA mutations.  Correlative studies will be 
performed to compare the mutation data generated from circulating tumor DNA with that 
from tumor tissue DNA.  Dynamic changes in mutant clone frequency measured in 
circulating tumor DNA over the course of treatment will be evaluated in relation to objective 
response and disease status.
In addition, archived or fresh biopsy tumor tissue samples collected during screening will be 
analyzed for somatic alterations and other biomarkers that may relate to sensitivity or 
resistance to MLN1117 plus docetaxel.
Pharmacokinetic samples will be collected as specified in the Pharmacokinetic Sampling 
Schedules to characterize the PK of MLN1117.  
4.1.1   
Phase 1b (Dose Escalation)
Approximately 15 patients with NSCLC regardless of histology (squamous or 
nonsquamous) will be enrolled in this phase of the study.  To determine the DLTs, MTD, 
and RP2D of MLN1117 plus docetaxel, a 3 + 3 dose escalation scheme (see Section 6.3) 
with a fixed dose of docetaxel and varying dose levels of MLN1117 will be used.
During a 21-day cycle of treatment, docetaxel (36 mg/m2) IV will be administered on Days 
1 and 8, and MLN1117 tablets (planned doses of 300, 600, and 900 mg) will be 
administered PO on a weekly schedule that includes 3 consecutive dosing days per week 


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(eg, Days 2, 3, 4, 9, 10, 11, 16, 17, and 18). If MTD or RP2D is not achieved by 900 mg, 
higher dose levels at 300 mg increments may be evaluated.  More conservative dose 
escalation, evaluation of intermediate doses, and expansion of an existing dose level 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 or exposure of MLN1117 plus docetaxel.  
If MLN1117 de-escalation is warranted, the daily dose of MLN1117 may be reduced or the 
number of treatment days per week may be reduced (eg, from 3 days to 2 days, or further to 
1◦day); see Section 6.1 for details.
Testing of escalating MLN1117 doses in combination with a fixed docetaxel dose and 
schedule is planned. However, if frequent docetaxel dose modifications are necessary when 
administered in combination with MLN1117, the fixed dose of docetaxel may be decreased 
(eg, –1 dose level) based on discussion and agreement between investigators and the 
Millennium project clinician; see Section 6.1.
4.1.2   
Phase 2 (Dose Expansion)
In Phase 2, the expansion phase of the study, up to 140 patients may be treated with the dose 
of MLN1117 that in combination with docetaxel is identified in Phase 1b as the RP2D 
(Arm A) or docetaxel alone (Arm B).  

Arm A: docetaxel 36 mg/m2 IV on Days 1 and 8 of a 21-day cycle plus MLN1117 
tablets, at the dose determined in Phase 1b, on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 
of a 21-day cycle. (An alternative combination dosing regimen of MLN1117 plus
docetaxel may be used based on the RP2D decision in Phase 1b if deemed 
appropriate by the sponsor.)  

Arm B: docetaxel 75 mg/m2 IV once every 3 weeks (per approved prescribing 
information) with dosing on Day 1 of each 21-day cycle
Phase 2 of the study will use a sequential, multistage Bayesian adaptive design and will 
consist of up to 3 parts as described below.  Each part is designed to evaluate MLN1117 
plus docetaxel versus docetaxel alone in a distinct population of NSCLC.  The study will 
start with Part 1 in patients with NSCLC inclusive of all histological types and all PIK3CA
genotypes (PIK3CA mutation, amplification, or wild-type).  The decision whether to 
proceed to Part 2 and expand the study to a specific histological type (either squamous or 


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nonsquamous) of NSCLC will be dependent on the efficacy data from Part 1. If patients 
with squamous NSCLC are selected for Part 2, the efficacy data from Part 2 will then be 
used to decide whether to proceed to Part 3, which will evaluate patients with a PIK3CA
(MUT/AMP) squamous NSCLC. Each part of the adaptive Phase 2 portion of the study is 
designed as a stand-alone, randomized study evaluating PFS as the primary efficacy measure 
between the 2 treatment arms (MLN1117 plus docetaxel vs docetaxel alone). There will be 
a primary, event-driven analysis of PFS after each part of the adaptive Phase 2 portion of the 
study.
Phase 2 of the study may consist of 3 parts:

Part 1:  NSCLC (see Section 4.1.2.1)

Part 2:  Histology-specific NSCLC (see Section 4.1.2.2)

Part 3:  Histology- and genotype-specific NSCLC (see Section 4.1.2.3)
4.1.2.1   
Phase 2, Part 1
Approximately 60 patients with NSCLC will be enrolled in this part of the study.  On the 
basis of histology confirmed at screening, patients will be assigned to 1 of 2 cohorts: 

Cohort 1: up to 30 patients with squamous NSCLC 

Cohort 2: up to 30 patients with nonsquamous NSCLC
In each cohort, patients will be randomized 1:1 to treatment with MLN1117 plus docetaxel 
(Arm A) or docetaxel alone (Arm B). 
The primary analysis of PFS will be performed when 50 events (death or PD) have been 
observed in 60 patients.  On the basis of this analysis, the study may be stopped for efficacy 
or futility (See Section 8.1). If neither the efficacy nor the futility boundary is met, a 
subgroup analysis of PFS based on histology will be performed.  A preferred histology 
(squamous or nonsquamous) will be determined, and the study will proceed to Part 2. If a
preferred histology cannot be determined, 20 additional patients (10 per histology) may be 
enrolled in Part 1, and a second analysis of PFS will be repeated when 65 events have 
occurred in 80 patients with NSCLC (40 squamous and 40 nonsquamous).  If neither 
efficacy nor a preferred histology is determined during the second interim analysis, the study 
will be stopped.


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4.1.2.2   
Phase 2, Part 2
On the basis of the results of the primary analysis of Part 1, only 1 histology subtype will be 
selected for study in Part 2.  Enrollment for Part 2, therefore, will be 1 of the following:
EITHER

Up to 30 patients with squamous NSCLC randomized 1:1 to treatment Arm A or 
Arm B.  This will provide a maximum of 60 patients with squamous NSCLC (Part 1 
and Part 2 combined).  PIK3CA genotypes (PIK3CA MUT/AMP versus PIK3CA
wild-type [WT]) will be used as 1 of the stratification factors during randomization. 
To ensure that patients with PIK3CA MUT/AMP and WT are evenly distributed 
between the 2 treatment arms, before enrolling patients in Part 2, the central testing 
laboratory results of PIK3CA genotypes will be available for all patients with 
squamous NSCLC who have completed Part 1.  Additional patients enrolled in Part 2 
must have known PIK3CA genotype status based on either local or central testing 
laboratory results during screening. For patients enrolled based on the local 
genotype data, central laboratory verification will be performed shortly after 
enrollment. Central laboratory data will be used as the default in case of a 
discrepancy, and adjustment in patient assignment may be needed.
OR

Up to 30 patients with nonsquamous NSCLC randomized 1:1 to treatment Arm A or 
Arm B.  This will provide a maximum of 60 patients with nonsquamous NSCLC 
(Part 1 and Part 2 combined). Patients with nonsquamous NSCLC with known 
mutations in EGFR, ALK, and KRAS are excluded.
An analysis of PFS for Part 2 (on squamous or nonsquamous patients, as applicable) will be 
performed when 50 events (death or PD) have been observed in 60 patients.   

If patients with nonsquamous NSCLC are selected for enrollment in Part 2, before
the analysis of PFS for Part 2, a central laboratory KRAS mutation test will be 
performed during the study to confirm KRAS WT status and to ensure that 60 KRAS
WT patients with nonsquamous NSCLC were enrolled in Phase 2 (Part 1 and Part 2 
combined) of the study.  Patients will be enrolled in the study on the basis of their 
local site’s KRAS mutational data or unknown status.  Additional patients with KRAS
WT nonsquamous NSCLC may be enrolled in Part 2 if needed to replace any 


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patients who may have been enrolled with a KRAS mutation as confirmed by central 
laboratory testing of KRAS mutation.  The primary analysis of PFS will then be 
conducted on the data from patients with KRAS WT nonsquamous NSCLC.

If patients with squamous NSCLC are selected for enrollment in Part 2, before
enrolling patients in Part 3, a primary analysis of PFS for Part 2 (includes Part 1 and 
Part 2 combined) patients with squamous NSCLC will be performed.  On the basis of 
this analysis, the study may be stopped for either efficacy or futility (see 
Section 8.1), or up to 30 additional patients with PIK3CA MUT/AMP squamous 
NSCLC will be enrolled in Part 3.  
4.1.2.3   
Phase 2, Part 3
On the basis of the results of the primary analysis of Part 2 (for squamous only), up to 
30 patients with PIK3CA MUT/AMP squamous NSCLC may be enrolled in Part 3 and 
randomized 1:1 to treatment Arm A or Arm B.  This will provide a maximum of 60 patients 
(Parts 1, 2, and 3 combined) based on an estimated 50% incidence of PIK3CA mutations and 
amplification in squamous NSCLC.
Patients enrolled in Part 3 must have PIK3CA MUT/AMP per either local or central 
laboratory data available during screening. For patients enrolled based on the local 
genotype data, central laboratory verification will be performed shortly after enrollment. 
Central laboratory data will be used as the default in case of a discrepancy, and replacement 
of patients may be needed for those who may have been enrolled with wild-type PIK3CA as 
confirmed by a central laboratory.  The primary analysis of PFS will be conducted when 
50 events (PD or death) occur in 60 patients with PIK3CA MUT/AMP squamous NSCLC.
4.2   
Number of Patients
Approximately 75 to 155 patients will be enrolled in this study from up to 35 study centers 
in North America and Europe.  Enrollment is defined as the time of the initiation of the first 
dose of study drug.
4.3   
Duration of Study
Treatment duration for all patients in Phase 1b and Phase 2 may be up to 9 cycles of either 
docetaxel alone or docetaxel in combination with MLN1117.  Patients receiving docetaxel 
plus MLN1117 may continue treatment with MLN1117 monotherapy beyond 9 cycles.  
Patients may continue to receive treatment until either PD, occurrence of unacceptable 


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toxicities, or death.  The maximum duration of treatment will be 9 cycles (approximately
6 months) for patients receiving docetaxel alone or 12 months for patients receiving 
MLN117 plus docetaxel (ie, 9 cycles of MLN1117 plus docetaxel followed by MLN1117 
alone) unless, after discussion between the investigator and sponsor, it is determined that a 
patient would derive benefit from continued treatment beyond 9 cycles or 12 months, 
respectively.  Patients may discontinue study treatment at any time.  Patients will attend the 
EOT visit 30 to 40 days after receiving their last dose of study drug.  
After EOT, patients will be followed for PFS and OS. For those patients who discontinue 
MLN1117 for any reason other than radiographic disease progression, CT (with contrast) or 
MRI scans should be completed every other cycle to further assess disease status until PD
(per modified RECIST, Version 1.1)(12), start of an alternative therapy, or 6 months after the 
last dose of study drug.  Patients who experience PD on or off study treatment will be 
contacted by phone every 3 months to assess for OS and for subsequent anticancer therapy.  
The OS follow-up period will be up to 12 months after the patient’s last dose of study 
treatment.  The final analyses for the clinical study report may be conducted after 
prespecified events (PD and death) have occurred for the event-driven PFS analysis 
conducted on the last Part of Phase 2 that has been completed (see Section 8.1). 
The study will be terminated 6 months after the last patient completes an EOT study visit.
It is anticipated that this study will last for approximately 24 to 36 months on the basis of the 
sequential and adaptive design of Phase 2 of the study.
5.   
STUDY POPULATION
5.1   
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study and 
randomized to treatment:
1. Male or female patients 18 years of age or older at time of consent.
2. Patients must have a histologically and/or cytologically confirmed diagnosis of 
NSCLC (squamous or nonsquamous).  The following apply to Phase 2 of the study: 

Squamous NSCLC:


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o
Patients with diagnosis of mixed squamous and nonsquamous (or 
adenosquamous) NSCLC are acceptable.

Nonsquamous NSCLC:
o
Patients with known driver mutations (EGFR and ALK) indicated for front-
line targeted therapy are excluded (local mutation data can be used for 
eligibility). 
o
Patients with known KRAS gene mutations are excluded (local mutation data 
can be used for eligibility).
3. Patients must have locally advanced or metastatic disease (Stage IIIb or Stage IV) 
with radiographically or clinically evaluable lesions: 

Measurable disease per modified RECIST criteria (Version 1.1)(12) by 
radiographic techniques (CT or MRI) is required for Phase 2 of the study only.
4. Patients must have experienced failure of at least 1 prior chemotherapy regimen:  

For Phase 2 of the study:
o
Patients must have received 1 prior platinum-based chemotherapy regimen
(excluding a docetaxel-containing regimen) for advanced or metastatic 
(Stage IIIb or Stage IV) disease followed by documented PD.

A drug provided as maintenance therapy following cytotoxic 
chemotherapy will be considered to be part of that regimen.

Patients who received prior therapy with paclitaxel as a part of the 
platinum-based doublet front-line regimen without PD on therapy are 
eligible for this trial.

Patients who, after the front-line, platinum-based, non-docetaxel-
containing chemotherapy, have been treated with 1 line of nivolumab or 
other immune-checkpoint inhibitors but progressed on or after the 
therapy, are eligible.


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
For Phase 1b of the study:
o
Patients who have experienced failure of multiple lines of prior 
chemotherapy are eligible.
5. The patient must have archived or fresh tumor biopsy samples obtained during 
screening sufficient for genotyping (Phase 2 only).  

Enrollment in Phase 2 is contingent on the local or central laboratory confirming 
receipt of an adequate amount of tissue including sufficient DNA for analysis.  
6. Patients must have adequate organ function, before the first dose of study drug, 
including the following:

Bone marrow reserve: absolute neutrophil count ≥ 1.5 × 109/L, platelet count 
≥100 × 109/L, hemoglobin ≥ 9 g/dL

Hepatic: total bilirubin ≤ the upper limit of the normal range (ULN), 
transaminases (AST and ALT) ≤ 1.5 × ULN, alkaline phosphatase (ALP)
≤2.5 ULN 

Renal: serum creatinine ≤ 1.5 × ULN or calculated or measured creatinine 
clearance > 50 mL/min based either on Cockroft-Gault estimate (see 
Section 14.2) or based on a 12- or 24-hour urine collection 

Metabolic: hemoglobin A1c (HbA1c) ≤ 6.5%; fasting serum glucose 
≤130 mg/dL; fasting triglycerides ≤300 mg/dL
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (refer to 
Section 14.1).
8. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method 
and 1 additional effective (barrier) method of contraception (see Section 14.5) at 
the same time, from the time of signing the informed consent through 30 days (or 


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longer, as mandated by local labeling [eg, USPI, SmPC, etc]) after the last dose 
of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods], withdrawal, spermicides only, and
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice highly effective barrier contraception during the entire study 
treatment period and through 120 days after the last dose of MLN1117 and, for 
docetaxel, for as long as is mandated by local labeling (eg, USPI, SmPC, etc); or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, 
symptothermal, postovulation methods for the female partner], withdrawal, 
spermicides only, and lactational amenorrhea are not acceptable methods of 
contraception. Female and male condoms should not be used together.)
9. 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.
10. Suitable venous access for the study-required blood sampling, including PK and PD
sampling.
11. Recovered (ie, Grade 1 toxicity or eligibility per this protocol is met) from the 
reversible effects of prior anticancer therapy.
12. In the opinion of the investigator, the patient or legal guardian is capable of 
understanding and complying with protocol requirements for the duration of the 
study.


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5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study or 
randomized to treatment.
1. Previous treatment with a PI3K or AKT inhibitor.
2. Prior cancer therapy or other investigational therapy within 2 weeks before the first 
administration of study drug or failed to recover from the reversible effects of prior 
anticancer therapies.  For prior therapies with a half-life longer than 3 days, the 
interval must be at least 28 days before the first administration of study drug, and the 
patient must have documented PD.
3. Poorly controlled diabetes mellitus defined as HbA1c > 6.5% (see Inclusion 
Criterion 6); patients with a history of transient glucose intolerance due to 
corticosteroid administration are allowed.
4. The patient has taken strong inhibitors or strong inducers of CYP3A4 within 14 days 
before the first dose of study drug (see Section 14.3).
5. The patient has taken histamine-H2 receptor antagonists and/or neutralizing antacids 
within 24 hours before the first administration of study drug.
6. The patient has taken proton pump inhibitors within 7days before the first 
administration of study drug.
7. The patient has a condition that requires the concomitant use of any of the excluded 
medications, supplements, or food products listed in Section 6.6 during the course of 
the study.
8. The patient has any clinically significant co-morbidities, such as uncontrolled 
pulmonary disease, known impaired cardiac function or clinically significant cardiac 
disease (specified below), active central nervous system disease, active infection, or 
any other condition that could compromise the patient’s participation in the study.  
Patients with any of the following cardiovascular conditions are excluded: 

Acute myocardial infarction within 6 months before starting study drug


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
Current or history of New York Heart Association Class III or IV heart failure 
(see Section 14.4)

Evidence of current uncontrolled cardiovascular conditions including cardiac 
arrhythmias, angina, pulmonary hypertension, or ECG evidence of acute 
ischemia or active conduction system abnormalities

Fridericia’s corrected QT interval > 475 milliseconds (msec) (males) or 
> 450 msec (females) on a 12-lead ECG during the Screening period

Abnormalities on 12-lead ECG including, but not limited to, changes in rhythm 
and intervals that in the opinion of the investigator are considered to be clinically 
significant
9. Known, previously diagnosed human immunodeficiency virus infection or active 
chronic hepatitis B or C.  Specific screening for chronic viral illness is at the 
discretion of the site or local institutional review board (IRB).
10. The patient has brain metastasis, except for those patients who have completed 
definitive therapy, are not on steroids, have a stable neurologic status for at least 
2 weeks after completion of the definitive therapy and steroids, and do not have 
neurologic dysfunction that would confound the evaluation of neurologic and other 
AEs.
11. Patients with active secondary malignancy that requires treatment.  Patients with 
nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they 
have undergone complete resection and are considered disease-free at the time of 
study entry.
12. Any serious medical or psychiatric illness, including drug or alcohol abuse, that 
could, in the investigator’s opinion, potentially interfere with the completion of 
treatment according to this protocol.
13. Male patients who intend to donate sperm during the course of this study or 120 days 
after receiving their last dose of study drug.
14. 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 administration of the first dose of study drug.


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15. Unwilling or unable to abide by the requirements of this study.
16. The patient is an immediate family member, study site employee, or in a dependant 
relationship with a study site employee who is involved in the conduct of this study 
(eg, spouse, parent, child, sibling), or they may consent under duress.
6.   
STUDY DRUG
6.1   
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
before drug administration.  Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
Study drug will be administered in 21-day dosing cycles.  Cycles are repeated every 3 weeks 
(21 days).  In Phase 1b (dose escalation), a 3 + 3 dose escalation will be used (see 
Section 6.3).  In this phase of the study, docetaxel (36 mg/m2) IV will be administered on 
Days 1 and 8 of the 21-day cycle.  MLN1117 tablets (planned doses of 300, 600, and 
900 mg) will be administered PO once daily on Days 2, 3, 4, 9, 10, 11, 16, 17, and 18 of the 
21-day cycle.
During Phase 1b, if MLN1117 de-escalation is warranted, the daily dose of MLN1117 may 
be reduced or the number of treatment days per week may be reduced (eg, from 3 days to 
2 days, or further to 1◦day) while maintaining the same weekly MLN1117 total dose.  
Subsequent escalation may be permitted based on observed safety and tolerability data.
These decisions will be made jointly by investigators and the Millennium project clinician. 
The alternative MLN1117 regimen may be carried forward into Phase 2 of the study if 
deemed appropriate by the sponsor, in consultation with the investigators.
Testing of escalating MLN1117 doses in combination with a fixed docetaxel dose and 
schedule is planned. However, if frequent docetaxel dose modifications are necessary when 
administered in combination with MLN1117, the fixed dose of docetaxel may be decreased 
(eg, –1 dose level) based on discussion and agreement between investigators and the 
Millennium project clinician. If decreased, the lower docetaxel dose may be carried forward 
into Phase 2 of the study if deemed appropriate by the sponsor, in consultation with the 
investigators.


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In Phase 2 (dose expansion), Parts 1, 2, and 3, patients will be randomized to 1 of 
2 treatment arms (Arm A or Arm B).  Patients randomized to Arm A will receive docetaxel 
(36 mg/m2) IV on Days 1 and 8 of the 21-day cycle.  MLN1117 tablets, at the dose 
determined in Phase 1b, will be administered PO once daily on Days 2, 3, 4, 9, 10, 11, 16, 
17, and 18 of the 21-day cycle. (An alternative MLN1117 or docetaxel dosing regimen may 
be used based on the RP2D decision in Phase 1b if deemed appropriate by the sponsor.)  
Patients randomized to Arm B will receive docetaxel (75 mg/m2) on Day 1 of each 21-day 
cycle.
During each phase of the study, patients will be treated with a maximum of 9 cycles of 
either docetaxel alone or docetaxel plus MLN1117.  Patients treated with docetaxel plus 
MLN1117 may receive subsequent MLN1117 monotherapy until PD, occurrence of 
unacceptable toxicities, or death.  The maximum duration of treatment for patients will be 
12 months unless, after discussion between the investigator and sponsor, it is determined 
that a patient would derive benefit from continued treatment beyond 12 months.  Patients 
will continue to be followed after discontinuation of study drug to collect PFS and OS data.  
Patients may withdraw from therapy at any time.   
6.1.1   
MLN1117 Administration
MLN1117 will be administered PO on an empty stomach in the morning (ie, approximately 
1 hour before a meal or 2 hours after a meal) with approximately 8 oz (240 mL) of water. 
Patients should be instructed to take their study medication at approximately the same time 
on each dosing day and to not take more than the prescribed dose at any time. Patients 
should swallow the study medication whole and not chew it, open it, or manipulate it in any 
way before swallowing. If a patient fails to take their MLN1117 dose within the time frame 
specified, 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. Additional information can be found in the 
Pharmacy Manual.  
If severe emesis or mucositis prevents the patient from taking scheduled doses of MLN1117, 
that dose will be skipped.  If emesis occurs after MLN1117 study medication ingestion, the 
dose will not be re-administered, and patients should resume dosing at the next scheduled 
time with the prescribed dosage.  Patients should record the time of the emesis in their 
dosing diaries (see the Study Manual).  Under no circumstance should a patient repeat a 
dose or double-up doses.


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6.1.2  
Reference/Control Therapy: Docetaxel Administration
Please refer to the docetaxel prescribing information for further details regarding docetaxel 
administration.
6.1.2.1   
Docetaxel Premedication
Premedication before and/or concomitant with docetaxel, including corticosteroids and anti-
emetics, will be administered in accordance with the recommendations in the docetaxel 
prescribing information.  Appropriate institutional practices consistent with docetaxel label 
and recommendation should be followed.  All patients receiving docetaxel should be 
premedicated with corticosteroids to reduce the incidence and severity of fluid retention and 
hypersensitivity reaction.  For example, dexamethasone 16 mg per day (eg, 8 mg BID) may 
be used for 3 days starting 1 day before docetaxel when docetaxel is administered every 
3 weeks. Other premedications including, but not limited to, 5-hydroxytryptamine (5-HT3) 
anti-emetics may be administered per the local standard of care on the day of docetaxel 
administration.
6.1.2.2   
Docetaxel Infusion
Docetaxel will be administered at 75 mg/m2 once every 3 weeks or at 36 mg/m2 once 
weekly, 2 weeks on, 1 week off (see Section 6.1), as an IV infusion per local practice.  
6.2   
Definitions of Dose-Limiting Toxicity 
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 
14 June 2010.(11)  These criteria are provided in the Study Manual.  Dose-limiting toxicity
will be defined as any of the following events that are considered by the investigator to be at 
least possibly related to therapy with MLN1117 plus docetaxel:

Grade 4 neutropenia (ANC 500 cells/mm3) lasting more than 7 consecutive days.

Grade 4 neutropenia of any duration accompanied by fever and/or systemic 
infection, where fever is defined as a temperature of 38.5C.

Grade 4 thrombocytopenia lasting more than 7 consecutive days.

≥ Grade 3 thrombocytopenia of any duration accompanied with clinically significant 
bleeding.


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
A platelet count 10,000/mm3 at any time.

Any other ≥ Grade 4 hematologic toxicity.

Grade 3 or greater nonhematologic toxicity with the following exceptions:
o
Grade 3 arthralgia/myalgia.
o
Brief (1 week) Grade 3 fatigue.
o
≥ Grade 3 nausea and/or emesis that can be controlled to ≤Grade 1 or baseline in 
1 week with the use of optimal anti-emetic prophylaxis.  Optimal anti-emetic 
prophylaxis is defined as an anti-emetic regimen that employs both a 5-HT3 
antagonist and a corticosteroid given in standard doses and according to standard 
schedules.
o
≥ Grade 3 diarrhea that can be controlled to ≤ Grade 1 or baseline in 1 week with 
optimal supportive therapy.
o
Grade 2 fasting hyperglycemia lasting ≤ 14 days with optimal treatment or 
Grade 3 fasting hyperglycemia lasting ≤ 24 hours with optimal treatment.
o
Grade 3 rash lasting ≤ 7 days with optimal treatment that includes topical steroid 
treatment, PO antihistamines, and pulse PO steroids, if necessary.
o
Any other Grade 3 nonhematologic toxicity that can be controlled to ≤ Grade 1 
or baseline in 1 week with appropriate treatment.  In this setting, a course of 
action will be determined jointly by the investigators and the sponsor.

Inability to administer at least 75% of planned doses of MLN1117 and/or docetaxel 
within Cycle 1 due to study-drug related toxicity.

Any clinically significant occurrence that the investigators and sponsor agree would 
place study subjects at undue safety risk.
Although DLTs may occur at any point during treatment, only DLTs occurring during 
Phase 1b, Cycle 1, of treatment will necessarily influence decisions regarding dose 
escalation, expansion of a dose level, or evaluation of intermediate dose levels for an entire 
dose-level cohort.  Patients in both Phase 1b and Phase 2 will be monitored through all 
cycles of therapy for treatment-related toxicities.


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6.3   
Phase 1b Dose Escalation Rules
The dose escalation phase of the study is designed to determine the DLT, MTD, and RP2D 
of MLN1117 when given in combination with docetaxel.  Approximately 15 patients are 
planned; the exact number of patients to be enrolled will depend on the number of dose-level 
cohorts, toxicities observed, and the PK results of the initial dose levels.
The dose intervals will follow a 3 + 3 dose escalation with a fixed dose of docetaxel and 
varying dose levels of MLN1117 (see Section 6.1) starting with the treatment of 3 patients at 
a planned dose-level cohort:
1. If 0 of 3 patients experiences DLT, the dose level is considered safe, and dose 
escalation will continue.
2. If 1 of 3 patients experiences DLT, 3 more patients will be enrolled at that same dose 
level.  
3. If 1 of 6 patients experiences DLT, the dose level is considered safe, and escalation 
will continue.
4. If 2 or more patients in any dose level experience DLT, the dose level is not 
considered safe, and escalation may not continue.  
Figure 6.a is a diagrammatical representation of these rules.


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Figure 6.a   
Dose Escalation Algorithm
Enter 3 at
same dose
> 1 of 6 DLTs
Stop
MTD = Previous dose
1 of 6 DLT 
Escalate to
next dose
0 DLTs
Enter 3
1 DLT
2-3 DLTs
Abbreviations:  DLT = dose-limiting toxicity; MTD = maximum tolerated dose.
Patients not receiving at least 75% of MLN1117 and/or docetaxel doses in Phase 1b, 
Cycle 1, for reasons other than DLTs will be replaced within the cohort.
If MTD or RP2D is not achieved by 900 mg, higher dose levels at 300 mg increments may 
be evaluated.  More conservative dose escalation, evaluation of intermediate doses, 
expansion of an existing dose level, and evaluation of alternative regimens for both 
MLN1117 and docetaxel 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 or exposure of MLN1117 plus docetaxel. These alternative 
combination dosing regimen(s) may be carried forward into Phase 2 of the study if deemed 
appropriate by the sponsor, after consultation with the investigators.


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6.4   
Maximum Tolerated Dose and Recommended Phase 2 Dose
The MTD is defined as the highest dose level of MLN1117 when administered with weekly
docetaxel at which no more than 1 of 6 patients experiences a DLT during the first cycle 
(21 days) of therapy in Phase 1b.
The RP2D of MLN1117 will be determined in Phase 1b on the basis of the totality of safety, 
tolerability, PK, and preliminary efficacy data (if available) observed in both Cycle 1 and 
Cycle 2 and beyond.  The RP2D will not exceed the MTD.  
While the primary escalation schema (see Figure 6.a) is designed to determine a classical 
Cycle 1-based MTD, dose escalation may be halted at any time after consultation between 
the sponsor and investigators if cumulative toxicity beyond Cycle 1 indicates that a given 
dose exceeds a tolerable RP2D.
6.5   
Dose Modification Guidelines
Patients on study drug(s) in both Phase 1b (dose escalation) and Phase 2 (dose expansion) of 
the study will be evaluated weekly for Cycle 1 (Days 1, 2, 8, 9, and 16) and on Day 1 and 
Day 8 (docetaxel dosing days for the first 9 cycles) of every cycle between Cycles 2 and 9, 
and then on Day 1 of every cycle thereafter following discontinuation of docetaxel for 
possible toxicities that may have occurred after the previous dose(s).  
Toxicities are to be assessed according to the NCI CTCAE, Version 4.03, effective date 
14 June 2010.(11)  The causal relationship of each AE should be assessed in relation to 
MLN1117 and in relation to docetaxel so that the dose modifications can be made 
accordingly. Administration and dose adjustment of docetaxel for patients treated with 
docetaxel alone or docetaxel in combination with MLN1117 will follow prescribing 
information for docetaxel and also the guidance on dose modification (Section 6.5.2.2) and 
management of clinical events (see Section 6.9).  Minimal requirements per the docetaxel
prescribing information have to be met before starting the next cycle or dose of docetaxel 
treatment (see Section 6.5.2.1). Dose modification guidelines for hematologic and 
nonhematologic toxicities are described below for both study drugs based on the type and 
severity of AEs, causality determination by investigators, and safety and tolerability profiles 
of each of the study drugs.  Further clarification can be obtained in consultation with the 
Millennium project clinician (or designee).  
Per dose modification guidelines, patients who have the study drug held because of 
treatment-related or possibly related AEs may resume study drug after resolution of the AE 


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but may either maintain the same dose level or have doses of study drug reduced (dose 
reduction) by at least 1 dose level.  Docetaxel may be reduced from 75 mg/m2 to 55 mg/m2
or from 36 mg/m2 to 30 mg/m2 for the docetaxel alone and docetaxel plus MLN1117 arm, 
respectively. When a dose reduction of MLN1117 occurs, the MLN1117 dose will be 
reduced to the next lower dose that has been established as a safe dose during dose 
escalation. During Phase 2, depending on the MTD/RP2D determined during Phase 1b, 
MLN1117 dose reduction will follow, in general, an increment of 300 mg, or an increment 
of 100 mg for doses ≤ 300 mg. If initial dose adjustment does not provide sufficient relief, 
the dose of MLN1117 can be further reduced if the treating physician considers that the 
patient is benefiting from study treatment and may benefit at a further reduced dose of 
MLN1117.  Up to 2 dose level reductions of MLN1117 due to AEs are generally 
recommended. If more than 2 dose reductions of MLN1117 are needed to manage 
MLN1117-related AEs, discontinuation of treatment should be considered unless the 
treating physician considers that the patient may benefit from continued study treatment 
after resolution of AEs to < Grade 1 or baseline, and consults with the sponsor.
If 1 study drug is delayed because of toxicity attributed to its use, the other study drug is to 
be administered as scheduled.  
Treatment with MLN1117 plus docetaxel will use a weekly schedule that includes 
3 consecutive dosing days per week for MLN1117.  For management of toxicity for 
individual patients, dose adjustment of MLN1117 normally includes a reduction in dose 
levels. However, a reduction in the number of treatment days per week (eg, reducing dosing 
days from 3 to 2 days or further to 1 day) at the same dose level could also be considered 
during dose escalation following discussions and agreement between investigators and the 
sponsor.  Alternative regimen(s) for docetaxel administration may also be incorporated 
following discussions and agreement between investigators and the sponsor.
6.5.1   
Phase 1b Intrapatient Dose Escalation
Once the RP2D is determined, all patients in Phase 1b actively receiving MLN1117 and 
docetaxel at a dose lower than the RP2D for a minimum of 2 cycles, in the absence of PD or 
unacceptable treatment-related toxicity per the investigator, may dose escalate to the RP2D 
at the investigator’s discretion and with the sponsor’s approval.  Patients in whom an 
increase in the dose of MLN1117 is being considered must have treatment-related AEs 
resolved to ≤ Grade 1 or baseline or to a level that is acceptable to the investigators 


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(nonhematologic toxicity must be ≤ Grade 2, and hematologic toxicities must be less than 
the minimal requirement for starting a new cycle of treatment).
6.5.2   
Phase 1b, Cycle 1, Intrapatient Dose Reduction
Intrapatient dose reductions of MLN1117 are not permitted during Phase 1b, Cycle 1, of 
therapy unless the patient experiences a DLT attributed to MLN1117.  Dose-limiting 
toxicities are defined in Section 6.2.  If a patient experiences a DLT during Phase 1b, 
Cycle 1, treatment should be held, and the event will be counted toward the assessment of 
MTD for the given cohort.  Patients experiencing DLTs in Phase 1b, Cycle 1, may continue 
in the study upon resolution of the toxicity; however, the dose of MLN1117 (in combination 
with docetaxel) will be reduced by at least 1 dose level (or by up to 50% if the patient is 
receiving the first dose level). Patients who receive a reduced dose of MLN1117 during 
Cycle 1 for reasons other than DLTs will be replaced for DLT evaluation and dose 
escalation.  Dose delay and dose reduction of docetaxel per docetaxel retreatment criteria 
(see Section 6.5.2.1) and dose modification guidelines is allowed in Cycle 1 during 
Phase 1b. Frequency of docetaxel dose delay and reduction will be taken into account in 
determining the RP2D for MLN1117 when administered with weekly docetaxel.
6.5.2.1   
Criteria for Beginning or Delaying a Docetaxel Cycle/Dose
The patient must meet the following criteria before starting the next dose of docetaxel in 
both the docetaxel plus MLN1117 and the docetaxel alone treatment arms:

ANC ≥ 1500/mm3

Platelet count ≥ 100,000/mm3

Total bilirubin < ULN, ALT/AST < 1.5 × ULN, ALP < 2.5 × ULN
For patients treated with docetaxel alone, 1 dose of 75 mg/m2 docetaxel is given per 21-day 
cycle.  If a patient fails to meet the docetaxel retreatment criteria, the next cycle of docetaxel 
dosing should be delayed for 1 week while supportive care is given based on the local 
standard practice or as specified in Section 6.9. The patient should be re-evaluated after
1 week to determine whether the criteria for docetaxel retreatment have been met. If the 
criteria have not been met, further delay of the next cycle of docetaxel and re-evaluation of 
docetaxel retreatment criteria will occur at weekly intervals until all retreatment criteria are 
satisfied.  Dose modification guidelines will be followed to determine whether the dose of 
docetaxel will be maintained or reduced when docetaxel dosing is resumed.


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For patients treated with docetaxel plus MLN1117, 2 doses of 36 mg/m2 docetaxel will be 
given on Day 1 and Day 8 of 21-day cycles. If the patient fails to meet retreatment criteria 
for docetaxel before Day 1 dosing in a given cycle, the start of the cycle will be delayed. If 
the retreatment criteria are not met for the Day 8 dosing of docetaxel, the Day 8 dose will be 
delayed to Day 15 (provided that all retreatment criteria are met on Day 15), and the cycle 
will be expanded to a 28-day cycle.  If further delay is needed, the second dose of docetaxel 
will be withheld, and docetaxel will be resumed in the next cycle.
Discontinuation of study should be considered if there is a delay of a new cycle (due to 
Day 1 docetaxel dosing delay for both docetaxel alone and MLN1117 plus docetaxel arm) or 
a delay of Day 8 docetaxel dosing (for MLN1117 plus docetaxel arm only) for ≥21 days 
(≥3 weeks) because of lack of adequate recovery of the toxicities, except in the case of 
investigator-determined clinical benefit and discussion with the Millennium project 
clinician. If the toxicities that result in failure of meeting the docetaxel retreatment criteria 
are determined to be related to docetaxel and not to MLN1117, patients should continue to 
receive MLN1117 according to the planned dose and regimen. If in the investigator’s 
opinion, MLN1117 contributes to the toxicities (related or possibly related) that lead to not 
meeting docetaxel retreatment criteria, dose delay or modification of MLN1117 should be 
considered per the dose modification guidelines in Section 6.5.2.2.
6.5.2.2   
Dose Modification for Hematologic and Nonhematologic Toxicity: 
MLN1117 and Docetaxel
A decision regarding which study drug requires dose modification will be dependent upon 
the toxicity, its onset, and time course.  The causal relationship of any reported events (AEs
or SAEs) should be assessed by the investigator in relation to MLN1117 and in relation to 
docetaxel. If multiple toxicities are noted, the dose adjustments and/or delays should be 
made according to the most severe toxicity guidelines and the causal relationship to one or 
both study drugs.  Guidelines for dose modifications for hematologic and nonhematologic 
toxicity are presented in Table 6.a and Table 6.b, respectively. After discussion between the 
investigator and the Millennium project clinician, alternative dose modifications may be 
recommended to maximize exposure of study treatment while protecting patient safety.  


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Table 6.a   
Guidelines for MLN1117 and Docetaxel Dose Modifications for 
Hematologic Toxicity
NCI CTCAE
Grade
MLN1117 Dose Modificationa
(For Patients Receiving 
MLN1117 Plus Docetaxel)
Docetaxel Dose Modification
(For Patients Receiving 
MLN1117 Plus Docetaxel and 
Docetaxel Alone)
Neutrophil Count (ANC) Decreased
Grade 2 or 3
(ANC < 1500-500/mm3; 
< 1.5-0.5 × 10e9/L)
No change. Continue MLN1117 
at same dose and schedule.  
Hold docetaxel until neutrophil 
count ≥1500/mm3 then restart 
docetaxel at 75 mg/m2 or 
36 mg/m2.
Grade 4
(< 500/mm3; < 0.5 × 10e9/L)
Hold MLN1117 until ANC
≥1500/mm3, restart MLN1117 at 
same dose and schedule.
Hold docetaxel until neutrophil 
count resolved to ≥ 1500/mm3 then 
restart docetaxel.
If resolved ≤7 days, maintain the 
same dose (75 or 36 mg/m2).
If resolved in > 7 days, reduce dose 
to 55 mg/m2 or 30 mg/m2.
Febrile neutropenia (ANC 
< 1000/mm3 and fever defined 
as a single temperature of 
> 38.3oC (101oF) or a sustained 
temperature of ≥ 38oC (100.4oF) 
for more than 1 hour)
       OR
Neutropenia (ANC 
< 1000/mm3) with systemic 
infection
Hold MLN1117 until ANC 
≥1500/mm3 and fever resolved, 
then restart MLN1117 at same 
dose and schedule.
Hold docetaxel until neutrophil 
count ≥1500/mm3 and fever and 
infection resolved, then restart 
docetaxel at 55 or 30 mg/m2.
Thrombocytopenia
Grade 1or 2
(PLT 50,000-100,000/mm3; 
< 50-100 × 10e9/L)
No change. Continue MLN1117 
at same dose and schedule.  
Hold docetaxel until PLT 
≥100,000/mm3, then restart 
docetaxel at 75 or 36 mg/m2.
Grade 3
(PLT 25,000-50,000/mm3; 
< 25-50 × 10e9/L)
Hold MLN1117 until PLT
≥100,000/mm3 or baseline, 
restart MLN1117 at same dose 
and schedule.
Hold docetaxel until PLT
≥100,000/mm3.  If resolved 
≤7 days, maintain the same dose of 
docetaxel.
If resolved > 7 days, restart 
docetaxel at 55 or 30 mg/m2.
Grade 4
(PLT < 25,000/mm3; 
< 25 × 10e9/L)
Hold MLN1117 until PTL 
≥100,000/mm3 or baseline, 
restart MLN1117 at same dose 
and schedule.
Hold docetaxel until PLT
≥100,000/mm3 or baseline, restart 
docetaxel at 55 or 30 mg/m2.


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Table 6.a   
Guidelines for MLN1117 and Docetaxel Dose Modifications for 
Hematologic Toxicity
NCI CTCAE
Grade
MLN1117 Dose Modificationa
(For Patients Receiving 
MLN1117 Plus Docetaxel)
Docetaxel Dose Modification
(For Patients Receiving 
MLN1117 Plus Docetaxel and 
Docetaxel Alone)
PLT < 10,000 cells/mm3 or 
clinically significant bleeding
Consider permanently 
discontinuing MLN1117, except 
in the case where the investigator 
determines that the patient is 
obtaining a clinical benefit and 
has discussed this with the project 
clinician or designee. If the 
patient is not discontinued, then 
the MLN1117 dose will be 
reduced to at least 1 dose level 
lower when PLT ≥ 100,000/mm3 
and/or clinically significant 
bleeding is completely resolved.
Consider permanently 
discontinuing docetaxel, except in 
the case where the investigator 
determines that the patient is 
obtaining a clinical benefit and has 
discussed this with the project 
clinician or designee. If the patient 
is not discontinued, then the dose 
of docetaxel will be reduced to 55
or 30 mg/m2 or lower per local 
standard practice and agreement 
between investigator and sponsor 
when PLT ≥ 100,000/mm3 and/or 
clinically significant bleeding is 
completely resolved.
Abbreviations:  ANC = absolute neutrophil count; NCI CTCAE = National Cancer Institute Common 
Terminology Criteria for Adverse Events; PLT = platelet count. 
a Patients receiving docetaxel plus MLN1117 may continue treatment with MLN1117 alone beyond 
9 cycles.  Following completion of Cycle 9, follow action for MLN1117 dose modifications.
Table 6.b   
Guidelines for MLN1117 and Docetaxel Dose Modifications for 
Nonhematologic Toxicity
NCI CTCAE
Grade
MLN1117 Dose Modificationa
(For Patients Receiving MLN1117 
Plus Docetaxel)
Docetaxel Dose Modification 
(For Patients Receiving MLN1117 
Plus Docetaxel and Docetaxel 
Alone)
Hepatotoxicity
ALT and/or AST > 1.5 
ULN to ≤5 × ULN
(Grade 1 or 2)

When ALP > 2.5 × ULN together
with bilirubin < ULN, hold 
MLN1117 until both ALT and 
AST ≤1.5 × ULN.
or

When ALP < 2.5 × ULN together 
with bilirubin < ULN, hold 
MLN1117 until both ALT and 
AST < 2.5 × ULN.
Then resume MLN1117 at the same 
dose and schedule.
Refer to Section 6.9 for guidelines on 
hepatic transaminase elevations.

When ALP > 2.5 × ULN 
together with bilirubin < ULN,
hold docetaxel until both ALT 
and AST ≤1.5 × ULN.
or

When ALP < 2.5 × ULN 
together with bilirubin < ULN,
hold docetaxel until both ALT 
and AST < 2.5 × ULN.
Then resume docetaxel at the same 
dose and schedule.
Refer to Section 6.9 for guidelines 
on hepatic transaminase elevations.


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Table 6.b   
Guidelines for MLN1117 and Docetaxel Dose Modifications for 
Nonhematologic Toxicity
NCI CTCAE
Grade
MLN1117 Dose Modificationa
(For Patients Receiving MLN1117 
Plus Docetaxel)
Docetaxel Dose Modification 
(For Patients Receiving MLN1117 
Plus Docetaxel and Docetaxel 
Alone)
ALT and/or AST > 5 ULN 
to ≤20 × ULN 
(Grade 3)

When ALP > 2.5 × ULN together
with bilirubin < ULN, hold 
MLN1117 until both ALT and 
AST ≤1.5 × ULN.
or

When ALP < 2.5 × ULN together 
with bilirubin < ULN, hold 
MLN1117 until both ALT and 
AST < 2.5 × ULN.
Then:

If resolved < 7 days, resume 
MLN1117 at the same dose and 
schedule.

If resolved > 7days, reduce 
MLN1117 by 1 dose level.

If recurred, reduce MLN1117 by 
1 dose level.

When ALP > 2.5 × ULN 
together with bilirubin < ULN,
hold docetaxel until both ALT 
and AST ≤1.5 × ULN.
or

When ALP < 2.5 × ULN 
together with bilirubin < ULN,
hold docetaxel until both ALT 
and AST < 2.5 × ULN.
Then resume docetaxel at the same 
dose and schedule.
ALT and/or AST > 20 
ULN 
(Grade 4)

When ALP > 2.5 × ULN together 
with bilirubin < ULN, hold 
MLN1117 until both ALT and 
AST ≤1.5 × ULN.
or

When ALP < 2.5 × ULN together 
with bilirubin < ULN, hold 
MLN1117 until both ALT and 
AST < 2.5 × ULN.
Then reduce MLN1117 by 1 dose 
level or consider permanently 
discontinuing MLN1117 if associated 
with symptoms or recurred with a 
severity of Grade 4.

When ALP > 2.5 × ULN 
together with bilirubin < ULN,
hold docetaxel until both ALT 
and AST ≤1.5 × ULN.
or

When ALP < 2.5 × ULN 
together with bilirubin < ULN,
hold docetaxel until both ALT 
and AST < 2.5 × ULN.
Then resume docetaxel at the same 
dose and schedule
Hyperglycemia
Grade 2 
(Fasting glucose value 
> 160-250 mg/dL; fasting 
glucose value > 8.9-
13.9 mmol/L)
Continue MLN1117 at same dose and 
schedule.  Refer to Section 6.9 for 
guidelines on hyperglycemia 
management.
Continue docetaxel at same dose 
and schedule.  Refer to Section 6.9
for guidelines on hyperglycemia 
management.


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Table 6.b   
Guidelines for MLN1117 and Docetaxel Dose Modifications for 
Nonhematologic Toxicity
NCI CTCAE
Grade
MLN1117 Dose Modificationa
(For Patients Receiving MLN1117 
Plus Docetaxel)
Docetaxel Dose Modification 
(For Patients Receiving MLN1117 
Plus Docetaxel and Docetaxel 
Alone)
Grade 3 
(> 250-500 mg/dL; 
> 13.9-27.8 mmol/L; 
hospitalization indicated)
Hold MLN1117 until hyperglycemia 
improves to ≤ Grade 2.  Refer to 
Section 6.9 for guidelines on 
hyperglycemia management.
Optimize antihyperglycemic therapy 
and resume MLN1117 based on 
timing of recovery.

≤ 1 week:  resume MLN1117 at 
same dose and schedule.

> 1 but ≤ 2 weeks or recurrent 
with antihyperglycemic 
treatment: reduce MLN117 dose 
to the next lower dose level for all 
subsequent cycles.

> 2 weeks:  stop MLN1117 and 
discontinue subject from study.
Continue docetaxel at same dose 
and schedule.  Refer to Section 6.9
for guidelines on hyperglycemia 
management
Grade 4
(> 500 mg/dL; 
> 27.8 mmol/L; life-
threatening consequences)
Hold MLN1117 until hyperglycemia 
is resolved to ≤ Grade 2.  Refer to 
Section 6.9 for guidelines on 
hyperglycemia management.

≤ 1 week:  reduce MLN117 dose 
to the next lower dose level for all 
subsequent cycles.

> 1 week:  discontinue.
Hold docetaxel until hyperglycemia 
improves to ≤ Grade 2.  Refer to 
Section 6.9 for guidelines on 
hyperglycemia management.
Other Nonhematologic 
Toxicities
Peripheral neuropathy
Grade 3
Maintain the same dose/regimen of 
MLN1117 if determined to be 
unrelated.
Permanently discontinue docetaxel.


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Table 6.b   
Guidelines for MLN1117 and Docetaxel Dose Modifications for 
Nonhematologic Toxicity
NCI CTCAE
Grade
MLN1117 Dose Modificationa
(For Patients Receiving MLN1117 
Plus Docetaxel)
Docetaxel Dose Modification 
(For Patients Receiving MLN1117 
Plus Docetaxel and Docetaxel 
Alone)
All other Grade 3 
nonhematologic toxicities 
with the exception of:

Grade 3 nausea, 
vomiting, and diarrhea 
resolved to ≤Grade 1 
or baseline within 
1 week with optimal 
anti-emetics and 
antidiarrheals
following SOC

Transient Grade 3 
fatigue (lasting 
< 1 week)

Grade 3 rash lasting 
≤7 days with optimal 
treatment 

Any other Grade 3 
nonhematologic 
toxicity that can be 
controlled to ≤Grade 1 
or baseline in 1 week 
with appropriate 
treatment in 7 days
Hold MLN117 if determined to be 
related to MLN1117 until resolution 
to ≤Grade 1, baseline, or a level 
acceptable by the investigator (must 
be ≤Grade 2): 

If resolved in ≤ 7 days, then 
maintain dose level.

If resolved in > 7 days, then dose 
reduce by 1 dose level.

If recurred, then dose reduce by 
1 dose level.

For the exceptions listed, 
maintain the dose level. 
Permanent discontinuation should be 
considered if the toxicities persist as 
≥Grade 3 for more than 21 days 
despite temporary disruption of study 
drug.
Hold docetaxel if determined to be 
related to docetaxel until resolution 
to ≤Grade 1, baseline, or a level 
acceptable by the investigator (must 
be ≤ Grade 2): 

If resolved in ≤ 7 days, then 
maintain dose level.

If resolved in > 7 days, then 
dose reduce by 1 dose level.

If recurred, then dose reduce by
1 dose level.

For the exceptions listed, 
maintain the dose level. 
Permanent discontinuation should 
be considered if the toxicities persist 
as ≥ Grade 3 for more than 21 days 
despite of temporary disruption of 
study drug.
All other Grade 4 
nonhematologic toxicities 
Consider permanently discontinuing 
MLN1117 based on causality 
determination except when the 
investigator determines that the patient 
is obtaining a clinical benefit and has 
discussed this with the project 
clinician or designee. If the patient is 
not discontinued, MLN1117 dose will 
be reduced to at least 1 dose level 
lower when toxicity resolves to 
≤Grade 1, baseline, or a level 
acceptable by the investigator (must 
be ≤Grade 2).
Consider permanently discontinuing 
docetaxel based on causality 
determination when the investigator 
determines that the patient is 
obtaining a clinical benefit and has 
discussed this with the project 
clinician or designee. If the patient 
is not discontinued, MLN1117 dose 
will be reduced to at least 1 dose 
level lower when toxicity resolves 
to ≤ Grade 1, baseline, or a level 
acceptable by the investigator (must 
be ≤Grade 2).
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse 
Events; SOC = standard of care; ULN = upper limit of the normal range.
a Patients receiving docetaxel plus MLN1117 may continue treatment with MLN1117 alone beyond 
9 cycles.  Following completion of Cycle 9, follow action for MLN1117 dose modification and delay.


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6.6   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Use of other investigational medicinal products or devices.

Other anticancer therapies, including chemotherapy, immunotherapy, 
radioimmunotherapy, targeted agents, radiation, or surgery (patients can have 
palliative radiation or surgery during the study for pre-existing lesions upon 
discussion with the Millennium project clinician).

Strong inhibitors/inducers of CYP3A4 (see Section 14.3).

Proton pump inhibitors (eg, esomeprazole, lansoprazole, pantoprazole).
6.7   
Permitted Concomitant Medications and Procedures 
Restricted use of H2-receptor antagonists or neutralizing antacids is permitted under the 
following conditions:

Treatment with H2-receptor antagonists is not permitted less than 24 hours before 
and within 6 hours after receiving a dose of MLN1117.  Examples of H2-receptor 
antagonist include ranitidine, famotidine, cimetidine, and nizatidine.  

Treatment with neutralizing antacids is not permitted less than 4 hours before and 
within 6 hours after receiving a dose of MLN1117.
Oral contraceptive pills or any other type of hormonal contraception is permitted.
Additional concomitant medications and procedures are permitted in the course of the study 
to prevent and/or actively manage AEs related or not related to the study drug(s) unless 
prohibited as specified in the protocol (see Section 6.9).
6.8   
Precautions and Restrictions 
It is not known what effects MLN1117 has on human pregnancy or development of the 
embryo or fetus. Docetaxel can cause fetal harm when administered to a pregnant woman, 
based on its mechanism of action and findings in animals.(13, 14) 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 


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male patients should use highly effective methods of contraception (see list provided in 
Section 14.5) through defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective method and 
1 additional effective (barrier) method of contraception (see Section 14.5) at the 
same time, from the time of signing of the informed consent form through 30 days
(or longer, as mandated by local labeling) after the last dose of study drug, or

Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods], withdrawal, spermicides only, and lactational amenorrhea 
are not acceptable methods of contraception. Female and male condoms should not 
be used together.)
Female patients must agree to not donate eggs (ova) during the course of this study or 
30 days after receiving their last dose of MLN1117 and, for docetaxel, for as long as is 
mandated by local labeling. 
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice highly effective barrier contraception during the entire study treatment 
period and through 120 days after the last dose of MLN1117 and, for docetaxel, for 
as long as is mandated by local labeling; or

Practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject.  (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner], withdrawal, spermicides only, and 
lactational amenorrhea are not acceptable methods of contraception. Female and 
male condoms should not be used together.)


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Male patients must agree to not donate sperm during the course of this study or 120 days
after receiving their last dose of MLN1117 and, for docetaxel, for as long as is mandated by 
local labeling.
6.9   
Management of Clinical Events 
Therapies that are required to manage AEs and control cancer symptoms are allowed based 
on standard clinical practice, unless specifically excluded. Supportive care agents, such as 
erythropoietin, granulocyte colony stimulating factor (G-CSF), blood products (red blood 
cell [RBC] and platelet transfusions), and pain medications are permitted as needed per 
American Society of Hematology (ASH)/American Society of Clinical Oncology (ASCO)
guidelines or local institutional practice.  However, these agents should not be used in this 
study in a manner that would either help establish eligibility for the study or support 
escalation of study drug dose during dose escalation (Phase 1b).
Please refer to the most recent docetaxel prescribing information (eg, SmPC, USPI, etc) for 
specific details regarding the management of docetaxel-related clinical events such as 
hypersensitivity reactions, respiratory disorders, fluid retention, cystoid macular edema, 
peripheral neuropathy, etc.
Hematologic Effect (Neutropenia, Thrombocytopenia, and Anemia)
Blood counts and hemoglobin should be monitored regularly as outlined in the protocol with 
additional testing obtained according to standard clinical practice.  Administration of study 
drug(s) should be modified per dose modification guidance in the protocol when the 
hematological toxicity occurs.  Myeloid growth factors (eg, G-CSF, granulocyte 
macrophage-colony stimulating factor) may be used to treat severe and/or febrile 
neutropenia according to ASCO guidelines. Platelet transfusion is allowed to manage severe 
thrombocytopenia to prevent and minimize bleeding according to ASH/ASCO guidelines.
In general, platelet transfusion should be given prophylactically to patients with platelet 
counts < 10,000/microL or to any patients with signs of overt bleeding, such as oral purpura. 
Packed RBC transfusion is permitted, as necessary, per local institutional practice. In 
general, RBC transfusion is recommended to all symptomatic patients with anemia or any 
asymptomatic patients with hemoglobin ≤ 7 to 8 g/dL with the purpose of maintaining the 
hemoglobin between 8 and 10 g/dL depending on the patients’ age, symptoms, and 
comorbid conditions.


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Hyperglycemia
Fasting serum glucose will be tested at the study site per the clinical visit schedule as 
outlined in the Schedules of Events. In addition, patients who experience hyperglycemia on 
trial will be given a glucometer to monitor their daily predose FBG at home (see 
Section 7.4.15).  Patients will be instructed to notify the study staff immediately with any 
abnormal readings (ie, ≥ 140 mg/dL) for further instructions on the management of their 
hyperglycemia.  
Hyperglycemia observed during home glucose monitoring should be confirmed in the clinic.  
Investigators will be responsible for reviewing the home glucose monitoring logs for 
hyperglycemia.  When hyperglycemia is resolved (based on FSG levels at a clinical visit), it 
is at the investigator’s discretion to discontinue or continue, either daily or at a reduced 
frequency, in-home FBG monitoring.  If continued in-home glucose monitoring is chosen by 
the investigator to observe any further irregularities in the FBG level, patients will continue 
to notify the investigator of FBG levels ≥140 mg/dL. If blood glucose levels are not well 
controlled or if a patient requires either PO antihyperglycemic agents or insulin to control 
blood glucose levels, then the frequency of in-home testing of FBG levels will be reinstated 
to daily. If no further irregularities are observed, the in-home glucose monitoring may be
discontinued if the investigator approves. Guidelines for management of hyperglycemia are 
presented in Table 6.c.
Table 6.c   
Management of Hyperglycemia
Grade
Description
Treatment
MLN0117 Dose Modification
1
Fasting blood 
glucose > ULN to 
≤160 mg/dL
Continue close monitoring of 
blood glucose or initiate oral 
antihyperglycemic agent.
None
2
Fasting blood 
glucose > 160 to 
≤250 mg/dL
Initiate oral 
antihyperglycemic agent 
and/or insulin if clinically 
indicated. Endocrinologist 
consult recommended.
None
≥ 3
Fasting blood 
glucose 
> 250 mg/dL
Initiate oral 
antihyperglycemic agent 
and/or insulin if clinically 
indicated. Endocrinologist 
consult recommended.
Hold drug until ≤ Grade 2.
Resume MLN1117 based on timing of 
recovery:

≤ 1 week:  resume at same dose and 
schedule.

> 1 but ≤ 2 weeks or recurrence:  
reduce to the next lower dose level.

2 weeks:  stop MLN1117 and 
discontinue patient from the study.


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Table 6.c   
Management of Hyperglycemia
Grade
Description
Treatment
MLN0117 Dose Modification
Prevention/Prophylaxis

Monitor fasting serum glucose levels during clinic visits.

Monitor home glucometer test results if applicable.

Check HbA1c levels every 3 months during therapy.

Recommend lifestyle modifications, as appropriate (balanced diet, limited alcohol consumption, 
increased physical activity).

Most episodes of Grade 1 and 2 hyperglycemia respond quickly to oral metformin.  Early initiation of 
therapy is recommended to prevent higher-grade hyperglycemia.

FBG levels ≥ 140 mg/dL by glucometer should be followed by closer monitoring of serum glucose and 
possible intervention.
Abbreviations: FBG = fasting blood glucose; HbA1c = hemoglobin A1c; ULN = upper limit of the normal 
range.
If any FSG reading performed in the clinic indicates hyperglycemia (FSG > ULN or 
≥110 mg/dL), the study staff should first confirm that the patient was fasting at the time of 
the blood draw (ie, nothing PO for at least 8 hours before).  To aggressively manage the 
hyperglycemia per standard clinical practice, the following guidelines are provided to aid the 
investigator in initiating antiglycemic therapies. 
All patients developing hyperglycemia on the study should have their glucose closely 
monitored by study staff.  The investigator may choose either to continue close monitoring 
of patients who develop Grade 1 hyperglycemia (FSG > ULN to ≤160 mg/dL) or consider 
initiating treatment with a PO antihyperglycemic agent, such as metformin.  All patients 
with ≥ Grade 2 hyperglycemia (fasting serum glucose > 160 mg/dL) must be treated 
aggressively with PO antihyperglycemic agents and/or insulin as clinically indicated while 
continuing on MLN1117 treatment.  The investigator should consult an endocrinologist if 
needed to aid in optimizing the hyperglycemia treatment plan of the patient.
It is recommended that patients be treated initially with a fast-acting insulin sensitizer, such 
as metformin at 500 mg PO QD, and titrate up to a maximum of 1000 mg PO BID as 
needed.  Concurrent addition to metformin of dipeptidyl peptidase-4 inhibitors (eg, 
sitagliptin or vildagliptin) and/or insulin should also be considered.  Oral sulfonylureas (eg, 
glipizide or glyburide) should be used with caution because of the higher risk of inducing 
hypoglycemia in patients.  The dose of PO antihyperglycemic agents should be adjusted in 
patients with renal insufficiency.


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Elevations in Hepatic Transaminases
Please see Section 1 and the IB regarding MLN1117 nonclinical and clinical hepatic safety.  
Information regarding hepatic impairment in patients with NSCLC receiving docetaxel can 
be found in the docetaxel prescribing information.  Per the docetaxel prescribing
information, docetaxel should not be given if bilirubin is > ULN or if AST and/or ALT is > 
1.5 × ULN concomitant with ALP > 2.5 × ULN.  Liver function test (ALT and AST) 
elevations increase the risk of severe or life-threatening complications of docetaxel.  Liver 
function test monitoring is planned per the Schedules of Events, and laboratory results are 
required before each dose of docetaxel.  The LFT retreatment criteria must be met before the 
next planned dose of docetaxel is given to a patient. If LFT retreatment criteria for 
docetaxel are not met, both study drugs will be delayed until the LFT elevation is resolved. 
Dose adjustment, if needed, will follow the dose modification guideline (see Section 6.5.2.2) 
when the study drugs resume. If the study drug has been held for 3 weeks because of a lack 
of resolution of LFT elevations, then permanent discontinuation of study drugs should be 
considered.
Idiosyncratic severe hepatic injury can occur with many drugs.  With severe hepatic injury, 
the liver has diminished capacity to excrete conjugated (or direct) bilirubin. Thus, in the 
absence of overt biliary tract disease, when ALT and/or AST is ≥ 3×ULN and when 
concomitant total bilirubin is ≥ 2 × ULN (> 35% direct bilirubin), significant liver injury 
may be present.  When no other reason can be found to explain the combination of increased 
hepatic transaminases and serum bilirubin, this event should be considered to be drug-
induced liver injury (defined as Hy’s Law) and should be reported as an SAE.  The study 
drug must be discontinued, and the patient must follow up with a hepatologist or specialist.  
Serial liver chemistries should be followed twice weekly until the event stabilizes or hepatic 
transaminases and bilirubin return to pretreatment values.
If the liver event does not meet SAE criteria, but symptoms of hepatic injury such as 
anorexia, fatigue, nausea, or abdominal pain occur in the presence of hepatic transaminase 
elevations > 3× ULN, dosing should be discontinued and immediate notification 
of/discussion with the study project clinician is required (within 24 hours) regarding the 
patient’s clinical status and follow-up plans.  


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Nausea and/or Vomiting
This study will not initially employ prophylactic anti-emetics before the first dose of the 
study drug during dose escalation.  However, a patient who develops nausea and/or vomiting 
will be actively managed by employing optimal antiemetic treatment based on local standard 
practice.  Additionally, anti-emetics could be used prophylactically as clinically indicated 
following the occurrence of the first event of study drug-related or possibly related nausea 
and/or vomiting. It is recommended that PO anti-emetics such as ondansetron and/or 
prochlorperazine, be used as initial therapies.  An optimal antiemetic regimen that is defined 
to employ both a 5-HT3 antagonist and a corticosteroid given in standard doses and 
according to standard schedules should be used to control nausea and/or vomiting, if needed. 
If ≥ Grade 3 study drug-related nausea and/or vomiting cannot be controlled by optimal 
antiemetic therapy within 7 days (not resolved to Grade 1 or baseline), dose modification 
guidelines for the study drug(s) should be followed (see Section 6.5.2.2).
Diarrhea
Prophylactic antidiarrheals will not be used in this study before dosing of study drug.  
However, diarrhea should be managed according to local standard practice, including the 
administration of antidiarrheals once infectious causes are excluded.  Fluid intake should be 
maintained to avoid dehydration.  Fluid deficit should be corrected before initiation of study 
drug and during the study.
Fluid Retention
Patients should be premedicated with PO corticosteroids before each docetaxel 
administration in both the MLN1117 plus docetaxel and docetaxel alone arm to reduce the 
incidence and severity of fluid retention. Dexamethasone 16 mg per day (eg, 8 mg BID) for 
3 days starting 1 day before docetaxel administration is recommended, or local institutional 
practice is followed. When fluid retention occurs during docetaxel treatment, peripheral 
edema usually starts in the lower extremities and may become generalized with a median 
weight gain of 2 kg. Patients developing edema may be treated with standard measures, 
such as salt restriction and PO diuretic(s).
Hypersensitivity Reactions
Patients should be closely observed for hypersensitivity reactions, especially during the first 
and second infusion of docetaxel. Severe hypersensitivity reactions characterized by 


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generalized rash/erythema, hypotension and/or bronchospasm, or very rarely anaphylaxis, 
have been reported in patients treated with docetaxel. Hypertension reactions may occur 
within a few minutes following initiation of a docetaxel infusion. If minor reactions such as 
flushing or localized skin reaction occur, interruption of therapy is not required. However, 
severe hypersensitivity reactions require immediate discontinuation of the docetaxel infusion 
and aggressive therapy per local institutional practice. Patients with a history of severe 
hypersensitivity reactions should not be rechallenged with docetaxel. All patients should be 
premedicated with a PO corticosteroid before the initiation of the docetaxel infusion (see 
Fluid Retention, above).
Respiratory Disorders
Acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung 
disease, pulmonary fibrosis and respiratory failure have been reported in patients receiving 
docetaxel treatment, and may be associated with fatal outcome.(13)
If new or worsening pulmonary symptoms develop, patients should be closely monitored, 
promptly investigated, and appropriately treated. Interruption of docetaxel therapy is 
recommended until diagnosis is available. Early use of supportive care measures may help 
improve the condition. The benefit of resuming docetaxel treatment must be carefully 
evaluated.  Investigators are instructed to consult the most recent local prescribing 
information (eg, SmPC, USPI, etc) for complete details regarding the administration and 
management of docetaxel.
6.10  
Blinding and Unblinding
This is an open-label study. 
6.11   
Description of Investigational Agents
MLN1117 will be supplied as tablets for PO administration and will be available in the 
following 2 dose strengths:

MLN1117 100 mg tablets

MLN1117 300 mg tablets
MLN1117 tablets have been developed as an immediate release tablet for PO administration. 
The drug product formulation consists of a mixture of drug substance, microcrystalline 
cellulose, low substituted hydroxypropyl cellulose, sodium croscarmellose, colloidal silicon 


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dioxide, and magnesium stearate.
Docetaxel is a commercially available drug administered IV.
6.12   
Preparation, Reconstitution, and Dispensation
MLN1117 will be provided in 30-cc high-density polypropylene (HDPE) bottles with child-
resistant caps and an induction seal.  MLN1117 bottles are to be dispensed according to the 
site procedures and according to instruction and guidelines provided in the study Pharmacy 
Manual, including the requirement that tablets are stored in their original containers.  
Materials provided by the sponsor should be dispensed to patients with clear administration 
instructions from the investigator.
MLN1117 is an anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling MLN1117 tablets.
Parenteral drug products should be inspected visually for particulate matter and 
discoloration before administration, whenever solution and container permit. 
6.13   
Packaging and Labeling
MLN1117 will be handled at the investigative site as open-label material.  MLN1117 tablets 
will be provided in 14-count, 30-cc HDPE bottles with child-resistant caps and an induction 
seal.  For both dose strengths, each bottle contains 14 tablets and will have a label 
containing pertinent study information, country-specific requirements, and a caution 
statement.  
Docetaxel may be supplied either by the site from commercial sources (US sites) or 
provided by Millennium (ex-US sites).  When provided by Millennium, docetaxel will be 
appropriately labeled in compliance with local and regional regulations.
6.14   
Storage, Handling, and Accountability
Upon receipt at the investigative site, MLN1117 study drug should be stored in the original 
bottles and stored at room temperature from 15C to 30C (59F-86F). All temperature 
excursions will be reported to the sponsor for assessment and authorization for continued 
use. All investigational supplies must be stored in a secure area with controlled access and 
will be stored in original packaging. All MLN1117 should be used before the retest expiry 
date.


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A drug dispensing log, including records of drug received from the sponsor and drug 
dispensed to the subjects, will be provided and kept at the study site. Storage area 
temperature conditions must be monitored and recorded daily. A daily temperature log will 
also be kept at the study site.
Because MLN1117 is an investigational agent, it should be handled with due care. Patients 
will receive instructions for home storage and administration of MLN1117.  Patients will 
receive diary cards to record dosing compliance of MLN1117. 
Patients will be instructed to return any unused study drug in the original packaging along 
with their completed diary cards at the appropriate visits
Please refer to the site Pharmacy Manual/Study Manual for additional instructions.
Docetaxel should be stored according to that label and the instructions provided in the 
manufacturer’s most recent package insert or Summary of Product Characteristics.
7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
7.1   
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory and 
any additional clinical laboratories, the coordinating investigator for each member 
state/country, and other vendors as necessary, such as the interactive voice/web response 
system (IXRS) 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 IRB/independent ethics 
committee (IEC).  It is not envisioned that prisoners (or other populations that might be 
subject to coercion or exploitation) will be enrolled into this study.


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7.3   
Treatment Group Assignments 
A centralized randomization procedure via IXRS will be used to for treatment assignment.  
Patients will be randomized strictly sequentially at a center as they become eligible for 
randomization and will be stratified as detailed in Section 8.1.2.  If a patient discontinues 
from the study, the randomization code will not be reused, and the patient will not be 
allowed to re-enter the study.
7.4   
Study Procedures
Refer to the Schedules of Events for timing of assessments.  Additional details are provided 
as necessary in the sections that follow.
7.4.1   
Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care.  
7.4.2   
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
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 
Schedules of Events.  Some physical examinations will be symptom directed, as noted in the 
Schedules of Events. All standard-of-care examinations will include a neurological 
assessment.
7.4.5   
Patient Height and Weight
Height will be measured only during screening.  Weight will be measured at the times 
specified in the Schedules of Events.


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7.4.6   
Vital Signs 
Vital signs will be measured at the times specified in the Schedules of Events.  Vital sign 
measurements include measurements of diastolic and systolic blood pressure, heart rate, and 
temperature.
7.4.7   
Pregnancy Test
A serum pregnancy test will be performed for women of childbearing potential at screening 
and within 3 days before the first dose of study drug.  The results from these tests must be 
available and negative before the first dose of study drug is administered.  If Cycle 1 Day 1 
serum pregnancy test results will not be available before dosing, a urine pregnancy test may 
be performed.  Urine pregnancy tests will also be performed on Day 1 of every cycle 
thereafter.
7.4.8   
Eastern Cooperative Oncology Group Scale for Performance Status
The ECOG Performance Status (refer to Section 14.1) will be assessed at the times specified 
in the Schedules of Events.
7.4.9   
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will 
recorded in the electronic case report form (eCRF) from first dose through 30 days after last 
dose of study drug.  See Section 6.6 and Section 6.7 for a list of medications and therapies 
that are prohibited or allowed during the study.  
7.4.10   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedules 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 study drug is 
administered.
Procedures for completing the enrollment information are described in the Study Manual.


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7.4.12   
Electrocardiogram
A 12-lead ECG will be administered at the time points specified in the Schedules of Events.  
Additional ECGs may be obtained as clinically indicated.
7.4.13   
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed using a central laboratory.  Local 
laboratories may be used as required for acute management of AEs.  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 the following clinical chemistry and hematological parameters 
and urine samples for urinalysis will be obtained as specified in the Schedules of Events.  
Hematology and serum chemistry laboratory results must be available and reviewed by the 
investigator before enrollment and study drug administration.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Bilirubin (total)

Urate

Lactate dehydrogenase 
(LDH)

Gamma glutamyl 
transferase (GGT)

Phosphate

Albumin

Alkaline phosphatase (ALP)

Aspartate aminotransferase 
(AST)

Alanine aminotransferase 
(ALT)

Glucosea

Sodium

Potassium

Calcium

Chloride

Carbon 
dioxide 
(CO2)

Magnesium
a See the Schedules of Events for serum glucose samples that must be obtained while the patient is fasting 
(nothing except water) for 8 hours before the measurement.


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Urinalysis

Turbidity and color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult blood

Nitrite

Urobilinogen

Glucose

Leukocytes
Metabolic Panel
Fasting Lipid Profile

Cholesterol

Triglycerides

High-density 
lipoprotein (HDL)
cholesterol

Low-density 
lipoprotein (LDL)
cholesterol
Other

Hemoglobin A1c

Creatinine clearance (calculated using the Cockroft-Gault estimate [see 
Section 14.2] or based on a 12- or 24-hour urine collection)
7.4.14   
Fasting Serum Glucose
Fasting serum glucose will be measured at the time points specified in the Schedules of 
Events before administration of study drug.  Patients are required to fast overnight (nothing 
except water and/or medications after midnight or for a minimum of 8 hours) for each of 
these measurements.  
7.4.15   
In-Home Daily Glucose Monitoring
Patients who experience hyperglycemia while on study will be given a glucometer to 
monitor their daily predose FBG at home.  Patients will be instructed to fast overnight 
(nothing except water and medications after midnight or for a minimum of 8 hours) for each 
of these measurements.  
Patients will be instructed to notify the study staff immediately of any abnormal readings (ie, 
≥140 mg/dL) for further instructions on the management of their hyperglycemia.  
Hyperglycemia observed during home glucose monitoring should be confirmed in the clinic.  
Investigators will be responsible for reviewing the home glucose monitoring logs for 
hyperglycemia.  When hyperglycemia is resolved (based on FSG levels at a clinical visit), it 
is at the investigator’s discretion to discontinue or continue, either daily or at a reduced 
frequency, in-home FBG monitoring.  If continued in-home glucose monitoring is chosen by 


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the investigator to observe any further irregularities in the FBG level, patients will continue 
to notify the investigator of FBG levels ≥140 mg/dL.  If blood glucose levels are not well 
controlled or if a patient requires either PO antihyperglycemic agents or insulin to control 
blood glucose levels, then the frequency of in-home testing of FBG levels will be reinstated 
to daily.  If no further irregularities are observed, the in-home glucose monitoring may be 
discontinued if the investigator approves.  
On study visit days where FSG is assessed in the clinic, the in-home daily fasting glucose 
monitoring does not need to be completed.
7.4.16   
Disease Assessment
Patients will undergo CT scan with contrast as appropriate, MRI, x-ray, and/or bone 
scanning to monitor and assess disease progression, using modified RECIST criteria 
(Version 1.1).(12)  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 using an imaging modality consistent 
with that used at screening.  Objective assessments will be performed at each time point as 
described in the Schedules of Events.  When possible, the same qualified physician will 
interpret results to reduce variability.  Radiographic images will be maintained at the site, 
and test results and physician’s findings will be filed in patient source documents.  In 
addition, during the Phase 2 portion of the study, a copy of the image(s) will be sent to a 
central imaging vendor for storage. Subsequent analysis of these images may be conducted
at the sponsor’s discretion. However, the response assessment during the study will be 
based solely on investigator assessment.
7.4.17   
Archival Tumor Tissue and Tumor Biopsies
During the Phase 1b dose escalation phase, in the absence of archival tissue material, a fresh 
tumor specimen will be collected at screening only when a biopsy is performed per standard 
of care. Tissue samples (archival or fresh) are mandatory for all patients at screening in the 
Phase 2 dose expansion portion.  Tumor tissue (either fresh or archival) samples will be 
analyzed for KRAS mutations and PIK3CA mutations and/or amplification (squamous 
patients only).  In addition, the sample will be used for analysis of predictive biomarkers of 
MLN1117 in combination with docetaxel response including, but not limited to, somatic 
mutations.  


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Patients undergoing tumor biopsy procedures must have a platelet count > 75,000/mm3 and 
activated partial thromboplastin time and prothrombin time/international normalized ratio
within the normal range; must have an ECOG Performance Status of 0 or 1; must not be 
receiving any anticoagulant therapy or antiplatelet agents; and must not have any other 
known coagulation abnormalities that would contraindicate the tumor biopsy procedure.  
The tumor biopsy procedure will be performed per local standard care, for example, by core 
needle, under radiological guidance if indicated, or surgically with punch biopsy if the site 
of disease is superficial and palpable or visible. It is at investigator’s discretion to determine 
a patient’s eligibility for biopsy and decide with the patient’s consent whether to perform a 
biopsy procedure based on a risk assessment to the patient.
The correlation of a panel of somatic mutations with MLN1117 activity in screening tumor 
biopsy samples and/or archival paraffin tumor tissue will be evaluated.  
7.4.18   
Pharmacokinetic Measurements
Blood samples will be collected for the determination of the plasma concentrations of 
MLN1117.  Plasma PK samples will be collected at the time points specified in the 
Pharmacokinetic Sampling Schedules.  The actual date and time of each PK sample 
collection and the date and time of MLN1117 dosing for the last most recent dose should be 
recorded accurately in the eCRF.  Instructions for collecting and processing PK blood 
specimens are provided in the Study Manual.
7.4.19   
DNA Measurements
  
 
 
 
 
 
 
.  
In addition, the sample may be used for identification of gene polymorphisms related to 
study drug-related toxicity and/or clinical response.  Detailed instructions for the collection, 
processing, and shipment of samples are provided in the Laboratory Manual.


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Such analyses will be used to determine eligibility in Phase 2 Part 2 and Phase 2 Part 3.
7.4.20   
will be 
administered as specified in the Schedules of Events for the Phase 2 portion of the study 
only.  
 
 
 
 
 
 
 
  
 
 
 
 
 will be collected as specified in the 
Schedules of Events, and they must be completed before other assessments are performed or 
study drug is administered.
7.5   
Completion of Treatment
Patients will be considered to have completed treatment if they discontinue treatment with 
study drug for any of the reasons outlined in Section 7.7.
The maximum duration of treatment for patients will be 12 months unless, after discussion 
between the investigator and sponsor, it is determined that a patient would derive benefit 
from continued treatment beyond 12 months.
7.6   
Completion of Study
Patients will be considered to have completed the study if they withdraw from the study for 
any of the reasons outlined in Section 7.8.  


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7.7   
Discontinuation of Treatment With Study Drug, and Patient Replacement
Treatment with study drug may be discontinued for any of the following reasons:

AE

Protocol violation

PD

Symptomatic deterioration 

Unsatisfactory therapeutic response 

Study terminated by sponsor

Withdrawal by subject

Lost to follow-up

Other
Once study drug has been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the Schedules of Events.  The primary reason for study drug 
discontinuation will be recorded on the eCRF.
Note that some patients may discontinue study drug for reasons other than PD before
completing the full treatment course; these patients will remain in the study for 
posttreatment assessments as outlined in the Schedules of Events until PD occurs.
Patients not receiving at least 75% of MLN1117 and/or docetaxel doses in Phase 1b, 
Cycle 1, for reasons other than DLTs will be replaced within the cohort.
7.8   
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up

Study terminated by sponsor

Withdrawal by subject


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
Other
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database.
7.9   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing.
Patients will receive a sufficient quantity of ML1117 (unless in Arm B of Phase 2) 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 MLN1117 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.
7.10   
Posttreatment Follow-up Assessments (Progression-Free Survival and Overall 
Survival)
Patients who stop treatment for any reason other than PD will continue to have PFS follow-
up visits.  The PFS follow-up visit should be conducted at the site every 2 months from last 
dose of study drug until PD for a maximum of 6 months from the date of the last dose of 
study drug.  After the occurrence of PD, patients will continue to have OS follow-up visits.  
The OS information will be collected every 3 months until 12 months from the date of the 
last dose of study drug.
Survivor information may be collected by methods that include, but are not limited to, 
telephone, e-mail, mail, or retrieval from online or other databases (eg, social security 
indexes).  In addition, the start of another anticancer therapy will be collected.
NOTE:  Related SAEs must be reported to the Millennium Department of 
Pharmacovigilance or designee.  This includes deaths that the investigator considers related 
to study drug that occur during the posttreatment follow-up.  Refer to Section 9 for details 
regarding definitions, documentation, and reporting of SAEs.


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8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
In general, summary tabulations will be presented by treatment arm and will display the 
number of observations, mean, standard deviation, median, minimum, and maximum for 
continuous variables, and the number and percentage per category for categorical data.  The 
Kaplan-Meier survival curves and 25th, 50th (median), and 75th percentiles will be provided 
along with their 2-sided 95% confidence intervals (CIs) for time-to-event data.  
Details for the statistical analysis will be provided in the statistical analysis plan (SAP).  The 
SAP will be written by Takeda and will be finalized before database lock for the final 
analysis.
Deviations from the statistical analyses outlined in this protocol will be indicated in the 
SAP; any further modifications will be noted in the final clinical study report.
8.1.1   
Determination of Sample Size
Phase 1b
The number of patients enrolled in this study will be driven initially by the dose escalation 
part and by the dose expansion part. In Phase 1b (dose escalation), approximately 
15 patients with NSCLC regardless of histology (squamous or nonsquamous) may be 
enrolled based on the dose escalation scheme outlined in Section 6.3. 
Phase 2
Phase 2 of this study (dose expansion) will use a sequential, multistage, Bayesian adaptive 
design (see Figure 8.a) to allow either to favor all NSCLC patients or to select a 
subpopulation defined by histology characteristics or tumor DNA genotype.  The primary 
efficacy endpoint is PFS (time from randomization to PD or death).  Assuming an 
exponential distribution for PFS, 50 to 65 PFS events out of 60 to 80 patients with NSCLC;
50 PFS events out of 60 patients with squamous or nonsquamous NSCLC (Parts 1 and 2 
combined); and 50 PFS events out of 60 patients with PIK3CA MUT/AMP squamous 
NSCLC (Parts 1, 2, and 3 combined), if applicable, will be required to target median PFS 
improvement of 2.5 months (median PFS of 2.5 months of single-agent docetaxel vs 
5 months of MLN1117 plus docetaxel, HR = 0.5) in any of these populations with 
80% power at the type I error of 0.05 (equal to HR ≤0.63 with 72% power based on the 
calculated posterior probability of success, see decision rules below for each part of 


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Phase 2). A maximum number of 140 patients will be randomized in a 1:1 ratio to receive 
either MLN1117 plus docetaxel or single-agent docetaxel, assuming an enrollment rate of 
6 patients per month and a dropout rate of approximately 10%. The maximum of 
140 patients included 80 patients with NSCLC, 60 patients with squamous or nonsquamous 
NSCLC (Parts 1 and 2 combined), and 60 patients with PIK3CA MUT/AMP squamous 
NSCLC (Parts 1, 2, and 3 combined). 
Phase 2, Part 1
Approximately 60 patients with NSCLC will be enrolled in this part of the study. On the 
basis of histology confirmed at screening, patients will be assigned to 1 of 2 cohorts: 

Cohort 1: up to 30 patients with squamous NSCLC 

Cohort 2: up to 30 patients with nonsquamous NSCLC
In each cohort, patients will be randomized 1:1 to treatment with MLN1117 plus docetaxel 
or docetaxel alone. Before enrolling patients in Part 2, the primary analysis of PFS will be 
performed when 50 events are observed. On the basis of this analysis, the actual number of 
patients enrolled in Part 2 will be determined. The decision rules are: 
1. If the posterior probability of overall hazard ratio (HRoverall) ≤ 0.63 is at least 72%, 
the study will stop for efficacy. MLN1117 plus docetaxel is considered as 
improving PFS over single-agent docetaxel in NSCLC patients.
2. If the posterior probability of HRoverall ≤ 0.63 is less than 15%, the study will be 
terminated for futility. 
3. If criteria 1 or 2 are not met, an adaptation rule will be employed to either define a 
subpopulation based on histology (squamous or nonsquamous) or decide whether to 
enroll additional patients with NSCLC (including both squamous and nonsquamous). 
The study will change to evaluate whether the PFS benefit of MLN1117 plus
docetaxel over single-agent docetaxel in patients with squamous NSCLC is superior 
to that in patients with nonsquamous NSCLC or vice versa:
3.1
If the posterior probability of squamous hazard ratio (HRsquamous) < nonsquamous 
hazard ratio (HRnonsquamous) (larger treatment effect in squamous vs nonsquamous) is at 
least 60%, proceed to Part 2 to enroll additional 30 patients with squamous NSCLC.


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3.2
If the posterior probability of HRsquamous > HRnonsquamous (smaller treatment effect in 
squamous vs nonsquamous) is at least 60%, proceed to Part 2 to enroll additional 
30 patients with nonsquamous NSCLC. 
If neither criterion 3.1 nor 3.2 is satisfied, 20 additional patients with NSCLC 
(10 squamous and 10 nonsquamous) will be randomized 1:1 to treatment with
MLN1117 plus docetaxol or docetaxol alone. When 65 events out of the 80 patients 
with NSCLC (40 squamous and 40 nonsquamous) are observed, evaluation of 
criteria 1 and 2 will be performed. If neither criterion 3.1 nor 3.2 is met, the study 
will be terminated.
Phase 2, Part 2 (Histology Specific)
On the basis of the results of the primary analysis of Part 1, only 1 histology subtype will be 
selected for study in Part 2. Enrollment for Part 2, therefore, will be 1 of the following: 
EITHER

A maximum of 30 patients with squamous NSCLC (to provide 60 patients in Part 1 
and Part 2 combined) will be randomized 1:1 to treatment with MLN1117 plus 
docetaxel or docetaxel alone stratified by prior therapy or PIK3CA mutational status.  
To ensure that patients with and without PIK3CA MUT/AMP are evenly distributed 
between the 2 treatment arms, before enrolling patients in Part 2, the local or central 
testing lab will confirm the histology and tumor DNA genotype of the patients who 
have completed Part 1. Additional patients enrolled in Part 2 must have histology 
and tumor DNA genotyping confirmed at screening. 
OR

A maximum of 30 patients with nonsquamous NSCLC (to provide 60 patients in
Part 1 and Part 2 combined) will be randomized 1:1 to treatment with MLN1117 plus 
docetaxel or docetaxel alone.
When 50 events out of 60 patients are observed and the status of each patient’s histology is 
available (squamous or nonsquamous), a primary analysis of PFS for Part 2 will be 
performed.  If the nonsquamous subtype is selected for Part 2, the study will be terminated 
after Part 2.  If the squamous subtype is selected, the study might further evaluate whether to 
proceed to Part 3. 


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
If patients with nonsquamous NSCLC are selected for enrollment in Part 2, before
the analysis of PFS for Part 2, a central laboratory KRAS mutation test will be 
performed during the study to confirm KRAS WT status and to ensure that 
60 patients with KRAS WT nonsquamous NSCLC were enrolled in Phase 2 (Part 1 
and Part 2 combined) of the study.  Patients will be enrolled in the study on the basis 
of their local site’s KRAS mutational status.  Additional patients with KRAS WT 
nonsquamous NSCLC may be enrolled in Part 2 if needed to replace any patients 
who may have been enrolled with a KRAS mutation as confirmed by central 
laboratory testing of KRAS mutation.  The primary analysis of PFS will be conducted 
to evaluate whether MLN1117 plus docetaxel improves PFS in patients with 
nonsquamous NSCLC relative to single-agent docetaxel. If the posterior probability 
of HRnonsquamous ≤ 0.63 is at least 72%, MLN1117 plus docetaxel is considered as 
improving PFS over single-agent docetaxel in patients with nonsquamous NSCLC.

If patients with squamous NSCLC are selected for enrollment in Part 2, before
enrolling patients in Part 3, a primary analysis of PFS in patients with squamous 
NSCLC (Part 1 and Part 2 combined) will be performed.
The decision rules are as follows: 
1. If the posterior probability of HRsquamous ≤ 0.63 is at least 72%, the study will stop 
for efficacy. MLN1117 plus docetaxel is considered as improving PFS over 
single-agent docetaxel in patients with squamous NSCLC.
2. If the posterior probability of HRsquamous ≤ 0.63 is less than 15%, the study will be 
terminated for futility. 
3. If neither criterion 1 nor 2 is satisfied, the study will proceed to Part 3 to evaluate 
patients with PIK3CA MUT/AMP squamous NSCLC by enrolling an additional 
30 patients with PIK3CA MUT/AMP squamous NSCLC.
Phase 2, Part 3 (Histology and Genotype Specific)
Patients enrolled in Part 3 must have histology and tumor DNA genotyping confirmed at 
screening. On the basis of results of the primary analysis of Part 2, a maximum of 
60 patients with PIK3CA MUT/AMP squamous NSCLC (Parts 1, 2, and 3 combined) will 
be enrolled in Part 3 and randomized 1:1 to treatment MLN1117 plus docetaxel or docetaxel 
alone.  When 50 events out of 60 patients are observed, a primary analysis of PFS for Part 3 


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PIK3CA MUT/AMP squamous NSCLC (Parts 1, 2, and 3 combined) will be performed. If 
the posterior probability of squamous PIK3CA mutation and/or amplification hazard ratio
(HRMUT/AMP ) ≤0.63 is at least 72%, MLN1117 plus docetaxel is considered as improving 
PFS over single-agent docetaxel in patients with PIK3CA MUT/AMP squamous NSCLC.
There may be 3 to 4 planned analyses (See Section 8.1.11). 
Figure 8.a   
Phase 2, Sequential and Bayesian Design
Phase 2 Expansion: Sequential & Adaptive Design
All-comer Cohort
60 pts balanced with Sq vs
Non-Sq
1:1 randomization 
treatment vs control
Primary analysis: PFS 
first 60 pts/ 51 events
≥ 80% probability of 
achieving HR ≤ 0.50
Primary endpoint met
IF >15% probability of 
achieving HR ≤ 0.50 in primary 
analysis, perform:
Subgroup analysis: PFS
in subsets of 30 pts/25 events
Sample size of 60+ could be 
adjusted based on probability
Yes
No
Study terminated
Histology-Specific 
Cohort
60+ pts with a given 
histology (Sq or Non-Sq)
1:1 randomization    
treatment vs control
Histology- & Genotype-
Specific Cohort
60+ pts with a given histology & 
genotype (PIK3CA MUT/AMP Sq 
or KRAS WT Non-Sq
1:1 randomization                
treatment vs control
Yes
Yes
No
No
Primary analysis
Subgroup analysis
Phase 1b Dose Escalation
Weekly docetaxel + MLN1117
Abbreviations:  HR = hazard ratio; MUT/AMP = mutation and/or amplification; Non-Sq = nonsquamous; 
NSCLC = non-small cell lung cancer; PFS = progression-free survival; Sq = squamous; pts = patients.
8.1.2   
Randomization and Stratification  
In Phase 1b of the study, there is no randomization or stratification; all patients will receive 
MLN1117 plus docetaxel.
The randomization scheme for Phase 2 of the study will be generated by an independent 
statistician at Takeda who is not on the study team.  Before dosing, a randomization number 
will be assigned to each patient.  The randomization assignment will be implemented by an 
IXRS.  Eligible patients will be randomized in a 1:1 ratio into either MLN1117 plus 
docetaxel or docetaxel alone, stratified by 1) 1 versus >1 prior therapies; or 2) PIK3CA


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mutational status (PIK3CA MUT/AMP or PIK3CA WT). Enrollment to this study will be 
based on histology status (squamous or nonsquamous). The study will balance enrollment 
of patients with squamous and nonsquamous NSCLC (approximately 30 squamous and
30 nonsquamous). Genotyping will be conducted while the study is ongoing.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:

Safety population:  The Safety population is defined as all patients who receive at 
least 1 dose of MLN1117 plus docetaxel or 1 dose of docetaxel alone.  Patients will 
be analyzed according to the treatment actually received.  That is, those patients who 
are randomized to the MLN1117 plus docetaxel arm but received 1 dose of docetaxel 
will be included in the docetaxel arm, and those patients who are randomized to the 
docetaxel arm but received MLN1117 plus docetaxel will be included in the 
MLN1117 plus docetaxel arm for safety analyses.  

Intent-to-Treat (ITT) population:  The ITT population is defined as all patients 
who are randomized and received at least 1 dose of any study drug.  The ITT 
population will be used for the analysis of PFS, TTP, and OS.  Patients will be 
analyzed according to the treatment they were randomized to receive, regardless of 
any errors of dosing.  

Response-Evaluable population: The Response-Evaluable population is defined as 
all patients with NSCLC having measurable disease at baseline, who receive at least 
1 dose of MLN1117 plus docetaxel or docetaxel alone, and have at least 1 
postbaseline response assessment. The Response-Evaluable population will be used 
for the analysis of RR (CR +PR), disease control rate (CR + PR + SD), and DOR. 

DLT-Evaluable population: The DLT-Evaluable population, defined as all patients 
in the Phase 1b portion of the study who either experience DLT during Cycle 1 or 
complete treatment with at least 75% of the planned doses of MLN1117 plus 
docetaxel, and have sufficient follow-up data to allow the investigators and sponsor 
to determine whether DLT occurred, will be used for analysis of DLT.  

PK-Evaluable population: The population of patients evaluable for the 
determination of the PK of MLN1117 is defined as all patients in the Phase 1 portion 


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of the study for whom there are sufficient dosing and MLN1117 concentration-time 
data to permit noncompartmental PK analysis. 
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, unless specified otherwise.  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
The demographic and baseline characteristics will be summarized in a descriptive fashion.  
Data to be evaluated will include age, gender, race, weight, baseline disease characteristics, 
histology, and genotype status.
8.1.6   
Efficacy Analysis
8.1.6.1   
Analyses of Primary Efficacy Endpoints
Phase 1b
There is no primary efficacy endpoint in the Phase 1 portion of the study.
Phase 2
Primary Efficacy
The primary endpoint for the Phase 2 portion is PFS. Progression-free survival is defined as 
the time from the date of randomization to the date of first documentation of PD or death 
due to any cause, whichever occurs first.  The censoring method will be described in the 
SAP.  Progression-free survival will be tested at the final analysis based on the ITT 
population.  A 1-sided unstratified log-rank test will be used to compare the treatment arms 
with respect to PFS.  In addition, an unadjusted Cox regression model will be used to 
estimate the hazard ratio and its 95% CI for the treatment effect.  The Kaplan-Meier survival 
curves, 25th, 50th (median), and 75th percentiles (if estimable), along with their 2-sided 95% 
CIs, will also be provided for each treatment arm.
8.1.6.2   
Analysis of Secondary Efficacy Endpoints
The secondary efficacy endpoints in the Phase 2 portion of the study include RR (CR + PR), 
disease control rate (CR + PR + SD), DOR, TTP, and OS. The estimate of the RR and 


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disease control rate (CR + PR + SD) will be presented with 2-sided 95% exact binomial CIs
for each treatment arm. The number and percentage of patients in each response category 
will be tabulated for each treatment arm based on RECIST, Version 1.1. Fisher’s exact tests 
will be performed for the comparison of RR and disease control rate between the treatment 
arms.  Response rate (RR) and disease control rate will be analyzed based on the Response-
Evaluable population.  
Duration of response is defined as the time from the date of first documentation of a 
response to the date of first documentation of PD. Patients without documentation of PD at 
the time of analysis will be censored at the date of their last response assessment that is SD 
or better.  
Time to progression is defined as the time from the date of randomization to the date of first 
documentation of PD. Patients without documentation of PD at the time of analysis will be 
censored at the date of their last response assessment that is SD or better.  
Overall survival is defined as the time from the date of randomization to the date of death. 
Patients without documentation of death at the time of analysis will be censored at the date 
last known to be alive.
Duration of response, TTP, and OS will be analyzed using the Kaplan-Meier method. 
Unstratified long-rank tests will be performed for the comparisons between the 2 treatment 
arms. Duration of response will be analyzed based on the responders in the Response-
Evaluable population.  Time to progression and OS will be analyzed based on the ITT 
population.
8.1.7   
Exploratory Analysis
 
 
. 
8.1.8   
  
8.1.8.1   
 


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Particularly, the symptom (cough, dyspnoea, pain) improvement rate and time to symptom 
(cough, dyspnoea, pain) deterioration will be compared between treatment groups.
Symptom improvement will be defined as a ≥10-point decrease from baseline, and 
symptom deterioration will be defined as a ≥10-point increase from baseline.
 will be used for scoring and handling 
missing data. Further investigation of missing patterns and details of imputation, including 
subsequent sensitivity analysis, may be considered.
8.1.9   
Pharmacokinetics/Biomarkers
Pharmacokinetic Analysis
Individual and mean plasma concentrations will be plotted over time for MLN1117 
(Cycle 1, Day 2). Noncompartmental PK analysis will be performed on individual 
concentration-time data to calculate plasma PK parameters, including, but not limited to, 
Cmax, AUClast, AUCinf, and t½ for MLN1117 (Cycle 1, Day 2), as permitted by the data. 
Descriptive statistics will be presented for plasma PK parameters of MLN1117 on Cycle 1
Day 2.
Pharmacokinetic data collected during the Phase 2 portion of the study (sparse PK) will be 
used only for future population PK analysis and may be combined with similar data from 
other studies of MLN1117, the results of which will not be presented in the clinical study 
report for this study. These concentration-time data in individual patients will, however, be 
listed.
Biomarkers
Descriptive statistics, graphical methods, and statistical modeling as appropriate will be used 
to explore the relationship between response and the levels of various biomarkers.


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Pharmacogenomic Analysis 
Genotyping of polymorphisms in genes encoding proteins involved in metabolism or 
disposition of MLN1117 may be performed, guided by emerging understanding of PK and 
clearance mechanisms of MLN1117.  In addition, gene polymorphisms related to AEs 
and/or clinical response may be included in analysis.  Individual germline genotype will be 
listed for each of the polymorphisms evaluated. Descriptive and graphical methods may be 
used to explore the relationship between genotype and selected PK parameters for those 
related to the metabolism or disposition of MLN1117.  Polymorphisms identified for AEs 
and/or clinical response will be tabulated based on AE and/or clinical response criteria. 
Pharmacogenomic data from this study may be combined with similar data from other 
MLN1117 clinical studies evaluating genetic polymorphism effects on MLN1117 PK (eg, as 
a part of a future population PK analysis), the results of which will be presented in a 
separate report and will not be presented in the clinical study report for this study.
8.1.10   
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes 
from baseline in the patient’s vital signs, weight, and clinical laboratory results using the 
Safety population.  Exposure to study treatment and reasons for discontinuation will be 
tabulated.  
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of study drug will be tabulated.  
Adverse events will be tabulated according to the Medical Dictionary for Regulatory 
Activities and will include the following categories:

TEAEs

Drug-related TEAEs

Grade 3 or higher TEAEs

Grade 3 or higher, drug-related, TEAEs

The most commonly reported TEAEs (ie, those events reported by ≥10% of all 
patients) 


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
SAEs
A listing of TEAEs resulting in study drug discontinuation will be provided. 
Clinical laboratory parameters will be summarized across time on study.  Shift tables will be 
produced for selected laboratory parameters.  These tables will summarize the number of 
patients with each baseline NCI CTCAE grade and changes to the worst NCI CTCAE grade 
during study.
Descriptive statistics for the actual values of vital signs and weight over time will be 
tabulated by scheduled time point.  All concomitant medications collected from the first 
dose throughout the study period will be summarized by preferred term according to the 
World Health Organization Drug Dictionary. 
Descriptive statistics for the actual values and changes from baseline in ECGs will be 
tabulated by time point including any unscheduled measurements.
Eastern Cooperative Oncology Group Performance Status and change from baseline will be 
summarized.  Shifts from baseline to the worst postbaseline score will be tabulated by 
treatment arm.  
Additional safety analyses may be determined at any time without prejudice to most clearly 
enumerate rates of toxicities and to further define the safety profile of study drugs.
8.1.11   
Interim Analysis
There are 2 to 3 formal interim analyses included in Phase 2 of the study.
First Interim Analysis
The first interim analysis will be performed when the first 50 events are observed. 
Second Interim Analysis
The second interim analysis will be performed when the first 55 events for overall patients 
with NSCLC (if addition of 20 patients recommended at first interim analysis) or 50 events 
for patients with squamous or nonsquamous NSCLC (if addition of 20 patients is not 
recommended at first interim analysis) are observed.


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Third Interim Analysis
The third interim analysis will be performed when 50 events for patients with squamous or 
nonsquamous NSCLC (if addition of 20 patients is recommended at first interim analysis) or 
50 events for patients with PIK3CA MUT/AMP squamous NSCLC (if addition of 
20 patients is not recommended at first interim analysis) are observed.
Final Analysis (if applicable)
The final analysis (if needed) will occur when the 50 events for patients with PIK3CA
MUT/AMP squamous NSCLC are observed.
9.   
ADVERSE EVENTS
9.1   
Definitions
9.1.1   
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.  


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9.1.2   
Serious Adverse Event Definition
Serious AE (SAE) means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification in the paragraph below on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions).

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.(11)  Clarification should be 
made between a serious AE (SAE) and an AE that is considered severe in intensity (Grade 3 
or 4), because the terms serious and severe are NOT synonymous.  The general term severe
is often used to describe the intensity (severity) of a specific event; the event itself, however, 
may be of relatively minor medical significance (such as a Grade 3 headache).  This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above, and is usually associated with events that pose a threat to a patient’s life or ability to 


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function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell 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
Toll-Free Fax #:
E-mail:
All Other Countries (Rest of World)
Fax #:  
E-mail:  
Planned hospital admissions or surgical procedures for an illness or disease that existed
before the patient was enrolled in the trial or before study drug was given are not to be 
considered AEs unless the condition deteriorated in an unexpected manner during the trial 
(eg, surgery was performed earlier or later than planned).


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


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If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor must also be contacted immediately by faxing a 
completed Pregnancy Form to the Millennium Department of Pharmacovigilance or 
designee (see Section 9.2).  Every effort should be made to follow the pregnancy for the 
final pregnancy outcome.
9.5   
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse 
reactions (SUSARs) and any other applicable SAEs to regulatory authorities, including the 
European Medicines Agency (EMA), investigators and IRBs or IECs, as applicable, in 
accordance with national regulations in the countries where the study is conducted. Relative 
to the first awareness of the event by/or further provision to the sponsor or sponsor’s 
designee, SUSARs will be submitted to the regulatory authorities as expedited reports within 
7 calendar days for fatal and life-threatening events and 15 calendar days for other serious 
events, unless otherwise required by national regulations. The sponsor will also prepare an 
expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of an investigational medicinal product or that would be sufficient to 
consider changes in the investigational medicinal product’s administration or in the overall 
conduct of the trial. The investigational site also will forward a copy of all expedited reports 
to his or her IRB or IEC in accordance with national regulations.
10.   
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.  


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Study monitors will discuss instances of missing or uninterpretable data with the 
investigator for resolution.  Any changes to study data will be made to the eCRF and 
documented via an electronic audit trail associated with the affected eCRF.
10.3   
Electronic Case Report Form Completion 
Millennium or designee will provide the study sites with secure access to and training on the 
EDC application, sufficient to permit site personnel to enter or correct information in the 
eCRFs for the patients for whom they are responsible.
eCRFs will be completed for each study patient.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible.  The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Millennium, or a designee, will retain the eCRF data and corresponding audit trails.  A copy 
of the final archival eCRF in the form of a compact disk or other electronic media will be 
placed in the investigator’s study file.
10.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation.  During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements.  The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.  


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10.5   
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the patients.  The study will 
be conducted only at sites where IRB/IEC approval has been obtained.  The protocol, IB, 
ICF, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC by the investigator or the sponsor, as allowed by local 
regulations.
10.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
10.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
10.8  
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies).  Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium.  Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients.  Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
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 


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circumstances permit, to discuss the planned course of action.  Any departures from the 
protocol must be documented.
10.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.
10.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator.  
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site.  Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
10.11   Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals 
who identify a potential product complaint situation should immediately contact 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 or Medication Errors:
US:  
International:
 (not toll-free)
Email:  
Fax: 
 (international; not toll-free)
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed and sent to
(refer to Section 9.2).


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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

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 


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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 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 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.
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 subject 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 subject matter. 


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
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 MLN1117-1501 Amendment 1:  A Phase 1b/Adaptive Phase 2 Study of 
Docetaxel With or Without MLN1117 in Patients With Locally Advanced or Metastatic 
Non-small Cell Lung Cancer 
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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13.   
REFERENCES
1.
 
 
2.
 
3.
 
4.
Sarris EG, Saif MW, Syrigos KN. The Biological Role of PI3K Pathway in Lung 
Cancer. Pharmaceuticals (Basel) 2012;5(11):1236-64.
5.
Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. 
Oncogene 2008;27(41):5497-510.
6.
Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, et 
al. An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT 
mutations in breast cancer. Cancer Research 2008;68(15):6084-91.
7.
Ollikainen M, Gylling A, Puputti M, Nupponen NN, Abdel-Rahman WM, Butzow 
R, et al. Patterns of PIK3CA alterations in familial colorectal and endometrial 
carcinoma. International Journal of Cancer 2007;121(4):915-20.
8.
Spoerke JM, O'Brien C, Huw L, Koeppen H, Fridlyand J, Brachmann RK, et al. 
Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic 
subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer 
preclinical models. Clinical Cancer Research 2012;18(24):6771-83.
9.
Zhang C, Awasthi N, Schwarz MA, Schwarz RE. The dual PI3K/mTOR inhibitor 
NVP-BEZ235 enhances nab-paclitaxel antitumor response in experimental gastric 
cancer. Int J Oncol 2013;43(5):1627-35.
10.
Di Maio M, Perrone F, Chiodini P, Gallo C, Camps C, Schuette W, et al. Individual 
patient data meta-analysis of docetaxel administered once every 3 weeks compared 
with once every week second-line treatment of advanced non-small-cell lung cancer. 
Journal of Clinical Oncology 2007;25(11):1377-82.
11.
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. 2010 14 
June 2010.
12.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer 2009;45(2):228-47.


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13.
TAXOTERE (docetaxel) [package insert]. Bridgewater, NJ 08807: Sanofi-Aventis; 
2014.
14.
TAXOTERE (docetaxel) [Summary of Product Characteristics]. Antony Cedex, 
France: Aventis Pharma S.A.; 2014.
15.
 
16.
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.
17.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.
18.
The Criteria Committee of New York Heart Association. Nomenclature and Criteria 
for Diagnosis of Diseases of the Heart and Great Vessels. 9 ed. Boston, MA: Little, 
Brown & Co; 1994.


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14.   
APPENDICES
14.1   
Eastern Cooperative Oncology Group Scale for Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours.
3
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair
5
Dead
Source: Oken MM, et al. 1982.(16)
14.2   
Cockcroft-Gault Estimate
Creatinine Clearance  =
0.85 (140 - age [years]) weight [kg]
72 (serum creatinine [mg/dL])
OR
0.85 (140 - age [years]) weight [kg]
0.81 (serum creatinine [µmol/L])
Source:  Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41.(17)
14.3   
List of Strong Inhibitors and Inducers of CYP3A4
Strong CYP3A4 Inhibitors
Strong CYP3A4 Inducers
Boceprevir, clarithromycin, conivaptan, grapefruit 
juice, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, 
nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin
Avasimibe, carbamazepine, phenytoin, rifampin, St. 
John’s wort
Source:  fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/
ucm093664.htm#cypEnzymes.


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14.4   
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
minimal cardiovascular 
disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of 
moderately severe 
cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source:  The Criteria Committee of New York Heart Association.  Nomenclature and Criteria for Diagnosis 
of Diseases of the Heart and Great Vessels.  9th Ed.  Boston, MA:  Little, Brown & Co; 1994:253-256.(18)
14.5   
Methods of Contraception Considered to be Effective
Acceptable Methods Considered Highly Effective
Birth control methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective. Such methods include:

combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 1:
oral
intravaginal
transdermal

progestogen-only hormonal contraception associated with inhibition of ovulation 1:
oral
injectable
implantable 2
intrauterine device (IUD)2
intrauterine hormone-releasing system (IUS)2


TAK-117 (MLN1117)
Clinical Study Protocol MLN1117-1501 Amendment 3, EudraCT:  2014-004281-25
Confidential
112
bilateral tubal occlusion2
vasectomised partner2,3
sexual abstinence 4
Methods that are Considered Less Highly Effective
Acceptable birth control methods that result in a failure rate of more than 1% per year 
include:
progestogen-only oral hormonal contraception, where inhibition of ovulation is not 
the primary mode of action
male or female condom with or without spermicide5
cap, diaphragm or sponge with spermicide5
_________________________________________________________________________________________
Source: European Heads of Medicines Agencies (HMA) Clinical Trial Facilitation Group (CTFG); see 
hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_
CTFG_Contraception.pdf
(1) Hormonal contraception may be susceptible to interaction with the investigational medicinal product, 
which may reduce the efficacy of the contraception method.
(2) Contraception methods that in the context of this guidance are considered to have low user 
dependency.
(3) Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the woman of childbearing potential participant of the study and that the vasectomised 
partner has received medical assessment of the surgical success.
(4) In the context of this guidance sexual abstinence is considered a highly effective method only if 
defined as refraining from heterosexual intercourse during the entire period of risk associated with the 
study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the subject.
(5) A combination of male condom with either cap, diaphragm or sponge with spermicide (double-barrier 
methods) are also considered acceptable, but not highly effective, birth control methods.


 
 
 
 
 
 
 
 
ELECTRONIC SIGNATURES 
 
Signed by 
Meaning of Signature 
Server Date 
(dd-MMM-yyyy HH:mm) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Amendment 3 - A Phase 1b/Adaptive Phase 2 Study of Docetaxel With or Without
MLN1117 in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer
Biostatistics Approval
19-Oct-2015 13:08
Clinical Pharmacology Approval
19-Oct-2015 13:26
Clinical Approval
20-Oct-2015 13:41

SAP_000.pdf: 
 
 
 
 
NOTE TO FILE 
 
12‐Jan‐2018 
Re: MLN1117‐1501 SAP for ClinicalTrials.gov results submission 
 
MLN1117‐1501 was a 2‐part (Phase 1/2) study. The Phase 1 portion of the 
study completed, but the Phase 2 portion of the study was cancelled though, 
due to decisions by the study team. Due to this early termination of the study, 
a statistical analysis plan was never drafted and analyses were not performed.