Clinical trial NCT02187991
Conditions: Breast Cancer Breast Carcinoma Breast Tumors Malignant Neoplasm of Breast
Keywords: metastatic breast cancer Human Epidermal Growth Factor Receptor 2-negative (HER2-) breast cancer Estrogen Receptor-positive (ER+) breast cancer Triple Negative breast cancer alisertib paclitaxel
Sponsor: US Oncology Research
Start date: 2015-02-12; Completion date: 2024-08-01
Enrollment: 169 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical research study is to learn if the study drug, alisertib (MLN8237), in combination with chemotherapy (paclitaxel), can shrink or slow tumor growth in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative or HR-negative, HER2-negative (triple negative) locally recurrent or metastatic breast cancer (MBC). The safety of alisertib in combination with paclitaxel will also be studied. The physical state of the patient, symptoms, changes in the size of the tumor, and laboratory findings obtained while on-study will help the research team decide if alisertib plus paclitaxel is safe and effective in patients with this type of breast cancer.

Alisertib belongs to a group of drugs called Aurora kinase inhibitors. Alisertib blocks the activity of Aurora A kinase, a protein that is involved in tumor cell multiplication and survival. Aurora A kinase is expressed at higher than normal levels in many types of cancer, including breast cancer, and preclinical studies suggest that blocking the activity of this protein can lead to the death of cancer cells.

Paclitaxel is a chemotherapy drug commonly used to treat many different kinds of cancer, including metastatic breast cancer. The reason to combine alisertib and paclitaxel is that in cancer therapy, combinations of drugs are often more effective as a treatment than either of the same drugs used alone.

Detailed description:
The rationale behind assessing the effectiveness of the addition of alisertib to weekly paclitaxel therapy in patients with Triple Negative Breast Cancer and highly proliferative estrogen receptor-positive (ER+) and HER2- breast cancer is based on the unmet clinical need for effective strategies to prevent or delay resistance to taxane therapy in the metastatic setting. Synergistic or additive effects have been observed in breast cancer xenograft models which involved alisertib added to either paclitaxel or docetaxel. Alisertib inhibited the Pgp-mediated efflux of paclitaxel in a cell culture model. In addition, Aurora Kinase A is frequently overexpressed in Triple Negative Breast Cancer (TNBC), and expression levels have been shown to be prognostic in both of these breast cancer subtypes. The combination of alisertib with paclitaxel has also been investigated in a Phase 1 study in patients with locally advanced or metastatic ovarian and breast cancers, with preliminary evidence of activity in both tumor types including 6 partial response (PR)s and 3 stable disease (SD) in 11 patients with metastatic breast cancer.

Arms: arm 1: Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle arm 2: Paclitaxel 60 mg/m2 intravenously (IV) on days 1, 8 and 15 of a 28-day cycle; Alisertib 40 mg twice a day (BID) on days 1-3, 8-10, and 15-17 of a 28-day cycle arm 3: Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle arm 4: Paclitaxel 60 mg/m2 intravenously (IV) on days 1, 8 and 15 of a 28-day cycle; Alisertib 40 mg BID on days 1-3, 8-10, and 15-17 of a 28-day cycle
Interventions: intervention 1: Paclitaxel intervention 2: Alisertib
Intervention descriptions: intervention 1: either 60 mg/m2 intravenously (IV) on days 1, 8 and 15 of a 28-day cycle (on Paclitaxel plus Alisertib arm) or 90 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle (on Paclitaxel Alone arm) intervention 2: 40 mg BID (twice a day) on days 1-3, 8-10, and 15-17 of a 28-day cycle

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 13-033 
ALISERTIB (MLN8237) 
A Phase II, Multicenter, Randomized, Parallel Group Study to Compare Alisertib in 
Combination with Paclitaxel vs. Paclitaxel Alone in Patients with Metastatic or Locally 
Recurrent Breast Cancer 
Protocol Number: 
13-033 
Indication: 
Breast Cancer   
Phase: 
II  
Sponsor: 
Delta Clinical Research, LLC
Therapeutic Area: 
Oncology  
Protocol History 
Original 
Amendment 1 
Amendment 2 
Amendment 3 
11July2014 
11Sep2014 
29Apr2015 
14Jun2016 
Investigator and Study Center: 
Joyce O’Shaughnessy, MD 
Baylor Sammons Cancer Center 
3410 Worth Street 
Dallas, TX 75246 
Telephone:  214-370-1796 
CONFIDENTIAL 
Information and data included in this protocol contain trade secrets and privileged or 
confidential information that is the property of Delta Clinical Research, LLC (“Delta”) and 
Millennium Pharmaceuticals, Inc. No person is authorized to make it public without written 
permission of Delta, and Millennium Pharmaceuticals, Inc. These restrictions on disclosure 
will apply equally to all future information supplied to you, which is indicated as privileged 
or confidential. This material may be disclosed to and used by your staff and associates as 
may be necessary to conduct this clinical study.


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PROTOCOL SUMMARY 
Study Title:  A Phase II, Multicenter, Randomized, Parallel Group Study to Compare 
Alisertib in Combination with Paclitaxel vs. Paclitaxel Alone in Patients with Metastatic or 
Locally Recurrent Breast Cancer 
Phase:  2
Objectives 
The primary objective of this study is: 
z
To demonstrate the superiority of alisertib plus paclitaxel compared with 
paclitaxel alone in progression-free survival (PFS) in two cohorts of patients with 
metastatic or locally recurrent breast cancer, one with Estrogen Receptor-positive 
(ER+), Human Epidermal Growth Factor Receptor 2-negative (HER2-) disease 
and the other with  triple-negative (TN) disease 
The secondary objectives of this study are: 
z
To assess the safety of alisertib combined with paclitaxel 
z
To compare the objective response rates (ORR; complete response [CR] plus 
partial response [PR]) between the two treatment arms in each of the two cohorts 
z
To compare the clinical benefit rate (CBR; CR + PR + stable disease [SD] 6 
months) between the two treatment arms in each of the two cohorts 
z
To assess overall survival (OS) in each of the treatment arms in each of the two 
cohorts 
z
To perform genomic profiling of patients’ archived primary breast cancer tissue to 
identify potential predictive markers for benefit from alisertib plus paclitaxel 
Patient Population 
Women (18 years) with ER+/HER2- (Ki67 15%) or with poorly differentiated and/or 
Grade 3 triple-negative (TN) locally advanced or metastatic breast cancer previously treated 
with 0-1 chemotherapy regimens for advanced disease. An Eastern Cooperative Group 
(ECOG) Performance Status of 0-1 and adequate organ function are required. Eligible 
patients must have measurable disease by Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1) criteria, or lytic or mixed blastic/lytic bone-only disease. Patients with 
untreated or progressing brain metastases, or those that require corticosteroids, are not 
eligible.  Additional inclusion and exclusion criteria are detailed in section 3.2 and section 
3.2.3, respectively. 
Number of Patients 
252 
Study Design and Methodology 
Randomized parallel group study; 2 patient cohorts 


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Duration of Study 
An accrual rate of 12-15 patients per month is anticipated with a similar distribution 
between cohorts; thus the accrual phase will be approximately 24 months. The last patient 
will be followed for approximately 12 months after enrollment, until disease progression or 
treatment-limiting toxicity occurs. Therefore the anticipated total length of the study is 
approximately 36 months. 
Treatments Administered 
Patients will be randomized to receive either Paclitaxel 60 mg/m2 intravenously (IV) on days 
1, 8 and 15 plus Alisertib 40 mg BID on days 1-3, 8-10, and 15-17 of a 28-day cycle or 
single-agent Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle. 
Efficacy Data Collected 
The following evaluations will be conducted to assess the efficacy of alisertib plus 
paclitaxel: 
z
Tumor response will be assessed locally according to RECIST Version 1.1. The 
local investigator’s assessment will be used for all endpoint analyses and for 
treatment decision making. 
z
The following imaging assessments will be performed: 
o
Computed tomography (CT) of chest, abdomen, and pelvis at 
screening. Chest and abdominal CT imaging will then be performed 
every 8 weeks after initiation of treatment for the first 32 weeks of 
treatment and every 12 weeks thereafter for the duration of the 
treatment period, and at End of Treatment. Pelvic imaging will be 
continued at subsequent tumor assessments only if pelvic metastases 
are identified at screening. 
o
A whole body Tc-99 bone scan at screening for bone lesions. If bone 
lesions are present at screening, bone scans will be repeated every 12 
weeks after initiation of treatment for the first 32 weeks of treatment 
and every 16 weeks thereafter for the duration of the treatment period, 
using the same methodology used at screening. An End of Treatment 
bone scan is required only if the patient has bone metastases present 
at screening, or has developed progressive disease in the bone during 
study treatment. Patients whose first follow-up bone scan is read as 
progressive disease may stay on study therapy if the treating 
physician does not think the patient’s disease has progressed 
clinically, i.e., no new bone pain or deterioration in performance 
status and no progression of disease in other sites.  Subsequent bone 
scans that are read as demonstrating progressive disease will lead to 
termination of study therapy. 
o
A baseline brain MRI at screening is only required for patients with a 
documented history of treated brain metastases (CT is allowed if MRI 
is contraindicated). A baseline brain MRI or CT scan is not required if 


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patients do not have a documented history of brain metastases. Brain 
MRI or CT will be obtained at each tumor assessment for patients 
with previously treated brain metastases. Imaging will then be 
performed every 8 weeks after initiation of treatment for the first 32 
weeks of treatment and every 12 weeks thereafter for the duration of 
the treatment period.  An End of Treatment Brain MRI or CT is 
required only for patients with historically treated brain metastases 
present at screening, or have developed brain metastases as part of 
their progressive disease during study treatment.  
o
Skin lesions, if present, will be documented at screening using a 
digital camera (color photography). Skin photographs will be 
continued at subsequent tumor assessments for any lesions that were 
photographed at screening. Skin lesions assessments should be 
performed every 8 weeks after initiation of treatment for the first 32 
weeks of treatment and every 12 weeks thereafter for the duration of 
the treatment period.  An End of Treatment Skin lesion assessments is 
required only for patients with a documented history of skin lesions, 
or for patients who developed skin lesions as part of the progressive 
disease during study treatment. 
Correlative Studies  
The following studies will be conducted to assess molecular biomarkers potentially 
associated with benefit from alisertib plus paclitaxel: 
z
FFPE tissue from study patients’ primary breast cancers will be retrospectively 
analyzed for potential biomarkers including, but not limited to expression of 
FOXM1 and AURKA, p53 mutation status, and degree of genomic instability. 
Safety Data Collected 
The following evaluations will be conducted to assess the safety of alisertib plus paclitaxel: 
z
Monitoring and recording of all adverse events and serious adverse events; 
regular monitoring of hematology, blood chemistry, regular measurement of vital 
signs, physical examination (including weight); and performance status. 
z
All patients who receive at least one dose of study drug will be evaluated for 
safety. Toxicities will be graded and reported according to the NCI CTCAE 
Version 4.03. Incidence and type of adverse events will be tabulated and 
summarized using descriptive statistics. 
Statistical Procedures 
Using a 2-stage sequential design, assuming that the addition of alisertib to paclitaxel will 
increase the median PFS time from 3.5 to 5.8 months and from 6 to 10 months in TN and in 
ER+/HER2- patients, respectively, 112 TN and 140 ER+/HER2- patients will be 
randomized to alisertib/paclitaxel or paclitaxel alone arms to detect a hazard ratio (HR) of 


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0.6.   
PFS and OS will be analyzed using the Kaplan-Meier method and the stratified logrank test. 
A Cox proportional hazard model will be performed to assess the potential prognostic 
factors. ORR and clinical benefit rate (CBR) will be examined using univariate and 
multivariate approaches with the Fisher’s exact tests and the logistic regression models. 
Toxicity will be reported using the NCI CTCAE Version 4.03 and tabulated by numbers and 
frequencies for all study related adverse events. Dose modifications will also be tabulated in 
the same way. 
An interim analysis will be performed when the event number reaches 34 for the TN cohort. 
For the ER+/HER2- cohort, an independent interim analysis will be performed when there 
have been 23 events. 
A Bayesian continuous interim monitoring rule will be applied to evaluate the probability of 
a 30% toxicity rate in the experimental arm and accrual will be halted if there is high 
probability of more than a 30% toxicity rate, where toxicity is defined as two or more delays 
and/or reductions due to toxicity in the first two cycles. The monitoring rule will be applied 
continuously after the first five patients are randomized to this arm. The statistical 
considerations section contains more details including the operating characteristics and 
stopping boundaries.  


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL 13-033 ...............................................................................1
PROTOCOL SUMMARY ........................................................................................................2
TABLE OF CONTENTS .........................................................................................................6
LIST OF IN-TEXT TABLES ...................................................................................................8
STUDY FLOW DIAGRAM .....................................................................................................9
KEY STUDY DEFINITIONS ................................................................................................10
SCHEDULE OF EVENTS .....................................................................................................11
LIST OF ABBREVIATIONS.................................................................................................17
1. INTRODUCTION AND STUDY RATIONALE ..............................................................21
1.1 Overview of the Disease ...............................................................................................21
1.2 Alisertib (MLN8237) ....................................................................................................22
1.2.1 Aurora A Kinases and the Aurora A Kinase Inhibitor Alisertib (MLN8237) .......22
1.3 Preclinical Experience with Alisertib ...........................................................................23
1.3.1 In Vitro Studies ......................................................................................................23
1.3.2 In Vivo Studies ......................................................................................................24
1.3.3 Safety Pharmacology, Toxicology, and Drug Metabolism....................................25
1.4 Clinical Experience .......................................................................................................26
1.5 Pharmacokinetics ..........................................................................................................27
1.6 Potential Risks and Benefits .........................................................................................30
1.7 Paclitaxel ......................................................................................................................31
1.7.1 Scientific Background............................................................................................31
1.7.2 Clinical Pharmacokinetics and Pharmacodynamics ..............................................31
1.7.3 Clinical Experience ................................................................................................32
1.7.4 Potential Risks of Paclitaxel ..................................................................................32
1.8 Paclitaxel plus alisertib – clinical experience ...............................................................33
1.9 Study rationale and selection of drug doses .................................................................34
1.9.1 Study rationale .......................................................................................................34
1.9.2 Dose selection ........................................................................................................34
1.9.3 Rationale for Correlative Biomarker Study ...........................................................35
2. STUDY OBJECTIVES ......................................................................................................37
2.1 Primary Objective .........................................................................................................37
2.2 Secondary Objectives ...................................................................................................37
2.3 Exploratory Endpoints ..................................................................................................37
3. INVESTIGATIONAL PLAN .............................................................................................38
3.1 Overall Design and Plan of the Study ..........................................................................38
3.2 Selection of Patients .....................................................................................................39
3.2.1 Registration Procedures .........................................................................................40
3.2.2 Inclusion Criteria ...................................................................................................40
3.2.3 Exclusion Criteria ..................................................................................................42
3.3 Study Treatments ..........................................................................................................44
3.3.1 Clinical Trial Materials ..........................................................................................44
3.3.2 Preparation, Handling, and Storage of Drugs ........................................................45
3.3.3 Dose Modification and Delay ................................................................................47


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3.3.4 Criteria for Retreatment and Dose Delays for Paclitaxel Plus Alisertib 
Combination Arm ...........................................................................................47
3.3.5 Dose Modifications for Paclitaxel Monotherapy Arm  .........................................52
3.3.6 Treatment Assignment ...........................................................................................53
3.3.7 Packaging and Labeling .........................................................................................54
3.4 Excluded Concomitant Medications and Procedures ...................................................54
3.5 Permitted Concomitant Medications and Procedures ...................................................55
3.6 Precautions and Restrictions .........................................................................................55
3.7 Management of Clinical Events ...................................................................................56
3.7.1 Nausea and Vomiting.............................................................................................56
3.7.2 Diarrhea .................................................................................................................56
3.7.3 Central Nervous System Effects ............................................................................56
3.7.4 Treatment Compliance ...........................................................................................57
3.8 Duration of Treatment and Patient Participation ..........................................................57
3.9 Schedule of Assessments ..............................................................................................57
3.9.1 Prestudy assessments .............................................................................................57
3.9.2 Assessments during treatment ...............................................................................58
3.9.3 Off-treatment assessments .....................................................................................60
3.9.4 Follow-up assessments ..........................................................................................61
3.10 Discontinuation of Treatment and/or Study Participation ..........................................62
3.10.1 Reasons Off Treatment ........................................................................................62
3.10.2 Reasons Off Treatment ........................................................................................63
3.11 Efficacy, Correlative Studies, and Safety Measurements ...........................................63
3.11.1 Efficacy Measurements........................................................................................63
3.11.2 Correlative Biomarker Study ...............................................................................64
3.11.3 Safety Measurements ...........................................................................................65
3.12 Study Drug Administration ........................................................................................65
3.13 Description of Investigational Agents ........................................................................66
3.14 Preparation, Reconstitution, and Dispensation ...........................................................66
3.15 Packaging and Labeling ..............................................................................................66
3.16 Storage, Handling, and Accountability .......................................................................67
4. ADVERSE EVENTS..........................................................................................................68
4.1.1 Adverse Event Definition ......................................................................................68
4.1.2 Serious Adverse Event Definition .........................................................................68
4.2 Procedures for Reporting Serious Adverse Events (SAEs) ..........................................69
4.3 Procedures for Reporting Drug Exposure during Pregnancy and Birth Events ...........71
4.4 Product Complaints ......................................................................................................71
5. STATISTICAL PROCEDURES ........................................................................................73
5.1 Study Design and Overview of Primary and Secondary Endpoints .............................73
5.2 Sample Size Estimation/Accrual Rate ..........................................................................73
5.3 Randomization and Stratification Factors ....................................................................74
5.4 Evaluation of Efficacy ..................................................................................................74
5.5 Evaluation of Safety .....................................................................................................75
5.6 Correlative Studies .......................................................................................................77
5.7 Interim Analysis  ..........................................................................................................77
6. ADMINISTRATIVE REQUIREMENTS ..........................................................................78


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6.1 Good Clinical Practice ..................................................................................................78
6.2 Ethical Considerations ..................................................................................................78
6.3 Patient Information and Informed Consent ..................................................................78
6.4 Patient Confidentiality ..................................................................................................78
6.5 Protocol Compliance ....................................................................................................79
6.6 On-site Audits ...............................................................................................................79
6.7 Drug Accountability .....................................................................................................79
6.8 Premature Closure of the Study ....................................................................................80
6.9 Record Retention ..........................................................................................................80
7. USE OF INFORMATION ..................................................................................................81
8. REFERENCES ...................................................................................................................82
9. APPENDICES ....................................................................................................................86
9.1 Appendix 1: Declaration of Helsinki ............................................................................86
9.2 Appendix 2: Common Terminology Criteria for Adverse Events Version 4.03 ..........90
9.3 Appendix 3: New York Heart Association Classification of Cardiac Disease .............91
9.4 Appendix 4: Eastern Cooperative Oncology Group Scale for Performance Status .....92
9.5 Appendix 5: Body Surface Area and Creatinine Clearance Calculations ....................93
9.6 Appendix 6: Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 ..............94
9.7 Appendix 7: Collection and Shipping Instructions for Tumor Blocks .........................95
9.8 Appendix 8: Oral Medication Patient Diary .................................................................96
LIST OF IN-TEXT TABLES 
Table 3-1   
Table of Alisertib Dose Adjustments ............................................................ 43 
Table 3-2   
Criteria for Alisertib Dose Modification on Combination Arm .................... 43 
Table 5-1    
Stopping boundaries for dose-modification (2 or more doses reduced or 
held) rate  20% for first 40 patients enrolled to alisertib and paclitaxel ...... 70


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Study Flow Diagram


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Key Study Definitions 
Term 
Definition 
Baseline assessment 
The assessment performed at the closest time before initiation of 
study drug administration. 
Study drug 
The term study drug is used in this protocol to represent alisertib 
(MLN8237).  
Progression-free 
survival 
Time from randomization to the date of first documented disease 
progression by RECIST (v1.1), or death from any cause, or last 
contact date. 
Overall survival 
Time from randomization to death from any cause. 
Abbreviations:  RECIST = Response Evaluation Criteria In Solid Tumors 


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Schedule of Events 
Evaluation and Visit Schedule
Screening 
phase 
Treatment phasej
28-Day Cycle 
(Day 22 begins rest week) 
Post-
treatment 
follow up 
phase 
Survival 
phase 
Cyclea
Cycle 1k
Cycle 2k
Subsequent Cyclesk
EOT 
Endpoint 
(safety and 
efficacy) 
follow up 
Survival 
follow up 
(every 3 
months)b
Days
-28 to -1
1 
8 
15 
1 
8 
15 
1 
8 
15 
Obtain study 
Informed 
Consent and 
HIPPA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test c
X 
As clinically indicated 
ER, PgR  and 
HER2 status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Ki67 statusd
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete 
medical 
history/current 
medical 
conditions  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
extent of cancer 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
antineoplastic 
therapy (surgery, 
medication, 
radiotherapy) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 
 
Xi/h 
Xi/h
Xi/h
Xi/h
Xl 


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Evaluation and Visit Schedule
Screening 
phase 
Treatment phasej
28-Day Cycle 
(Day 22 begins rest week) 
Post-
treatment 
follow up 
phase 
Survival 
phase 
Cyclea
Cycle 1k
Cycle 2k
Subsequent Cyclesk
EOT 
Endpoint 
(safety and 
efficacy) 
follow up 
Survival 
follow up 
(every 3 
months)b
Days
-28 to -1
1 
8 
15 
1 
8 
15 
1 
8 
15 
Brief medical 
history 
 
X 
 
X 
X 
Performance 
status (ECOG) 
X 
Xi
Xi
Xh
Xl 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight  
X 
X
X
X
Xl 
Vital signs 
X 
X
X
X
Xl 
Hematology 
(CBC)
X 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe 
Xe
Xe
Xe
X 
 
 
Serum chemistry 
(CMP)
X 
Xf
Xf
Xf
 
 
X 
 
 
CT (Chest, 
Abdomen, Pelvis) 
Xn 
Xn 
Performed every 8 weeks after initiation of treatment for the first 32 weeks of 
treatment and every 12 weeks thereafter for the duration of the treatment 
period. 
Xn 
Xn 
Brain MRI  
Xg 
Xg 
Performed every 8 weeks after initiation of treatment for the first 32 weeks of 
treatment and every 12 weeks thereafter for the duration of the treatment 
period.  
Xg
Xg
Whole body Tc-
99 bone scan
Xo 
Xo 
Performed every 12 weeks after initiation of treatment for the first 32 weeks of 
treatment and every 16 weeks thereafter for the duration of the treatment 
period.
Xo 
Xo


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Evaluation and Visit Schedule
Screening 
phase 
Treatment phasej
28-Day Cycle 
(Day 22 begins rest week) 
Post-
treatment 
follow up 
phase 
Survival 
phase 
Cyclea
Cycle 1k
Cycle 2k
Subsequent Cyclesk
EOT 
Endpoint 
(safety and 
efficacy) 
follow up 
Survival 
follow up 
(every 3 
months)b
Days
-28 to -1
1 
8 
15 
1 
8 
15 
1 
8 
15 
Skin Lesions 
Xp 
Xp 
Performed every 8 weeks after initiation of treatment for the first 32 weeks of 
treatment and every 12 weeks thereafter for the duration of the treatment 
period.  
Xp
RECIST  
Version 1.1 
Xq 
Xq 
Performed every 8 weeks after initiation of treatment for the first 32 weeks of 
treatment and every 12 weeks thereafter for the duration of the treatment 
period, and at End of Treatment.  
Xq 
Xq 
Antineoplastic 
therapies since 
discontinuation 
of study 
treatment 
X 
X 
Alisertib 
administration 
 
Days 1-3, 8-10, and 15-17 of each 28-day cycle 
Paclitaxel 
administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Prior/ 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Up to 30 
days after 
last dose 
of 
treatment) 
Adverse eventsm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
(Up to 30 
days after 


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Evaluation and Visit Schedule
Screening 
phase 
Treatment phasej
28-Day Cycle 
(Day 22 begins rest week) 
Post-
treatment 
follow up 
phase 
Survival 
phase 
Cyclea
Cycle 1k
Cycle 2k
Subsequent Cyclesk
EOT 
Endpoint 
(safety and 
efficacy) 
follow up 
Survival 
follow up 
(every 3 
months)b
Days
-28 to -1
1 
8 
15 
1 
8 
15 
1 
8 
15 
last dose 
of 
treatment) 
Patient pill diary 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Archival tissue 
block 
X 
Collect and send tumor biopsy (archival FFPE blocks or slides).   One formalin fixed paraffin 
embedded tumor block (or 20 unstained slides if tumor block is not available) from the primary 
breast cancer.
Survival follow 
up 
 
 
X 
Abbreviations: CT = Computed Tomography;  ECOG = Eastern Cooperative Group;  EOT = End of Treatment;  ER = Estrogen Receptor;  FFPE = Formalin-Fixed 
Paraffin-Embedded; MRI = Magnetic Resonance Imaging;  PgR = Progesterone Receptor;  WOCBP = Women of Child-bearing Potential;  
a  A complete cycle is defined as 28 days. 
b Additional survival assessments may be performed more frequently if required. Survival follow-up will continue for up to 2 years from date of registration.  There is a +/- 
7 business day window for follow up visit assessments. Any delay within this window is NOT a deviation. 
c Serum or urine pregnancy test (-HCG) is required for all women of child-bearing potential at screening, within 3 business days prior to the first dose of paclitaxel alone 
or paclitaxel plus alisertib.  
 
d  Ki67 status should be obtained anytime before randomization.  Ki67 should be documented in the eCRF for patients with ER+, HER2- MBC if testing was previously 
performed. 
 
e  CBC with differential and platelet count. CBC is to be done within 3 business days prior to scheduled dosing on Day 1 of each Cycle for both treatment arms; CBCs 
also need to be done on Days 8 and 15 of each cycle.  Results must be known prior to dosing the patient on days when these assessments are done.   
f  Serum chemistry includes the following parameters: K+, Na+, Ca++, ALT, AST, total bilirubin, BUN, creatinine, alkaline phosphatase, bicarbonate, glucose, albumin, 
total protein, and creatinine clearance. CMP is to be done within 3 business days prior to scheduled dosing on Day 1 of each Cycle for both treatment arms.  Results 
must be known prior to dosing the patient on days when these assessments are done.  Calculation of creatinine clearance based on the creatinine values obtained from 
the CMP. 
 
g  A baseline brain MRI at screening is only required for patients with a documented history of treated brain metastases (CT is allowed if MRI is contraindicated). A 


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Evaluation and Visit Schedule
Screening 
phase 
Treatment phasej
28-Day Cycle 
(Day 22 begins rest week) 
Post-
treatment 
follow up 
phase 
Survival 
phase 
Cyclea
Cycle 1k
Cycle 2k
Subsequent Cyclesk
EOT 
Endpoint 
(safety and 
efficacy) 
follow up 
Survival 
follow up 
(every 3 
months)b
Days
-28 to -1
1 
8 
15 
1 
8 
15 
1 
8 
15 
baseline brain MRI or CT scan is not required if patients do not have a documented history of brain metastases. Brain MRI or CT will be obtained at each tumor 
assessment for patients with previously treated brain metastases. Imaging will then be performed every 8 weeks after initiation of treatment for the first 32 weeks of 
treatment and every 12 weeks thereafter for the duration of the treatment period. An End of Treatment Brain MRI or CT is required only for patients with historically 
treated brain metastases present at screening, or have developed brain metastases as part of their progressive disease during study treatment. 
h  Complete physical examination (including vital signs, height, oxygen saturation, performance status and body weight) must be obtained within 4 weeks prior to 
registration.  Patients randomized to the paclitaxel and alisertib arm will be seen for Cycle 1 on days 1, 8 and 15 to have a brief physical exam, review of AEs, 
concomitant medications, vitals, weight (day 1 of each cycle only), and performance status (day 1 of each cycle only);  for Cycle 2 on days 1 and 15 to have a brief 
physical exam, review of AEs, concomitant medications, vitals, weight (day 1 of each cycle only), and performance status (day 1 of each cycle only);  and for Cycle 3 and 
subsequent cycles, patients will have a brief physical exam, review of AEs, concomitant medications, and vitals, weight, and performance status on day 1 of each cycle.  
Additional unscheduled visits may occur as required, such as in the case of an adverse event requiring medical attention.  Patients receiving paclitaxel alone will be seen 
day 1 of each cycle to have a brief physical exam, review of AEs, concomitant medications, vitals, weight, and performance status. 
i  Patients receiving paclitaxel alone will have CBCs on days 1, 8 and 15 and will be seen by their oncology care provider every 28 days. 
j  Treatment must begin within 5 business days after patient registration on study, not including weekends or holidays. 
k  Cycle 1 only, the baseline values for those assessments that are done prior to cycle 1  may be used for Cycle 1 assessments as long as they are completed within 3 
business days prior to the patient receiving their first dose of study drug. If more than 3 business days have elapsed since the baseline assessment, the assessment 
must be repeated.  There is a window (up to 3 days prior to the scheduled time) for assessments during the study.  Cycle 2 and subsequent cycles, there is a window of 
+3 days for treatment administration during the study. 
i  Up to 7 business days to complete “end of  treatment” assessments following the last treatment. 
m  AEs will be collected within 4 weeks of patient starting study treatment, to include assessment of peripheral neuropathy.  AEs will need to be entered into the EDC 
within 5 days. 
 
n  Computed tomography (CT) of chest, abdomen, and pelvis at screening. Chest and abdominal CT imaging will then be performed every 8 weeks after initiation of 
treatment for the first 32 weeks of treatment and every 12 weeks thereafter for the duration of the treatment period, and at End of Treatment. Pelvic imaging will be 
continued at subsequent tumor assessments only if pelvic metastases are identified at screening. 
o  If bone lesions are present at screening, bone scans will be repeated every 12 weeks after initiation of treatment for the first 32 weeks of treatment and every 16 weeks 
thereafter for the duration of the treatment period, using the same methodology used at screening. An End of Treatment bone scan is required only if the patient has 
bone metastases present at screening, or has developed progressive disease in the bone during study treatment. 


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Evaluation and Visit Schedule
Screening 
phase 
Treatment phasej
28-Day Cycle 
(Day 22 begins rest week) 
Post-
treatment 
follow up 
phase 
Survival 
phase 
Cyclea
Cycle 1k
Cycle 2k
Subsequent Cyclesk
EOT 
Endpoint 
(safety and 
efficacy) 
follow up 
Survival 
follow up 
(every 3 
months)b
Days
-28 to -1
1 
8 
15 
1 
8 
15 
1 
8 
15 
p   If present, will be documented at screening using a digital camera (color photography). Skin photographs will be continued at subsequent tumor assessments for any 
lesions that were photographed at screening. Skin lesions assessments should be performed every 8 weeks after initiation of treatment for the first 32 weeks of 
treatment and every 12 weeks thereafter for the duration of the treatment period. An End of Treatment Skin lesion assessments is required only for patients with a 
documented history of skin lesions, or for patients who developed skin lesions as part of the progressive disease during study treatment. 
q  Performed every 8 weeks after initiation of treatment for the first 32 weeks of treatment and every 12 weeks thereafter for the duration of the treatment period, and at 
End of Treatment. Tumor response will be assessed locally according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
C 
degrees Celsius 
M 
micromolar 
-hCG 
Beta human chorionic gonadotropin 
5-HT3 
5-Hydroxytryptamine type 3 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
AURKA 
Aurora kinase A 
BA 
Bioavailability 
BID 
twice a day 
BRCA 
breast cancer gene 
BSA 
body surface area 
BZD 
benzodiazapine 
CBR 
CGH 
clinical benefit rate 
comparative genomic hybridization 
CLIA 
Clinical Laboratory Improvement Amendments 
cm 
centimeter 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
(NCI) Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTI 
Clinical Trial Information 
CTMS 
Clinical Trial Management System 
CYP 
cytochrome P450 
DEHP 
di(2-ethylhexyl)phthalate 
dL 
deciliter 
DLBCL 
diffuse large B cell lymphoma 
DLT 
dose-limiting toxicity 
DNA 
deoxyribonucleic acid 


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Abbreviation 
Definition 
DS&E 
Drug Safety and Epidemiology 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Group 
eCRF 
electronic case report form 
ECT 
enteric-coated tablet 
ED 
efficacious dose 
EGFR 
epidermal growth factor receptor 
EOT 
end of treatment 
ER 
estrogen receptor 
FDA 
Food and Drug Administration 
FDG 
fluorodeoxyglucose 
FFPE 
formalin fixed paraffin embedded 
FISH 
Fluorescence in-situ hybridization 
FOXM1 
forkhead box protein M1 
GABAA1 
gamma-amino butyric acid A1 
GAR 
Global Alert and Response 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 
H2 
histamine H2 receptor 
HDL 
high density lipoprotein 
HDPE 
high-density polyethylene 
HER2 
human epidermal growth factor receptor 2 
hERG 
Human Ether-à-go-go Related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
ht 
height 
IB 
I kappa B kinase; cytokine response kinase that activates transcription 
factor NF-kappa b at serine 32 and 36 
IB 
Investigator’s Brochure 
ICAM-1 
intercellular adhesion molecule 1 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 


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Abbreviation 
Definition 
IHC 
Immunohistochemistry 
IND 
Investigational New Drug 
IRB 
institutional review board 
IV 
intravenous 
kg 
kilogram 
Ki 
inhibitory constant 
lbs 
pounds 
LDL 
low density lipoprotein 
m2 
square meters 
MBC 
metastatic breast cancer 
mg 
milligram 
MI 
mitotic index 
min 
minute 
mL 
milliliter 
mm3 
cubic millimeters 
mmol 
millimole 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
mTOR 
Mammalian Target of Rapamycin 
NaF 
sodium fluoride 
NCI 
National Cancer Institute 
NF-B 
nuclear factor-B 
ng 
nanogram 
nM 
nanomole 
NYHA 
New York Heart Association 
ORR 
objective response rate 
OS 
overall survival 
p21 
p21 (ras) farnesyl-protein transferase 
p27 
cyclin-dependent kinase inhibitor 
p53 
tumor suppressor protein with molecular weight of 53 kDa 
PARP 
poly (ADP-Ribose) polymerase 
PET 
positron emission tomography 
PFS 
progression-free survival 
Pgp 
P-glycoprotein 


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Abbreviation 
Definition 
PgR 
progesterone receptor 
PIC 
powder-in-capsule 
PK 
pharmacokinetic 
PPI 
proton pump inhibitor 
PR 
partial response 
PVC 
polyvinyl chloride 
QD 
once a day 
Rb 
retinoblastoma protein 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RP2D 
recommended phase 2 dose 
SAE 
serious adverse event 
SD 
stable disease 
SGOT 
serum glutamic-oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvic transaminase 
TGI 
tumor growth inhibition 
Tmax 
time to maximal plasma concentration 
TN 
triple negative 
TNBC 
triple negative breast cancer 
TTP 
time to progression 
UGT 
UDP-glucuronosyltransferase 
UGT1A1 
UDP-glucuronosyltransferase 1A1 
ULN 
upper limit of normal 
UPN 
Unique patient number 
US 
United States 
USP 
United States Pharmacopeia 
VCAM-1 
vascular cell adhesion molecule 1 
w/w 
weight-to-weight ratio 
WHO 
World Health Organization 
wt 
weight 
WOCBP 
women of childbearing potential 


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1.    INTRODUCTION AND STUDY RATIONALE 
1.1    Overview of the Disease 
Breast cancer is the most common malignancy in women worldwide, with incidence rates as 
high as 89.7 per 100,000 women.1 Although there have been a number of important 
treatment advances in recent years, and overall mortality is declining due to earlier detection 
and more effective treatment of early stage disease, metastatic breast cancer (MBC) remains 
incurable and is the second leading cause of cancer deaths among women.2
It is now recognized that breast cancer is a heterogeneous disease, with distinct subtypes 
distinguished by expression of hormone receptors and human epidermal growth factor 
receptor 2 (HER2) as well as by characteristic gene expression profiles.3,4 Breast cancers 
that express estrogen receptors (ER) or progesterone receptors (PgR) generally have the best 
prognosis out of all of the subtypes. They are typically sensitive to endocrine agents such as 
tamoxifen and aromatase inhibitors, and may respond to multiple lines of treatment with 
these agents in the metastatic setting; however, resistance ultimately develops and at this 
point, cytotoxic chemotherapy becomes the mainstay of treatment.2
Triple-negative breast cancer (TNBC) is defined by the absence of ER, PgR, and HER2 
receptor expression. By hierarchical clustering of gene expression patterns, these cancers 
most often segregate with the ‘basal-like’ intrinsic subtype, although additional subtypes 
have been identified, including ‘claudin-low’, ‘HER2-enriched with or  without HER2 gene 
amplification’, ‘luminal B’, ‘luminal A’ and ‘molecular apocrine’.5 Compared with other 
breast cancer subtypes, TNBC is associated with a worse prognosis, including a shorter time 
to recurrence in early-stage disease, and a shorter time between recurrence and death in the 
metastatic setting.6 TNBC is insensitive to currently available targeted therapies (endocrine 
or HER2-directed agents), as would be expected by the absence of hormone or HER2 
receptors, and thus, cytotoxic chemotherapy remains the foundation of treatment for patients 
with this subtype of breast cancer.2 To date, although no clear molecular target has been 
identified and proven to have therapeutic value, a number of targeted agents have been 
evaluated with mixed results, including inhibitors of epidermal growth factor receptor 
(EGFR) and poly-(ADP-ribose) polymerase (PARP), and clinical trials are ongoing to 
evaluate the potential role of antiangiogenic agents and androgen receptor antagonists.6 
For the first line cytotoxic treatment of HER2 negative (HER2-) patients with MBC, various 
chemotherapy agents can be used, including taxanes which are among the most active agents 
in BC. Single agent objective response rates (ORRs) range from 20 to 50%.7 However, 


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eventually all patients will progress with a median time to progression (TTP) of 5 to 8 
months. As an example of the single agent response rates, in the recent E21008 and 
AVADO9 randomized Phase III trials in first-line HER2- MBC, the response rates were 22% 
and 46% and median progression-free survival (PFS) was 5.8 and 8.1 months, respectively 
for the paclitaxel and docetaxel control arms (single agent control arm data presented from 
the combination trials with bevacizumab).  
Aurora Kinase A (AURKA) is a serine/threonine kinase that is important in regulating the 
transition from G2 in mitosis, and is itself regulated by the pro-proliferative cell cycle 
transcription factor FOXM1.10,11 Genomic instability can be induced in several cancers, 
including breast cancer, due to increased levels of AURKA. In breast cancer, the 
Translational Genomics Research Institute (TGen) has performed whole genome and RNA 
sequencing on the metastatic cancer and normal tissue harvested from 14 patients with 
metastatic TNBC. Results demonstrated co-overexpression of FOXM1 and AURKA in 10 
of the 14 metastatic TNBC patients, in association as well with other markers of rapid 
proliferation.12 Overexpression of these genes has been validated at Caris Diagnostics using 
CLIA-certified array expression analysis of the patients’ cancers. Another study of archival 
formalin-fixed paraffin-embedded (FFPE) TNBC tissue has also shown overexpression of 
FOXM1 and AURKA.13 Two retrospective studies of patients with early-stage breast cancer 
have shown an association between AURKA expression and prognosis. In the first study, 
which included 122 patients with TNBC, high expression of AURKA was associated with 
shorter overall and recurrence-free survival compared with lower expression levels, 
particularly when Ki-67 expression was also high.14 The second study found higher AURKA 
expression predicted for shorter metastasis-free survival in node-negative patients with ER+, 
HER2- breast cancer.15
Thus, there is a need for improved therapies for endocrine-resistant hormone receptor 
positive MBC as well as metastatic TNBC, and AURKA may be a therapeutic target in these 
patient populations.  
1.2    Alisertib (MLN8237) 
1.2.1    Aurora A Kinases and the Aurora A Kinase Inhibitor Alisertib 
(MLN8237) 
Alisertib (International Proprietary Name, also known as MLN8237) is a selective small 
molecule inhibitor of Aurora A kinase that is being developed for the treatment of advanced 
malignancies.  Aurora A kinase belongs to a highly conserved family of serine/threonine 


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protein kinases that also includes Aurora B and Aurora C.  Aurora A and Aurora B are 
expressed in all actively dividing cells, while Aurora C expression is largely restricted to 
dividing germ cells.16   Aurora A localizes to centrosomes and the proximal mitotic spindle 
during mitosis where it functions in a diverse set of mitotic processes.  
The evidence supporting Aurora A kinase as a therapeutic target for the treatment of 
malignancies comes from several sources.  First, the Aurora A kinase gene is amplified, 
overexpressed, or both in many tumors, including colon, breast, pancreatic, and bladder 
cancers, as well as certain lymphomas, leukemias, and myeloma.17,18,19,20,21  Aurora A 
overexpression in human cancers has been correlated with increased aneuploidy and 
centrosome amplification.22   Second, forced overexpression of Aurora A kinase in 
experimental models results in the transformation of normal cells, suggesting that Aurora A 
overexpression may be oncogenic.17  Lastly, in a number of different experimental systems, 
Aurora A inhibition leads to mitotic delays and severe chromosome alignment and 
segregation defects, followed by cell death.23,24,25,26   Overall, the essential role of Aurora A 
in mitotic progression and its dysregulation in certain cancers makes it an attractive 
therapeutic target.   
Given the obligatory role of mitosis in tumor proliferation, an Aurora A inhibitor would be 
expected to have potential applications across a broad range of human tumors.  Indeed, 
alisertib has demonstrated activity against a variety of nonclinical solid tumor and 
hematologic malignancy models grown in vitro and in vivo, as described below.  Alisertib is 
also expected to be toxic to proliferating normal tissues, such as the bone marrow, 
gastrointestinal (GI) epithelium, and hair follicles because any cell that is in mitosis, where 
Aurora A is expressed and active, should be susceptible to the effects of an Aurora A kinase 
inhibitor. 
1.3    Preclinical Experience with Alisertib 
1.3.1       In Vitro Studies 
Alisertib (MLN8237) is an ATP-competitive and reversible inhibitor of Aurora A kinase in 
vitro with an inhibition constant (Ki) of 0.43 nM. The data from both enzymatic and cell-
based assays demonstrated that alisertib is a selective and potent inhibitor of Aurora A 
kinase. Alisertib inhibited proliferation of a wide variety of tumor cell lines grown in 
culture. Moreover, treatment of tumor cell lines with alisertib induced phenotypes consistent 
with Aurora A kinase inhibition, including mitotic spindle defects, mitotic delay, and 
apoptosis.26, ,27,28,29 For further details, refer to the Investigators’ Brochure (IB).  


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1.3.2       In Vivo Studies 
Alisertib (MLN8237) demonstrated antitumor activity when administered orally on a daily 
basis for approximately 21 days (maximal tumor growth inhibition [TGI] > 90%) in several 
experimental human solid and hematologic tumor models grown as xenografts in 
immunocompromised mice. The maximally efficacious dose (ED) for each model varied: 
between 10 and 30 mg/kg if given once daily (QD) and 20 mg/kg if given twice daily (BID). 
Studies in the HCT-116 colon tumor model showed that less frequent dosing (eg, 5 days on 
followed by 5 days off) was also efficacious, demonstrating that continuous dosing is not 
necessary for antitumor activity. A single oral dose of alisertib given to nude mice bearing 
subcutaneous HCT-116 human colon tumors resulted in inhibition of activated Aurora A 
kinase and an increase in mitotic cells. Therefore, mitotic index (MI) can be used as a 
pharmacodynamic marker of alisertib in some in vivo settings. The relationship between 
pharmacokinetics (PK), pharmacodynamics, and efficacy was further studied in HCT-116 
xenografts using oral dosing and subcutaneous osmotic mini-pumps. Both a 
pharmacodynamic response and efficacy (antitumor activity) were achieved using either 
route of administration. The data from these studies suggest that the maximum 
pharmacodynamic effect (mitotic accumulation) and efficacy are achieved at steady state 
plasma concentrations of 1 µM. Moreover, the maximally efficacious oral doses of alisertib 
in the HCT-116 model (30 mg/kg QD) resulted in plasma concentrations of 1 µM for 8 to 12 
hours post-dose. Plasma concentrations of alisertib associated with saturating levels of 
pharmacodynamic and antitumor activity (1 M) were exceeded at the recommended phase 
2 dose (RP2D) of alisertib in patients (50 mg BID). 
To determine whether alisertib would enhance the antitumor effects of standard of care 
agents in solid and hematologic malignancies, nonclinical combination studies were 
performed. Combination therapy with alisertib and docetaxel resulted in additive or 
synergistic effects during the dosing period, with prolonged tumor growth delay in multiple 
solid tumor xenograft models after terminating treatment. These effects were also observed 
in alternative intermittent dosing schedules. Combination treatment with paclitaxel in 2 
xenograft models of breast cancer generally resulted in additive or synergistic antitumor 
activity, with tumor growth delay observed. In diffuse large B cell lymphoma (DLBCL) 
xenograft models, combination therapy with alisertib and rituximab resulted in synergistic, 
additive, or subadditive effects depending on the dose and model; however, prolonged tumor 
growth delays were observed in every case after terminating treatment, and in some cases 
complete cures were maintained. 


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1.3.3    Safety Pharmacology, Toxicology, and Drug Metabolism 
Safety pharmacology studies with alisertib (MLN8237) did not identify significant adverse 
effects in nonclinical studies, including in the central nervous system (CNS) and 
cardiovascular systems. No alisertib-related effects on clinical signs or physical examination 
findings indicative of impaired respiratory function (i.e., labored or shallow breathing), or 
microscopic changes in the lungs of animals that survived until scheduled termination, were 
noted at tolerated doses in Good Laboratory Practice (GLP)-compliant, repeat-dose, 
toxicology studies. Alisertib exhibited minimal activity against the rapidly activating 
component of IKr, which is encoded by hERG (IC50 and Ki > 100 µM). Alisertib had in vitro 
activity against the GABAA1 benzodiazepine binding site (Ki = 290 nM). 
The dose-limiting toxicities (DLTs) for alisertib in both rats and dogs after repeat daily oral 
dosing for 2 cycles (each cycle consisted of 7 consecutive days separated by a 14-day dose 
holiday) or for 6 cycles (each cycle consisted of 21 consecutive days of dosing separated by 
a 7-day dose holiday) were consistent with inhibition of Aurora A kinase by alisertib. 
Principal findings in toxicology studies in rats and dogs included GI signs, panleukopenia, 
decreased reticulocyte counts, and increased mitotic figures and apoptosis (single-cell 
necrosis) in tissues with a high basal cellular replication rate. These findings are indicative 
of toxicity to rapidly replicating cell populations and are consistent with the outcomes 
associated with Aurora A kinase inhibition. No off-target effects were seen in the GLP-
compliant toxicology studies. Alisertib was negative in the bacterial reverse mutation assay 
(Ames assay) both in the absence and presence of Aroclor™ 1254-induced rat liver S9 
fractions. In a rat bone marrow micronucleus assay, alisertib was considered to be equivocal 
for clastogenicity. 
Alisertib is metabolized by multiple phase I (cytochrome P450 [CYP]3A4, CYP2C9, 
CYP2C19, and CYP1A2) and phase II (uridine diphosphate glucuronosyltransferase [UGT] 
1A1, 1A3, and 1A8) enzymes.  Using human liver microsomes with the appropriate 
cofactors, the percent contribution of CYP and UGT was calculated to be 13.1% and 86.9%, 
respectively, showing that CYP isozymes play a minor role in the metabolism of MLN8237.  
MLN8237 is unlikely to inhibit the 5 major CYP enzymes, 1A2, 2C9, 2C19, 2D6, and 
3A4/5 (IC50 > 100 M) when administered at the projected human efficacious dose.  
MLN8237 is not a mechanism-based inhibitor of CYP3A4/5.  Alisertib inhibited the 
P-glycoprotein (Pgp)-mediated efflux of paclitaxel (Taxol) in Caco 2 cells with an IC50 of 
4.0 M. 


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Detailed information regarding the nonclinical pharmacology and toxicology of alisertib 
may be found in the IB. 
1.4    Clinical Experience 
As of 29 March 2015, the following company-sponsored alisertib studies were in progress or 
completed: 10 single-agent phase 1 studies (C14001, C14002, C14003, C14010, C14013, 
C14014, C14017, C14019, TB-MA010030, and TB-MA010033); 2 single-agent, phase 1, 
DDI studies (C14015 and C14020); 3 single-agent, phase 2 studies (C14004, C14005, and 
C14006); 1 single-agent, phase 1/2 study (C14007); 1 single–agent, phase 3 study (C14012); 
and 5 combination studies (C14008 [phase 1/2] with paclitaxel, C14009 [phase 1] with 
docetaxel, C14011 [phase1] with either rituximab, or rituximab + vincristine, C14018 with 
paclitaxel [phase 2], and C14022 with paclitaxel [phase 1]).Three dosage forms of alisertib 
have been developed for clinical studies: powder in capsule (PIC), enteric-coated tablet 
(ECT), and oral solution. The initial phase 1 (C14001 through C14003) and phase 2 
(C14004 through C14006) studies employed the PIC formulation. Studies C14001 and 
C14003 were amended to evaluate the ECT formulation; C14001 evaluated the relative 
bioavailability (BA) of the PIC and ECT formulations in solid tumor patients, and C14003 
evaluated the clinical safety and pharmacokinetic (PK) of the ECT formulation in patients 
with hematologic malignancies. Relative BA of the PIC, ECT, and oral solution has also 
been investigated in Study C14010. The ECT formulation is being used in more recent 
studies (C14007 through C14009, C14011 through C14015, C14017, TB-MA010030 and 
TB-MA010033) and will be used in future studies.The dose-escalation, phase 1 study, 
C14007, evaluated multiple dose levels from 10 to 60 mg BID for 7 days in repeat, 21-day 
cycles and 50 mg BID has been determined to be the MTD. The recommended phase 2 dose 
(RP2D) was established in Studies C14001 and C14002 at 50 mg BID for the 7-day 
schedule followed by a 2-week, treatment-free period. Study C14007 confirmed the RP2D 
and schedule for the ECT formulation. 
Alisertib has also been evaluated as a single agent in a phase 1/2 study in adults with solid 
tumors; phase 2 data from the breast cancer cohort were recently presented.30 Fifty-three 
patients with relapsed/refractory breast cancer, previously treated with 4 prior cytotoxic 
regimens for metastatic or recurrent disease, received alisertib 50 mg BID for 7 days 
followed by 14 days rest in 21-day cycles. Forty-nine patients were evaluable for response, 
with an ORR of 18% for all patients. The ORR was 23% in the ER+/HER2- cohort (n=26) 
and 7% in the triple-negative cohort (n=14), with a median PFS of 7.9 months and 1.5 
months respectively. Patients with HER2+ disease (n=7) had an ORR of 22% and a median 


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PFS of 4.1 months. Some responses in the ER+/HER2- and HER2+ cohorts have been 
maintained for > 1 year. Grade 3 drug-related AEs were reported in 72% of patients. Grade 
3 neutropenia occurred in 49% of patients, with 4% of patients experiencing febrile 
neutropenia. Treatment emergent SAEs occurred in 21% of patients; the most common 
events were aphthous stomatitis (n=3), anemia, febrile neutropenia, and neutropenia (each 
n=2), and 57% of patients required alisertib dose reductions. No on-study deaths were 
reported. 
Alisertib is structurally related to the benzodiazepines (BZD) (eg, diazepam, lorazepam) and 
also has activity against the GABAA1 BZD receptor.  BZD-like effects (eg, somnolence, 
confusion, memory loss) have been observed to be associated with the onset of maximal 
plasma concentration (e.g., Tmax [time to maximum plasma concentration]).  CNS effects 
associated with peak plasma levels have been generally managed by administration of 
divided doses (e.g., BID administration), although dose reductions have sometimes been 
required.  While CNS effects attributed to alisertib were also generally reversible and 
manageable by dose delay or reduction, the causal relationship, and thus optimal approach to 
management, were sometimes confounded by diverse causes including, but not limited to, 
concomitant medications (e.g., narcotic analgesics, antianxiety medications), comorbidities 
(e.g., infection, anemia, electrolyte abnormalities), or progressive malignancy (e.g., brain 
metastases). 
The clinical experience with alisertib includes treatment with multiple doses and schedules 
and is summarized in the IB.   
1.5    Pharmacokinetics 
Following oral administration of alisertib as an ECT formulation, peak concentrations of 
alisertib were generally achieved by 3 hours post-dose.  The overall median Tmax was 3 
hours following 7 days of BID multiple oral dose administration.  The overall peak-to-
trough ratio was 2.2 and accumulation ratio was 2.4.  The terminal half-life was 
approximately 21 hours following 7 days of multiple dosing.    Steady-state plasma 
exposures of alisertib increased in an approximately dose-proportional manner over the 
range of 5 to 200 mg/day in patients with advanced solid tumors.  Pharmacokinetic steady-
state conditions were approximately achieved by Day 7 following daily oral administration.  
The predominant route of elimination for alisertib is fecal, consistent with hepatic 
metabolism and biliary excretion of alisertib. Renal clearance of unchanged alisertib was 
negligible. Based on the results from the radio-labeled human ADME study (C14014) and 


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the follow-up in investigations, alisertib is metabolized by both oxidation and 
glucuronidation pathways, and multiple cytochrome P450 (CYP) isozymes (CYP3A4, 2C8, 
2C9, 2C19, and 1A2) and UGT isozymes (UGT1A1, 1A3, and 1A8) are involved. Phase 1 
oxidative metabolism was identified to be of quantitative importance, with an estimated 
contribution of CYP3A4 of approximately 60% to overall apparent oral clearance (CL/F) in 
humans. Therefore, moderate to strong inhibitors of CYP3A4 and clinically significant 
inducers may alter systemic exposures of alisertib and should be avoided. The 
pharmacokinetic properties of alisertib in patients with hematologic malignancies were 
generally consistent with those observed in patients with nonhematologic malignancies. 
Based on the results of a population PK analysis in 363 adult cancer patients, the CL/F of 
alisertib was unaffected by age, body weight, BSA, or UGT1A1 genotype (number of *28 
alleles). These results support the use of a common fixed starting dose of alisertib in the 
adult patient population in the ongoing and planned clinical trials. Clinical pharmacokinetic 
data available as of 29 March 2015 are summarized in the IB. 
The effect of a high-fat meal on the single-dose PK of alisertib administered as 5 × 10-mg 
ECT was evaluated in Study C14017. The geometric mean AUC0-inf  following alisertib 
single dose administration under fed conditions was 115% of that under fasted conditions 
(90% CI: 96%, 139%), with a substantial overlap in the range of individual values of AUC0-
inf when dosed in the fed versus fasted states. Based on the relatively minor (15%) increase 
in alisertib geometric mean AUC0-inf upon administration with a high-fat meal in relation to 
overall PK variability (45% coefficient of variation [CV] in AUC0-inf), it is concluded that 
food does not produce a clinically relevant effect on alisertib PK. The results of this study 
support a conclusion that alisertib can be administered without regard to the timing of meals 
in future clinical trials, unless otherwise specified in the clinical study protocol. 
The relative BA of the oral solution in reference to PIC in 14 patients was estimated to be 
1.26 in reference to the PIC (90% CI: 1.09 – 1.47). The rate of absorption of alisertib from 
the oral solution was higher than that from the PIC formulation, based on a shorter median 
time to first maximum plasma concentration ([Tmax] 1 hour for the oral solution vs 2 hours 
for the PIC). The geometric mean ratio of dose-normalized Cmax of oral solution vs PIC was 
1.90 (90% CI: 1.52 – 2.37). 
Across a total of 56 patients from 3 phase 1 studies in Asian patients, the geometric mean 
dose-normalized steady-state AUC0- is 750 nM.hr/mg (43% CV), which is approximately 
67% higher than the corresponding geometric mean dose-normalized steady-state AUC0- in 
the Western population (N = 363). 


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Co-administration of alisertib with esomeprazole, a proton pump inhibitor (PPI) resulted in a 
28% increase in total systemic exposure (AUC0-inf) of alisertib, supporting the conclusion 
that gastric acid-reducing agents be avoided in patients receiving alisertib. 
Co-administration of alisertib with rifampin, a strong metabolic enzyme inducer resulted in a 
47% decrease in total systemic exposure (AUC0-inf) of alisertib, supporting the conclusion 
that chronic use of concomitant strong inducers of pregnane x-receptor (PXR)-inducible 
enzymes be avoided in patients receiving alisertib. 
Alisertib (50 mg) in single doses and after multiple doses BID for 7 days was not associated 
with any clinically relevant changes or findings in the electrocardiogram (ECG), did not 
prolong the QT interval, and can be concluded not to affect cardiac repolarization dynamics. 
No alisertib concentration-effect relationship was identified, consistent with findings from 
the statistical analyses in supporting a lack of effect on the QT interval. 
Pharmacodynamic evaluations have been performed in patient skin and tumor biopsies using 
assays that reflect Aurora A kinase inhibition. The data collected to date from these biopsies 
provide evidence that a dominant mechanism of alisertib is inhibition of Aurora A kinase in 
both skin and tumor, and these effects are generally dose- and/or exposure-dependent.  
Adverse events (AEs) observed to date (as of 29 March 2015) are generally reversible, dose-
dependent, and are consistent with the pharmacologic profile of alisertib as an anti-mitotic 
agent with predominant effects in proliferative tissues. The more commonly observed (
30% incidence) treatment-emergent AEs (TEAEs) all grades from pooled data across the 
alisertib single-agent studies include: neutropenia (48%), anemia (47%), fatigue (46%), 
diarrhea (44%), alopecia (36%), stomatitis (32%), and nausea (31%).  
Central nervous system (CNS) effects, including transient dose-dependent somnolence 
and/or confusion, have also been observed. These CNS effects may not be associated with 
Aurora A kinase inhibition but instead likely represent benzodiazepine-like effects of 
alisertib due to its structural similarity to benzodiazepine. At higher dose levels evaluated in 
phase 1 studies, severe CNS effects were sometimes considered DLTs, although these 
effects abated during the planned treatment-free period. In the phase 1 studies, CNS effects 
appeared to be related to high peak plasma levels resulting from single daily doses of 
alisertib. The frequency and/or severity of benzodiazepine-associated CNS toxicities may be 
reduced in adult patients enrolled to recent studies that administered alisertib with divided 
doses (eg, BID), a schedule designed to reduce peak plasma levels while maintaining overall 
AUC. CNS effects have been reversible with cessation of alisertib treatment, dose reduction, 


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and dose modification of other sedative medications. 
1.6    Potential Risks and Benefits 
As of 29 March 2015, 1197 patients (including 23 patients from 2 company-sponsored, non-
US IND studies in Japan and excluding patients from ongoing, double-blind study C14018) 
have been treated with alisertib, in company-sponsored studies. Clinical safety data include 
experience from patients who received multiple cycles followed by treatment-free periods 
between each cycle, and from patients who reduced or discontinued treatment.  Based on the 
available clinical data, drug abuse, dependency, and drug withdrawal effects were not 
observed.  
The identified risks associated with alisertib treatment include: reversible myelosuppression 
including anemia; febrile neutropenia (including fatal febrile neutropenia); leukopenia; 
lymphopenia; neutropenia (including fatal neutropenia); pancytopenia (including fatal 
pancytopenia); thrombocytopenia; GI toxicity including abdominal pain, diarrhea, 
dyspepsia, mucosal inflammation, nausea, oral pain, stomatitis, and vomiting; asthenia; 
fatigue; pyrexia; infection (including fatal infection); sepsis (including fatal sepsis); liver 
function test abnormal including aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), bilirubin, alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT); 
decreased appetite; dehydration; gait disturbance; sedation; somnolence; confusional state; 
disorientation (and associated memory loss); alopecia; rash (including bullous dermatitis); 
and palmar-plantar erythrodysesthesia syndrome. 
While all of these toxicities are potentially associated with risk or discomfort to the patient, 
they are anticipated to be reversible. However, it is possible that alisertib will have other 
toxicities that have not been observed in or predicted from its evaluation in rats and dogs 
and from ongoing studies in humans. Alisertib has a very low potential to prolong the QT 
interval in vivo based upon its extremely weak in vitro binding to hERG (IC50 and Ki both > 
100 µM).To mitigate the inherent risks in clinical studies of alisertib, patients are evaluated 
frequently while they are receiving treatment. Guidance for reducing doses is provided in 
the protocols, and drug dosage can be reduced by either reducing the daily dose 
administered or by interruption of the scheduled treatment within a cycle.   
Because alisertib inhibits Aurora A kinase, it is possible that alisertib may interfere with 
cancer growth and cause cancer cell death. Preclinical results indicate that alisertib is not a 
major substrate for efflux mechanisms that have been associated with cross-resistance 
between some types of anticancer agents. Thus, alisertib has potential through a potentially 


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non-cross resistant pathway as compared to other agents the patients may have received. 
Based on laboratory studies with agents that target Aurora A kinase, it is also possible that 
alisertib will induce cancer cell senescence, leading to a terminal outcome for cancer cells 
that may be initially represented by stable disease (SD) instead of immediate tumor 
reduction (response). The clinical utility of these effects will be investigated in current and 
future studies.   
This study will be conducted in compliance with the protocol, applicable regulatory 
requirements, and International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP), guidelines. 
1.7    Paclitaxel 
1.7.1    Scientific Background 
Paclitaxel is a cytotoxic agent with proven antitumor activity in a variety of solid tumors, 
including breast cancer, ovarian cancer, and lung cancer. The antitumor activity of paclitaxel 
is based on tubulin-binding and stabilization of non-functional microtubule bundles, thereby 
blocking normal mitotic spindle development and subsequent cell division.31
1.7.2    Clinical Pharmacokinetics and Pharmacodynamics 
Paclitaxel demonstrated a biphasic decline in plasma concentrations following intravenous 
administration. An initial rapid decline represents distribution of the drug to the peripheral 
compartment as well as elimination, while the second phase represents the slower efflux of 
drug from the peripheral compartment.32
Pharmacokinetic parameters were studied in a phase 3 trial in patients with ovarian cancer, 
using dosages of 135 mg/m2 IV and 175 mg/m2 IV administered as 3- or 24-hour infusions. 
Terminal half-life ranged from 13.1 to 52.7 hours, Cmax ranged from 195 ng/mL to 3650 
ng/mL, and total body clearance ranged from 12.2 to 23.8 L/h/m2. The pharmacokinetics of 
paclitaxel administered as singles doses at 15 to 135 mg/m2 administered as a 1-hour 
infusion, 30 to 275 mg/m2 by 6-hour infusion, and 200 to 275 mg/m2 as a 24 hour infusion, 
in adult patients with other cancers were consistent with these values.  
Clearance of paclitaxel is primarily through non-renal pathways. A study of radiolabeled 
paclitaxel showed that 71% of radioactivity was excreted in the feces and 14% through the 
urine in 120 hours. Paclitaxel is metabolized primarily by the cytochrome P450 isozymes 
CYP2C8 and CYP3A4. 


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Additional details regarding the pharmacology of paclitaxel can be found in the package 
insert. 
1.7.3    Clinical Experience 
In breast cancer, paclitaxel is used both in combination with other agents and as a single 
agent. In the pivotal Phase 3 trial 2 doses of paclitaxel (135 mg/m2 IV or 175 mg/m2 IV), 
both administered q3w, were compared in 471 patients who had received 1-2 prior 
chemotherapy regimens. The ORRs were 29% and 22% for the high and low dose 
respectively. Median TTP was 4.2 versus 3.0 months (P=.027), and median OS was 11.7 
months and 10.5 months (P=.321) for the 175 mg/m2 and 135 mg/m2 dosages, respectively.32
An ORR of 25% was reported for q3w paclitaxel at a dosage of 175 mg/m2 in another phase 
3 trial in patients with MBC that had progressed on an anthracycline-containing regimen, 
with a median TTP of 3.6 months and a median OS of 12.7 months.33 Paclitaxel has also 
been studied in anthracycline-naïve MBC. As first-line therapy, ORRs of 25%-34% have 
been reported, with median OS ranging from 15.6 months to 22.2 months.34,35,36
A weekly (qw) over a three-weekly (q3w) administration schedule has been shown to be 
more effective in the metastatic as well as in the adjuvant setting after standard 
chemotherapy.37,38 In these two large randomized phase 3 studies the overall toxicity profile 
was similar between the qw and q3w schedule except for neuropathy (higher in the qw arm) 
while other studies have described a more favorable toxicity profile with the qw 
administration.7
1.7.4    Potential Risks of Paclitaxel 
The reported toxicity profile of paclitaxel is based upon the experiences of 812 patients with 
ovarian or breast cancer who received treatment with single agent paclitaxel in 10 clinical 
studies.32
Adverse events that have been observed in patients with paclitaxel include: (1) reversible 
myelosuppression including neutropenia, leukopenia, thrombocytopenia, and anemia; (2) 
peripheral neuropathy; (3) GI toxicity including nausea, vomiting, diarrhea, and mucositis; 
(4) alopecia; (5) myalgia and/or arthralgia; (6) bleeding; (7) infection; (8) abnormal liver 
function tests (including AST, ALP, and bilirubin; (9) cardiovascular events, including 
hypotension, bradycardia, and hypertension; (10) abnormal electrocardiogram (ECG) and 
(11) injection site reaction.  


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Anaphylaxis and severe hypersensitivity reactions occurred in 2-4% of patients treated with 
paclitaxel on clinical trials, and fatal reactions have been reported. All patients should be 
pretreated with corticosteroids, diphenhydramine, and histamine H2-receptor antagonists. 
Patients who experience severe hypersensitivity reactions to paclitaxel should not be 
rechallenged with the drug. 
Additional details regarding adverse events associated with paclitaxel can be found in the 
package insert. 
1.8    Paclitaxel plus alisertib – clinical experience 
The combination of alisertib plus paclitaxel has been investigated in a Phase 1B dose 
escalation study (C14008) in patients with previously treated, metastatic or locally recurrent 
ovarian or breast cancer (N=49; 38 ovarian cancer, 11 breast cancer). The maximum 
tolerated doses (MTDs) were determined to be paclitaxel 80 mg/m2 IV (days 1, 8, and 15) 
plus alisertib 10 mg BID (days 1-3,8-10,15-17) and paclitaxel 60 mg/m2 IV (days 1, 8, and 
15) plus alisertib 40 mg BID (days 1-3,8-10,15-17) of a 28 day cycle.39,40 This dosing 
schedule was selected to maximize concomitant exposure of alisertib and paclitaxel, while 
providing treatment-free periods for recovery from toxicities like neutropenia and 
mucositis.40 The most common dose-limiting toxicities were neutropenia, with or without 
fever. Thirty-eight patients experienced Grade 3 adverse events; the most common were 
neutropenia (61%) and leukopenia (33%).  
Preliminary data from the combination study of alisertib + paclitaxel (C14008) suggest that 
there is an increased risk of stomatitis for patients receiving the combination of alisertib + 
paclitaxel, when compared with patients receiving either single-agent alisertib or single-
agent paclitaxel. 
The effect of alisertib on paclitaxel PK was assessed at the RP2D of 40 mg BID of alisertib 
+ 60 mg/m2 of paclitaxel. In this study, alisertib 40 mg BID was administered for 3 days 
on/4 days off, repeated weekly for 3 weeks in a 28-day cycle (alisertib administered on Days 
1-3, 8-10, 15-17) and weekly paclitaxel at either 60 mg/m2 on Days 1, 8, and 15 or weekly 
paclitaxel 80 mg/m2 on Days 1, 8, and 15, of a 28-day cycle. Based on the preliminary data, 
it appears that there is a small (10%-19%) increase in paclitaxel total systemic exposures 
(AUC) achieved when co-administered with 40-mg BID alisertib. The exposures of 
paclitaxel achieved at 60 mg/m2 when co-administered with 40-mg BID alisertib are not 
higher than those achieved with paclitaxel when administered alone at the standard single-


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agent weekly dose of 80 mg/m2, indicating the lack of any clinically concerning increases in 
paclitaxel exposures when co-administered with alisertib at the RP2D of the combination. 
One patient with ovarian cancer had a complete response by RECIST as well as CA125.39
Sixteen patients had a PR, including 10 patients with ovarian cancer and 6 patients with 
breast cancer. Fourteen additional patients had a best response of SD, including 11 patients 
with ovarian cancer and 3 with breast cancer. 
1.9    Study rationale and selection of drug doses 
1.9.1    Study rationale 
The rationale behind assessing the effectiveness of the addition of alisertib to weekly 
paclitaxel therapy in patients with TNBC and highly proliferative ER+ and HER2- breast 
cancer is based on the unmet clinical need for effective strategies to prevent or delay 
resistance to taxane therapy in the metastatic setting. As described in Sections 1.3.2 and 
1.3.3, synergistic or additive effects have been observed in breast cancer xenograft models 
which involved alisertib added to either paclitaxel or docetaxel. Alisertib inhibited the Pgp-
mediated efflux of paclitaxel in a cell culture model. In addition, as described in Section 1.1 
AURKA is frequently overexpressed in TNBC, and expression levels have been shown to be 
prognostic in both of these breast cancer subtypes. The combination of alisertib with 
paclitaxel has also been investigated in a Phase 1 study in patients with locally advanced or 
metastatic ovarian and breast cancers, with preliminary evidence of activity in both tumor 
types including 6 PRs and 3 SD in 11 patients with MBC.40
1.9.2    Dose selection 
A Phase 1B dose escalation study investigating the combination of alisertib plus paclitaxel 
was conducted in patients with metastatic or locally recurrent ovarian or breast cancers.40,40
Paclitaxel was administered on days 1, 8 and 15 of a 28-day cycle, with alisertib given orally 
on days 1-3, 8-10, and 15-17. This dosing schedule was selected to maximize concomitant 
exposure of alisertib and paclitaxel, while providing treatment-free periods for recovery 
from toxicities like neutropenia and mucositis.41 Two maximum tolerated doses (MTDs) 
were determined: MTD1 (paclitaxel 80 mg/m2 IV plus alisertib 10 mg BID), or MTD2 
(paclitaxel 60 mg/m2 IV plus alisertib 40 mg BID).  


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Based on pharmacokinetic and pharmacodynamic analyses, the RP2D is MTD2 (paclitaxel 
60 mg/m2 IV plus alisertib 40 mg BID) which demonstrated 4-fold higher dose density 
compared to MTD1, and this dose density was nearly 80% of the current RP2D/RP3D 
dosage for single-agent alisertib. In addition, the systemic exposure achieved at this dosage 
and schedule was similar to the exposures found to be associated with AURKA inhibition in 
tumors in prior studies. No clinically concerning drug-drug interactions were noted at 
MTD2, and translational assessment of exposure efficacy relationships in nonclinical 
xenograft studies predict greater antitumor efficacy for MTD2 compared with MTD1. 
Therefore, the initial dose and schedule selected for this study, based on the phase 1B 
experience with this combination regimen, is paclitaxel 60 mg/m2 IV administered on days 
1, 8 and 15 and alisertib 40 mg BID on days 1-3, 8-10, and 15-17 of a 28-day cycle.  
1.9.3    Rationale for Correlative Biomarker Study 
Currently there are no validated biomarkers that predict for the effectiveness of alisertib. 
FOXM1 is a pro-proliferative cell cycle transcription factor that is upregulated in several 
cancers. It is responsible for regulating the G2/M phase of mitosis, DNA damage repair, and 
is required for cell cycle progression. In addition, it drives other G2/M regulatory genes such 
as survivin, centromere proteins A/B/F, and AURKA.41  It was recently determined that 
FOXM1 is downregulated by the p53 tumor suppressor via the p21/Rb/E2F pathway. This 
indicates that in cancers where p53 is mutated or not functional, FOXM1 contributes to 
increased proliferation/uncontrolled mitosis and genomic instability.42 AURKA is a 
serine/threonine kinase that is important in regulating the transition from G2 in mitosis.10
FOXM1 transcriptionally regulates AURKA in order for the cell to progress from the G2 to 
the M phase.11 In addition to being regulated by FOXM1, AURKA is also responsible for 
the phosphorylation of p53, which leads to its ubiquitination and degradation. In turn, with 
the degradation of p53, FOXM1 is also downregulated, thereby regulating cell cycle 
progression. Genomic instability can be induced in several cancers, including breast cancer, 
due to increased levels of AURKA. In ovarian cancer, AURKA induces genomic stability, 
cell cycle progression, and anti-apoptosis by downregulating p21, Rb, and BRCA2.43
As described in Section 1.1, FOXM1 and AURKA have been shown to be co-overexpressed 
in some TNBC tumors, and expression levels of AURKA have demonstrated prognostic 
value in early-stage breast cancers. 
In order to develop hypotheses regarding potential predictive biomarkers for benefit from 
alisertib, FFPE tissue from study patients’ primary breast cancers will be retrospectively 


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analyzed for expression of FOXM1 and AURKA, p53 mutation status, and degree of 
genomic instability, as potential predictors of benefit from the combination of alisertib and 
paclitaxel. 


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2.    STUDY OBJECTIVES 
2.1    Primary Objective 
The primary objective of this study is: 
z
To demonstrate the superiority of alisertib plus paclitaxel compared with 
paclitaxel alone in PFS in two cohorts of patients with metastatic or locally 
recurrent breast cancer, one with ER+, HER2- disease and the other with  triple-
negative (TN) disease 
2.2    Secondary Objectives 
The secondary objectives of this study are: 
z
To assess the safety of alisertib combined with paclitaxel 
z
To compare the objective response rates (ORR; complete response [CR] plus 
partial response [PR]) between the two treatment arms in each of the two cohorts 
z
To compare the clinical benefit rate (CBR; CR + PR + stable disease [SD] 6 
months) between the two treatment arms in each of the two cohorts 
z
To assess overall survival (OS) in each of the treatment arms in each of the two 
cohorts 
2.3    Exploratory Endpoints 
z
To perform genomic profiling of patients’ archival primary breast cancer tissue to 
identify potential predictive markers for benefit from alisertib plus paclitaxel 


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3.    INVESTIGATIONAL PLAN 
This is an investigator-initiated study.  The principal investigator is Joyce O’Shaughnessy, 
MD, and the study sponsor is Delta Clinical Research, LLC. 
3.1    Overall Design and Plan of the Study 
This will be a randomized, multicenter, parallel group study to evaluate alisertib plus 
paclitaxel compared with paclitaxel alone in the treatment of metastatic or locally recurrent 
breast cancer in each of the two patient cohorts. The two cohorts will consist of: 1) ER+, 
HER2-, disease, and 2) poorly differentiated (and/or Grade 3) TNBC.  Up to 1 prior 
chemotherapy regimen for metastatic disease will be allowed, with no limit on the number 
of prior endocrine therapies. Prior adjuvant taxane therapy is allowed as long as the patient 
has been disease-free for at least 1 year from the end of adjuvant chemotherapy to the 
development of metastatic disease. Prior taxane for metastatic disease is not permitted. 
Previous therapy with an mTOR inhibitor is allowed. Untreated or progressing brain 
metastases are not allowed, and patients cannot require steroid therapy for the treatment of 
brain metastases. 
General eligibility criteria may be assessed prior to the formal Screening period. However, 
per the Schedule of Events, formal screening will occur during the Screening period, which 
may last for up to 28 days prior to the baseline visit. Following Screening, patients will be 
assigned to the appropriate Cohort, stratified by number of prior chemotherapy regimens for 
metastatic disease (0 or 1) and by prior (neo)adjuvant taxane (yes or no), and randomized to 
receive either paclitaxel alone or paclitaxel in combination with alisertib, in an unblinded 
manner. Treatment periods will be defined as 28 day cycles, which will be chronologically 
timed regardless of whether patients are on study medication. Paclitaxel will be administered 
IV on days 1, 8 and 15, and alisertib will be administered BID on days 1-3, 8-10, and 15-17 
of each treatment cycle. Week 4 is a rest week. Patients will remain on treatment until 
disease progression, unacceptable toxicity, or discontinuation of treatment for other reasons 
(see section 3.10). 
Patients randomized to the paclitaxel and alisertib arm will be seen by their oncology care 
provider for Cycle 1 on days 1, 8 and 15 to have a brief physical exam, review of AEs, 
concomitant medications, vitals, weight (day 1 of each cycle only), and performance status 
(day 1 of each cycle only);  Cycle 2 on days 1 and 15 to have a brief physical exam, review 
of AEs, concomitant medications, vitals, weight (day 1 of each cycle only), and performance 
status (day 1 of each cycle only); for Cycle 3 and subsequent cycles, patients will have a 


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brief physical exam, review of AEs, concomitant medications, and vitals, weight, and 
performance status on day 1 of each cycle.   Additional unscheduled visits may occur as 
required, such as in the case of an adverse event requiring medical attention.  Patients 
receiving paclitaxel alone will have CBCs on days 1, 8 and 15 and will be seen by their 
oncology care provider every 28 days. An End of Treatment visit will occur within 30 days 
of receipt of last dose of study drug(s), and patients will continue to be followed for other 
follow-up assessments specified in the Schedule of Events, including survival. 
The primary endpoint of this study is PFS. ORR, CBR, and OS are secondary endpoints. 
Patients will undergo computed tomography (CT) scans of the chest, abdomen and pelvis 
during the Screening period, and will be reassessed with chest and abdominal imaging every 
8 weeks following initiation of treatment for the first 32 weeks of study treatment, then 
every 12 weeks for the duration of the study treatment period (pelvic CT will only be 
performed if metastatic lesions are detected at baseline). Patients will undergo a whole body 
Tc-99 bone scan at baseline, and will be reassessed every 12 weeks for the first 32 weeks of 
study treatment, then every 16 weeks for the duration of the study treatment period only if 
metastatic lesions are detected at baseline. Patients with a history of treated brain metastases 
will have a baseline MRI of the brain; reassessment imaging will be performed at 8 week 
intervals for the first 32 weeks of study treatment, then every 12 weeks for the duration of 
the study treatment period (CT may be used if MRI is contraindicated). Skin lesions will be 
documented by color photography and reassessed every 8 weeks for the first 32 weeks of 
study treatment, then every 12 weeks for the duration of the study treatment period, if 
present at baseline. Toxicities will be evaluated according to NCI Common Toxicity Criteria 
for Adverse Events (CTCAE) Version 4.03. 
A correlative molecular biomarker study will also be performed. An FFPE archived tumor 
block (or 20 unstained slides if tumor block is unavailable) from the primary breast cancer 
will be required from each patient. Samples will be retrospectively analyzed for potential 
predictors of benefit from the combination of alisertib and paclitaxel, including but not 
limited to expression of FOXM1 and AURKA, p53 mutation status, and degree of genomic 
instability.  
3.2    Selection of Patients 
The total number of patients to be enrolled on this study is 252 (Cohort 1 [ER+/HER2-] 
n=140; Cohort 2 [TNBC] n=112). 


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3.2.1    Registration Procedures 
The registration process begins when the coordinator has obtained a signed informed 
consent from the patient. Please enter patient demographics into the Clinical Trial 
Management System (CTMS); this is the Web-based intranet system for the delivery of trial 
information between Delta and it is used across all sites. A unique patient number (UPN) 
will be assigned to the patient at that time. Entering a patient into CTMS does not signify 
that you have registered the patient in the study. If you have any difficulty with CTMS 
please contact the Clinical Trial Manager. 
Once the patient has an UPN number, the coordinator can go to their Patient Report and 
select the patient that they want to register.  Located to the left of the patient’s UPN will be 
the letters “Reg” in blue.  The coordinator will click on the blue “Reg” to open up that 
patient’s information.  Each page that needs to be completed will be in yellow.  The site will 
answer the questions on the Inclusions and Exclusions.  Once all questions on each page are 
answered, that page will turn green.  Once all the pages turn green, click on the “verify data” 
tab, then click the “register” tab.  The register page will open, “click to register”.  An ID 
number will be directly assigned. For any difficulties with entering the data, please contact 
the Project Manager of the study. 
Treatment must begin within 5 working days after the patient’s registration on the 
study, not including weekends or holidays. 
3.2.2    Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
z
Voluntary written informed consent before performance of any study-related 
procedure not part of normal medical care, with the understanding that consent 
may be withdrawn by the subject at any time without prejudice to future medical 
care, and signed Health Insurance Portability and Accountability Act (HIPAA) 
form. 
z
Female subject (18 years old), who is either:  
o
post-menopausal for at least one year before the screening visit, or 
o
 surgically sterilized, or  


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o
willing to use an acceptable method of birth control (i.e., a hormonal 
contraceptive, intra-uterine device, diaphragm with spermicide, or 
condom with spermicide) for the duration of the study. 
z
Metastatic or locally recurrent breast cancer with histologic confirmation (on 
either primary or metastatic tumor) of one of the following: 
o
ER+, HER2- invasive breast cancer (any PgR status) 
o
TNBC, defined as:  

HER2 negative status (based on most recently analyzed 
biopsy) is defined as immunohistochemistry (IHC) status of 0, 
1+ or 2+ (if IHC 2+, a negative FISH test is required, i.e.,  
HER2 fluorescence in situ hybridization (FISH) ratio < 2.0 
with an average HER2 copy number <4.0 signals/cell);  ER-
negative and PR-negative status is defined as ER and PgR 
<1% nuclei positive by IHC   
z
Measurable disease by modified Response Evaluation Criteria in Solid Tumors 
(RECIST) (v1.1) or non-measurable lytic, bone-only disease (mixed blastic/lytic 
bone disease is allowed); if patient has bone-predominant disease with no 
measurable disease, there must be a lytic component to the bone metastases that is 
visible on plain X-ray or CT scan that can be serially followed 
z
Absolute neutrophil count (ANC) > 1500/mm³, platelets  100,000/mm³, Hgb  9 
g/dL. Values must be obtained without need for myeloid growth factor or platelet 
transfusion support within 14 days, however, erythrocyte growth factor is allowed 
as per published ASCO guidelines (available at: http://www.asco.org/quality-
guidelines/asco-ash-clinical-practice-guideline-update-use-epoetin-and-
darbepoetin-adult). 
z
Total bilirubin  1.5 x upper limit of normal (ULN), SGOT (AST) and SGPT 
(ALT) < 2.5 x ULN. AST and/or ALT may be up to 5 x ULN if patient has 
known liver metastases 
z
Adequate renal function as defined by:  Calculated creatinine clearance must be 
30 mL/minute (see Cockcroft-Gault formula in Appendix 5) 


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z
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (refer to 
Appendix 4) 
3.2.3    Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 
z
More than 1 previous chemotherapy regimen for metastatic disease 
o
No limit on previous endocrine therapy 
o
Previous mTOR therapy, e.g., everolimus, is allowed  
o
Prior adjuvant taxane therapy is allowed, provided the disease-free 
interval from the end of (neo)adjuvant chemotherapy to the 
development of metastatic disease was  1 year 
o
No prior taxane for metastatic disease  
z
Previous radiation therapy covering the whole pelvis 
z
Suspected brain metastases, untreated brain metastases or current clinical or 
radiologic progression of known brain metastases or requirement for steroid 
therapy for brain metastases 
o
Patients with treated brain metastases are eligible if they have been 
stable and off steroids for  3 weeks 
z
Prior allogeneic bone marrow or organ transplantation 
z
Known GI disease or GI procedures that could interfere with the oral absorption 
or tolerance of alisertib. Examples include, but are not limited to partial 
gastrectomy, history of small intestine surgery, and celiac disease 
z
Known history of uncontrolled sleep apnea syndrome and other conditions that 
could result in excessive daytime sleepiness, such as severe chronic obstructive 
pulmonary disease; requirement for supplemental oxygen. 


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z
Requirement for administration of proton pump inhibitor, or for constant 
administration of H2 antagonist, or pancreatic enzymes.  Intermittent uses of 
antacids or H2 antagonists are allowed as described in Section 3.4. 
z
Systemic infection requiring IV antibiotic therapy within 14 days preceding the 
first dose of study drug, or other severe infection. 
z
Myocardial infarction within 6 months prior to enrollment or has New York Heart 
Association (NYHA) Class III or IV heart failure (see Appendix 3), uncontrolled 
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic 
evidence of acute ischemia or active conduction system abnormalities. Prior to 
study entry, any ECG abnormality at Screening has to be documented by the 
investigator as not medically relevant. 
z
Female subject who is pregnant or breast-feeding.  Confirmation that the subject 
is not pregnant must be established by a negative serum -human chorionic 
gonadotropin (-hCG) pregnancy test result obtained during screening, within 72 
hours prior to first dose of study drug(s).  Pregnancy testing is not required for 
post-menopausal or surgically sterilized women. 
z
Patient has received an investigational agent within 30 days before enrollment 
z
Serious medical or psychiatric illness likely to interfere with participation in this 
clinical study. 
z
Other severe acute or chronic medical and/or psychiatric condition(s), including 
but not limited to uncontrolled diabetes, malabsorption, resection of the pancreas 
or upper small bowel, requirement for pancreatic enzymes, any condition that 
would modify small bowel absorption of oral medications, or laboratory 
abnormalities that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the patient not 
eligible for enrollment for this study. 
z
Diagnosed or treated for another malignancy within 3 years of enrollment, with 
the exception of complete resection of basal cell carcinoma or squamous cell 
carcinoma of the skin, or an in situ malignancy, or a stage I cancer with a 5-year 


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DFS of  90% (survival rates by stage are available for most cancers on the 
American Cancer Society website).   
z
Treatment with clinically significant enzyme inducers, such as the enzyme-
inducing antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or 
rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first 
dose of alisertib and during the study. 
z
Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or 
hepatitis C.  Testing is not required in the absence of clinical findings or 
suspicion. For guidance in defining active infection for hepatitis B, please refer to 
the WHO guidelines. (World Health Organization, Global Alert and Response 
(GAR), Hepatitis B.  
http://who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index4.html) 
z
Prior administration of an Aurora A kinase-targeted agent, including alisertib 
z
Need for ongoing therapeutic steroid therapy.  Intermittent steroid use for the 
control of nausea and vomiting is allowed.  Premedication with dexamethasone 
prior to paclitaxel administration is allowed. Topical steroid use is permitted.  
Inhaled steroids are permitted. Replacement doses of hydrocortisone up to 15 
mg/day are allowed. 
z
Inability to swallow oral medication or inability or unwillingness to comply with 
the administration requirements related to alisertib. 
z
Administration of myeloid growth factors or platelet transfusion within 14 days 
prior to the first dose of study treatment. 
z
Peripheral neuropathy > grade 1 
z
Known severe hypersensitivity to paclitaxel 
3.3    Study Treatments 
3.3.1    Clinical Trial Materials  
Alisertib drug product is supplied as the ECT dosage form in 10 mg strength, with dose 
strength expressed as the milligrams of active drug (free acid).  The key formulation 


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excipients of the alisertib tablet formulation that aid in the in vivo absorption of the drug are 
the buffer (sodium bicarbonate), the surfactant (sodium lauryl sulfate), and the enteric 
coating. 
Paclitaxel is a commercially available product. If available, generic paclitaxel should be 
used as part of study treatment, when possible. Paclitaxel will be prescribed by the 
investigator and obtained as outlined in the investigator Clinical Trial Agreement. Paclitaxel 
is available in 30 mg (5 mL), 100 mg (16.7 mL) and 300 mg (50 mL) multidose vials. Each 
mL of sterile nonpyrogenic solution contains 6 mg paclitaxel, 527 mg of purified 
Cremaphor® EL (polyoxyethylated castor oil) abd 49.7% (v/v) dehydrated alcohol, USP. 
3.3.2    Preparation, Handling, and Storage of Drugs 
Alisertib ECT are packaged in a 60-cc high-density polyethylene (HDPE) bottle with a 
rayon coil, induction seal, desiccant packs, and a polypropylene child-resistant cap. 
Alisertib is an anticancer drug, and as with other potentially toxic compounds, caution 
should be exercised when handling MLN8237. 
Per the package insert, Paclitaxel Injection is supplied as a sterile, non-pyrogenic, 
nonaqueous solution intended for dilution with a suitable parenteral fluid prior to 
intravenous infusion. Contact of the undiluted concentrate with plasticized polyvinyl 
chloride (PVC) equipment or devices used to prepare solutions for infusion should be 
avoided.  
In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], 
which may be leached from PVC infusion bags or sets, diluted paclitaxel solutions should 
preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, 
polyolefin) and administered through polyethylene-lined administration sets. Paclitaxel 
should be administered through an in-line filter with a microporous membrane not greater 
than 0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short 
inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP. 
Drug Administration and Dosage Schedule
Patients will be randomized to receive either: 
z
Weekly paclitaxel (90 mg/m2 IV) (standard arms) 


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z
Weekly paclitaxel (60 mg/m2 IV) plus alisertib (40 mg BID) (experimental arms) 
Patients on the standard arms will receive paclitaxel at a dosage of 90 mg/m2 on days 1, 8 
and 15 of a 28-day cycle. Patients on the experimental arms will receive paclitaxel at a 
dosage of 60 mg/m2 on days 1, 8 and 15 of a 28-day cycle. Alisertib will be administered to 
patients on the experimental arms at a dosage of 40 mg BID on days 1-3, 8-10, and 15-17 of 
the 28-day cycle. Week 4 is a rest week. Cycle 2 and subsequent cycles, only, there is a 
window of +3 days (after the scheduled time) for treatment administration during the 
study. 
Patients will be treated until disease progression, unacceptable toxicity, death or 
discontinuation from study treatment due to any other reason.  
Alisertib Administration
 Alisertib will be given PO in a dosage of 40 mg BID on days 1-3, 8-10 and 15-17 of each 
28-day treatment cycle.   
Patients will be instructed to take each oral dose of alisertib with 8 ounces (1 cup, 240 mL) 
of water.  For BID dosing, the doses must be taken at least 6 hours apart. 
Alisertib will be supplied as 10 mg ECT, with the dose strength expressed as milligrams of 
active drug (free acid).  All tablets are to be ingested whole; patients who have difficulty 
swallowing tablets will be excluded from the study.  Antiemetogenic agents may be 
administered at the discretion of the investigator.  Prophylactic antiemetic therapy will not 
be used in this study unless it becomes clear that alisertib causes acute or delayed nausea 
and/or vomiting.   
Neutralizing antacids and calcium-containing supplements cannot be taken within 2 hours 
prior to alisertib dosing until up to 2 hours after dosing. PPIs are not permitted for patients 
on the alisertib arm at any time during the study. H2 receptor antagonists may be used, 
except within 24 hours prior to the initiation of alisertib administration through the 3-day 
alisertib administration period. (See Section 3.4 regarding PPIs and H2 receptor antagonists) 
Although not prohibited, the use of benzodiazepines for the prophylaxis or treatment of 
nausea or vomiting is strongly discouraged because of the potential benzodiazepine-like 
effects of alisertib. 


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Study drug will be administered only to eligible patients under the supervision of the 
investigator or identified subinvestigator(s). 
Paclitaxel Administration
Paclitaxel will be administered at a dosage of 90 mg/m2 IV (standard arm) or 60 mg/m2 IV 
(experimental arm) on days 1, 8 and 15 of a 28-day cycle. Paclitaxel will be administered as 
a 1-hour intravenous infusion following standard premedications. 
Standard premedications prior to each dose of paclitaxel should be administered according 
to local practice. The following treatment is recommended: 
z
Dexamethasone 10 mg IV 
z
Diphenhydramine 25-50 mg IV (H1 receptor) 
z
Ranitidine 50 mg IV (H1 receptor). Note: Cimetidine is a CYP3A4 and CYP1A2 
inhibitor and therefore should not be administered. 
Standard premedication treatment should be given 30 to 60 minutes before the paclitaxel 
infusion and may vary according to local standard of care. 
All premedication and other concomitant medication given during the study must be 
recorded on the Concomitant Medication page of the eCRF. 
3.3.3    Dose Modification and Delay 
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective 14 June 2010.44 (see 
Appendix 2)  
To manage excessive toxicity, reduction of the total alisertib dose can be done by reducing 
the daily dose administered and/or by interruption of the scheduled treatment within a cycle. 
Any dosage deviations (or ongoing dosage changes) must be scrupulously recorded.    
3.3.4    Criteria for Retreatment and Dose Delays for Paclitaxel Plus Alisertib 
Combination Arm 
Treatment with paclitaxel plus alisertib will be repeated every 28 days.  In order for a new 
cycle of therapy to begin, the patient must meet the following criteria: 


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z
ANC must be  1,500/mm3 on day 1 
z
Platelet count must be  75,000/mm3 on day 1 
z
In addition, all toxicities considered by the investigator to be related to therapy with 
alisertib and/or paclitaxel must have resolved to  Grade 1 (with exception of fatigue 
and neuropathy which may be  Grade 2). 
If the patient does not meet the above-cited criteria for retreatment, then that 3-day sub-cycle 
of alisertib dosing should be held and paclitaxel will also be held.  At the end of that week, 
the patient should be re-evaluated to determine whether the criteria for retreatment have 
been met. If above criteria are met, patient should resume alisertib treatment at the next 
planned 3-day sub-cycle (Days 8-10) and should resume paclitaxel on Day 8. Should 
treatment need to be delayed for more than 1 week because of incomplete recovery from 
treatment-related toxicity, the dose of alisertib will be reduced (Table 3-1 and Table 3-2) to 
30 mg BID (Dose Level -1) when therapy resumes on Day 15. The dose of paclitaxel will 
not be reduced below 60 mg/m2.  A second dose reduction of alisertib to 20 mg BID (Dose 
Level -2) may occur should treatment need to be delayed for more than 1 week because of 
incomplete recovery from treatment-related toxicity on the reduced dosage of 30 mg BID.  
Patients who require further dose reductions will be removed from the study.  Should 
treatment need to be delayed for more than 3 weeks at any dose, therapy with alisertib will 
be discontinued. 
On days 8 and 15 of each cycle, the patient must have an ANC  1000/mm3 and platelets 
75,000/mm3 in order to receive the treatment with paclitaxel and the next sub-cycle of 
alisertib. If a patient cannot receive the Day 8 or Day 15 dose on time, that dose is 
postponed until ANC recovers; the patient will then receive that postponed dose (still calling 
it Day 8 or Day 15) and continue with either Day 15 dose (if Day 8 was postponed) or 
skipping Day 22 if Day 15 was postponed.  If day 8 or 15 is skipped due to 
myelosuppression, resume therapy at the next scheduled visit with one alisertib dose level 
reduction.  
Skipped doses of alisertib/paclitaxel will not be made up but rather therapy will be resumed 
when re-treatment criteria are met at the next treatment day. The cycle length will remain 
constant at 28 days. 


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Table 3-1    
Table of Alisertib Dose Adjustments 
Dose Level 
Dose 
Schedule 
Cycle Length 
Starting 
40 mg 
PO BID 
Days 1-3, 8-10 and 15-17 
of a 28-day cycle 
-1 
30 mg 
PO BID 
Days 1-3, 8-10 and 15-17 
of a 28-day cycle 
-2 
20 mg 
PO BID 
Days 1-3, 8-10 and 15-17 
of a 28-day cycle 
-3 
Discontinue 
3.3.4.1    Dose Modifications for Hematologic Toxicity (Combination Arm) 
If a patient experiences any of the following hematologic toxicities during the dosing period, 
alisertib will be discontinued for the remainder of that cycle and the dose will be decreased 1 
level for all subsequent cycles of treatment (Table 3-2). 
z
Grade 4 neutropenia (ANC  500 cells/mm3) lasting more than 3 consecutive days 
z
Grade 4 thrombocytopenia (platelet count < 25,000/µL) lasting more than 
3 consecutive days 
z
Platelet count less than 10,000/µL at any time 
z
Grade 3 or 4 neutropenia with fever or infection, or both, where fever is defined as 
an oral temperature greater than 38.5C 
z
Grade 3 thrombocytopenia with clinically significant bleeding 
Paclitaxel may be administered during the remainder of the cycle while alisertib is being 
held if ANC is  1000/mm3 and platelets are  75,000/mm3. Treatment with paclitaxel 
should be held on a given week for ANC <1000 cells/mm3 or a platelet count < 75,000/mm3. 
3.3.4.2    Dose Modifications for Non-Hematologic Toxicities (Combination Arm) 
If a patient experiences any of the following toxicities during a cycle, alisertib dosing will be 
discontinued for the remainder of that cycle and the dose will be decreased 1 level for all 
subsequent cycles of treatment (Table 3-2). Treatment may resume on Day 1 of the 
following cycle provided drug-related toxicities have resolved to  Grade 1 or to baseline 
(with the exception of fatigue and neuropathy which may be  Grade 2). 


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z
Any Grade 3 non-hematologic toxicity that is considered by the investigator to be 
related to study treatment other than: 
o
Grade 3 or greater nausea or emesis, or both, that occurs in the absence 
of optimal antiemetic therapy that includes a 5-hydroxytryptamine 3 [5-
HT3] serotonin receptor antagonist; 
o
Grade 3 fatigue that lasts less than 2 weeks 
z
Grade 2 non-hematologic toxicities that are considered by the investigator to be 
related to study treatment and in the opinion of the investigator require dose 
reduction. Alisertib dose reductions for Grade 2 non-hematologic toxicity may be 
made without interrupting alisertib administration.
In general, alisertib treatment should be discontinued if a patient experiences a Grade 4 non-
hematologic toxicity.  If, in the opinion of the onsite investigator and study Principal 
Investigator it is in the patient’s interest to continue therapy with alisertib, then after 
recovery from the toxicity or toxicities in question to  Grade 1 or to baseline values, the 
dose of alisertib should be reduced to 20 mg BID with subsequent cycles of therapy. 
Retreatment with alisertib in patients who develop Grade 4 non-hematologic toxicity must 
be discussed with the study Principal Investigator. 
When a dose reduction of alisertib is required, no re-escalation of dose will be permitted.  If 
a patient requires more than 2 dose reductions, therapy with alisertib will be discontinued. If 
alisertib is discontinued patients may continue treatment with paclitaxel days 1, 8 and 15 
every 28 days at either 60 mg/m2 IV or 80 mg/m2 IV at the physician’s discretion. 
Paclitaxel dosing may be reduced on the combination arm by 25% (i.e., to 45 mg/m2) for 
grade 2 peripheral neuropathy. If neuropathy worsens, paclitaxel can be stopped and 
patients may continue treatment with alisertib.  


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Table 3-2
Criteria for Alisertib Dose Modification on Combination Arm 
Event 
Dose Modification 
Treatment delay >1 week due to incomplete recovery from 
treatment-related toxicity 
1st Occurrence: Reduce 
alisertib to Dose Level -1 
2nd Occurrence: Reduce 
alisertib to Dose Level -2 
3rd Occurrence: Discontinue 
alisertib 
Treatment delay >3 weeks due to incomplete recovery from 
treatment-related toxicity
Discontinue alisertib 
Hematologic Toxicities: 
z
Grade 4 neutropenia (ANC  500 cells/mm3) lasting more 
than 3 consecutive days 
z
Grade 4 thrombocytopenia (platelet count < 25,000/µL) 
lasting more than 3 consecutive days 
z
Platelet count less than 10,000/µL at any time 
z
Grade 3 or 4 neutropenia with fever or infection, or both, 
where fever is defined as an oral temperature greater than 
38.5C 
Grade 3 thrombocytopenia with clinically significant bleeding 
1st Occurrence: 
Discontinue alisertib for the 
remainder of that cycle; 
reduce alisertib dosage to 
Dose Level -1 for all 
subsequent cycles of 
treatment 
2nd Occurrence: 
Discontinue alisertib for the 
remainder of that cycle; 
reduce alisertib dosage to 
Dose Level -2 for all 
subsequent cycles of 
treatment 
3rd Occurrence: 
Discontinue alisertib 
Grade 2 Non-Hematologic Toxicity (considered related to study 
treatment and in investigator’s opinion requiring a dose reduction) 
NOTE: It is strongly recommended that alisertib be interrupted and 
the dose be reduced at the first occurrence of grade 2 stomatitis – 
alisertib may resume once grade 2 stomatitis has recovered at one 
dose level reduction within the same cycle.    
1st Occurrence: 
Reduce alisertib dosage to 
Dose Level -1 (alisertib 
interruption for remainder of 
cycle not required) 
2nd Occurrence: 
Reduce alisertib dosage to 
Dose Level -2 (alisertib 
interruption for remainder of 
cycle not required) 
3rd Occurrence: 
Discontinue alisertib 


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Event 
Dose Modification 
Grade 3 Non-Hematologic Toxicity (excluding Grade 3 nausea or 
emesis, or both, that occurs in the absence of optimal antiemetic 
therapy that includes a 5-hydroxytryptamine 3 [5-HT3] serotonin 
receptor antagonist; or Grade 3 fatigue lasting < 2 weeks) 
1st Occurrence: 
Discontinue alisertib for the 
remainder of that cycle; 
reduce alisertib dosage to 
Dose Level -1 for all 
subsequent cycles of 
treatmenta
2nd Occurrence: 
Discontinue alisertib for the 
remainder of that cycle; 
reduce alisertib dosage to 
Dose Level -2 for all 
subsequent cycles of 
treatmenta
3rd Occurrence: 
Discontinue alisertib 
Grade 4 Non-Hematologic Toxicity 
Discontinue alisertibb
a Treatment may resume on Day 1 of the following cycle provided drug related toxicities have resolved to 
Grade 1 or to baseline (with the exception of fatigue and neuropathy which may be  Grade 2). 
b If, in the opinion of the investigator and study Principal Investigator it is in the patient’s interest to continue 
therapy with alisertib, then after recovery from the toxicity or toxicities in question to  Grade 1 or to baseline 
values, the dose of alisertib should be reduced to 20 mg BID with subsequent cycles of therapy. Retreatment 
with alisertib in patients who develop Grade 4 non-hematologic toxicity must be discussed with the study 
Principal Investigator. 
3.3.5    Dose Modifications for Paclitaxel Monotherapy Arm  
Treatment with paclitaxel will be administered on days 1, 8 and 15 of a 28-day cycle. 
Paclitaxel administration should be held on a given week if the patient does not meet the 
following criteria on days 1, 8 and 15: 
z
ANC must be  1,000/mm3
z
Platelet count must be  75,000/mm3


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Treatment with paclitaxel should be held on a given week if ANC or platelet values are 
below these thresholds. That week’s paclitaxel dose should be skipped and treatment 
resumed at the following planned visit either at a reduced paclitaxel dose of 70 mg/m2 or 
with the addition of prophylactic Neupogen to the regimen if the physician wishes to keep 
the paclitaxel dose at 90mg/m2.   If the ANC decrease to < 1,000/mm3 in spite of Neupogen 
use, then the paclitaxel dose will be reduced to 70 mg/m2.  Physicians may continue to use 
Neupogen prophylactically if the paclitaxel dose is reduced to 70mg/m2.  If patients’ ANC if 
< 1000/mm3 on a day of treatment at 70mg/m2, with or without Neupogen, the paclitaxel 
treatment may be discontinued or further reduced to 60 mg/m2 at the physician’s discretion. 
Treatment with paclitaxel should be held for any grade 3 or 4 non-hematologic toxicity until 
it is resolved to  Grade 1 (with the exception of fatigue and neuropathy which may be 
Grade 2), and then resumed at the next scheduled treatment cycle visit at a reduced dose of 
70 mg/m2.  If a patient cannot receive the Day 8 or Day 15 dose on time, that dose is 
postponed; the patient will then receive that postponed dose (still calling it Day 8 or Day 15) 
and continue with either Day 15 dose (if Day 8 was postponed) or skipping Day 22 if Day 
15 was postponed. Paclitaxel dose may be further reduced to 60 mg/m2 for a second 
occurrence of Grade 3 non-hematologic toxicity and discontinued for second occurrence of 
Grade 4 non-hematologic toxicity. Should treatment need to be delayed for more than 3 
weeks at any dose, therapy with paclitaxel will be discontinued. 
3.3.6    Treatment Assignment 
A total of 252 patients will be randomized in this study: 140 patients with ER+/HER2- MBC 
in Cohort 1 and 112 patients with metastatic TNBC in Cohort 2. Within these groups, 
patients will be stratified by number of previous chemotherapy regimens for metastatic or 
recurrent breast cancer (no previous chemotherapy [0]; one previous chemotherapy regimen 
[1]), and by prior (neo)adjuvant taxane (yes or no), and will be randomized 1:1 to either: 
z
Arm A: 60 mg/m2 paclitaxel IV days 1, 8, and 15 plus alisertib 40 mg PO BID days 
1-3, 8-10, and 15-17 of a 28-day cycle, or 
z
Arm B: 90 mg/m2 paclitaxel IV days 1, 8 and 15 of a 28-day cycle. 
Randomization will be done in blocks of four using SAS software.  


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3.3.7    Packaging and Labeling 
The study drug, provided by Millennium, will be labeled and handled at the investigative 
site as open-label material; packaging labels will fulfill all requirements specified by 
governing regulations.  Alisertib will be supplied as ECT in 10 mg strength.  The 60-cc 
HDPE bottles will have a child-resistant cap and be labeled for take-home use.  Patients will 
receive instructions for home use of Alisertib, including the requirement that Alisertib be 
administered as intact tablets. 
Paclitaxel is a commercially available product. Medication labels will comply with all legal 
requirements. 
3.4    Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study: 
z
Alternative therapy, including palliative radiotherapy, for treatment of the patient’s 
malignancy  
z
Any investigational therapy other than alisertib  
z
Requirement for administration of any proton pump inhibitor (PPI) 
(paclitaxel/alisertib combination arm only).  Patients receiving alisertib are at risk 
of having a 30% increase in alisertib blood levels with PPIs with a resultant 
increase in the potential for toxicity. Use of any PPI in either continued or 
intermittent use will be prohibited on the combination arm during the conduct of 
the study and patients must discontinue any use of PPI within five days prior to the 
first dose of alisertib.  Patients may be administered alternative agents to manage 
gastric acidity or reflux (e.g., H2 receptor antagonists, antacids) with exceptions 
described below. PPI use is allowed for patients on the paclitaxel alone arm.
z
Histamine-2 (H2) receptor antagonists are not permitted from within 24 hours of 
the initiation of alisertib administration through the end of the 3 days of alisertib 
dosing, except as required for paclitaxel premedication. H2 receptor antagonists are 
allowed for patients on the paclitaxel alone arm.
z
Enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, 
carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's 
Wort within 14 days prior to the first dose of alisertib. 


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z
Antacids are permitted; however, they should not be administered within 2 hours 
before or 2 hours after administration of alisertib. 
3.5    Permitted Concomitant Medications and Procedures 
Myeloid growth factors to treat patients with neutropenia are permitted, and given 
prophylactically as needed at the discretion of the physician.   Patients who receive 
prophylactic myeloid growth factors whose ANC >1000 can continue with Neupogen and 
maintain the current treatment dose of paclitaxel.   Patients should undergo alisertib dose 
reduction if ANC is not adequate for treatment.  Antiemetic agents may be administered at 
the discretion of the investigator but are not generally required as a prophylactic agent.  All 
other manifestations of the patient’s malignancy should be treated at the discretion of the 
investigator. 
Antacids are permitted; however, they should not be administered within 2 hours before or 
2 hours after administration of alisertib.   
Medications with potential CNS effects are not prohibited in this study, but it is 
recommended that their use be minimized to avoid confusion in the interpretation of CNS 
effects should they occur during the course of treatment with alisertib.  Because of alisertib’s 
structural and pharmacological similarity to the benzodiazepines, concomitant therapy with 
benzodiazepines is strongly discouraged. 
Because paclitaxel is metabolized by CYP2C8 and CYP3A4 enzymes, caution should be 
used when concomitantly administering paclitaxel with known CY3A4 substrates, CYP3A4 
inhibitors, and CYP3A4 inducers, as well as CYP2C8 substrates, inhibitors, and inducers. 
All other medical conditions should be treated at the discretion of the investigator in 
accordance with local community standards of medical care.
3.6    Precautions and Restrictions  
Patients should not drive, operate dangerous tools or machinery, or engage in any other 
potentially hazardous activity that requires full alertness and coordination if they experience 
sedation while enrolled in this study. 
Patients are to be instructed to limit the use of alcohol while enrolled in this study.  Patients 
should consume no more than 1 standard unit of alcohol per day during the study and for 


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30 days from the last dose of alisertib.  A standard unit of alcohol is defined as one 12 oz 
beer (350 mL), 1.5 oz (45 mL) of 80-proof alcohol, or one 6-oz (175 mL) glass of wine. 
It is not known what effects alisertib has on human pregnancy or development of the embryo 
or fetus.  Therefore, female patients of childbearing potential must be surgically sterilized or 
be willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-
uterine device, diaphragm with spermicide, or condom with spermicide) for the duration of 
the study. 
3.7    Management of Clinical Events 
3.7.1    Nausea and Vomiting 
Prophylactic antiemetic therapy will not be used in this study unless it becomes clear that 
alisertib causes acute or delayed nausea and/or vomiting.  If prophylactic antiemetic therapy 
is needed, 5-HT3 receptor antagonists should be tried first.  Because of the potential of 
benzodiazepines to cause sedation, the use of benzodiazepines for antiemetic prophylaxis 
should be reserved for patients who cannot be satisfactorily managed otherwise. 
Although this study will not initially employ prophylactic antiemetics in cycle 1, there is no 
prohibition against antiemetic use in the management of a patient who develops nausea or 
vomiting, or both. 
3.7.2    Diarrhea 
Antidiarrheal medications will not be used prophylactically; however, patients will be 
instructed to take loperamide, 4 mg, at the occurrence of the first loose stool and then 2 mg 
every 2 hours until they are diarrhea-free for at least 12 hours.  During the night, patients 
may take 4 mg of loperamide every 4 hours.  Fluid intake should be maintained to avoid 
dehydration. 
3.7.3    Central Nervous System Effects 
If a patient experiences excessive sedation believed to be related to alisertib, treatment with 
alisertib should be interrupted.  Patients whose sedation is not considered immediately life-
threatening should be carefully monitored and given appropriate supportive care. 
If the patient’s level of consciousness is considered to be life-threatening, necessary 
measures should be instituted to secure the airway, ventilation, and intravenous access.  


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Flumazenil (Romazicon®) is a selective benzodiazepine receptor antagonist that is intended 
as an adjunct to, not as a substitute for, the proper management of benzodiazepine overdose.  
Although there is neither preclinical nor clinical experience with flumazenil and alisertib, 
the use of flumazenil should be considered if the level of alisertib-associated sedation is 
considered to be life-threatening.  Patients treated with flumazenil should be monitored for 
resedation, respiratory depression, and other residual benzodiazepine effects for an 
appropriate period after treatment.  Continued monitoring is particularly important in the 
case of alisertib given its half-life and the comparatively brief half-life of flumazenil in the 
CNS (20-30 minutes).  Flumazenil should be administered according to its label. 
3.7.4    Treatment Compliance 
All drug(s) will be administered to eligible patients under the supervision of the investigator 
or identified sub-investigator(s).  The pharmacist will maintain records of drug receipt (if 
applicable), drug preparation, and dispensing, including the applicable lot numbers, patients’ 
height, body weight, and body surface area (see Appendix 5), and total drug administered in 
milliliters and milligrams.  Any discrepancy between the calculated dose and dose 
administered and the reason for the discrepancy must be recorded in the source documents. 
3.8    Duration of Treatment and Patient Participation 
Patients will remain on study treatment until disease progression, intolerable toxicity, or any 
other reason mentioned in section 3.10, whichever is earlier. Patients will continue to be 
followed on study for survival after they have discontinued treatment for up to 2 years from 
the date of registration.   
3.9    Schedule of Assessments 
3.9.1     Prestudy assessments 
The following assessments will be performed prior to registration: 
1. A signed Patient Informed Consent Form must be obtained prior to registration.  
2. A signed Patient Authorization Form (HIPAA) has been obtained prior to 
registration. 
3. It has been confirmed that the patient meets all inclusion criteria and none of the 
exclusion criteria. All data for the Inclusion/Exclusion criteria must be verifiable in 
the patient’s source document. 
Note: Receptor status (ER, PgR, HER2) and Ki67 status may be obtained anytime 
before randomization to the study. 
4. A complete medical history must be obtained within 4 weeks prior to registration. 


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5. A complete physical examination (including vital signs, height and body weight) 
must be obtained within 4 weeks prior to registration. 
6. Assessment of performance status on the ECOG scale (Appendix 4) must be 
obtained within 4 weeks prior to registration. 
7. Assessment of concomitant medications must be obtained within 4 weeks prior to 
registration. 
8. A complete blood count (CBC) with differential and platelet count within 4 weeks 
prior to registration. 
9. Complete metabolic profile (CMP) including: serum chemistries (creatinine, glucose, 
total protein, blood urea nitrogen [BUN], total bicarbonate [CO2], albumin, total 
bilirubin, alkaline phosphatase, and aspartate transaminase [AST] and alanine 
transaminase [ALT] and electrolytes (total calcium, chloride, potassium, sodium), 
must be performed within 4 weeks prior to registration. 
10. Calculation of creatinine clearance based on the creatinine values obtained from the 
CMP within 4 weeks prior to registration, (see Appendix 5). 
11. Women of childbearing potential must have a documented negative serum or urine 
pregnancy test performed within 3 business days prior to first dose of paclitaxel 
or paclitaxel plus alisertib. 
12. A clinical assessment of the patient’s disease (specifically, by physical examination) 
must be performed within 4 weeks prior to registration. 
13. Radiologic assessment of tumors: patients must have a CT of the chest, abdomen and 
pelvis, and a bone scan, within 4 weeks prior to registration. Only patients with a 
documented history of treated brain metastases should have an MRI or CT of the 
brain performed within 4 weeks prior to registration (CT may be used if MRI is 
contraindicated). Patients with skin lesions should have the lesion documented by 
color photography. Please see Appendix 6 for RECIST criteria for measurable 
disease performed within 4 weeks prior to registration. Under RECIST criteria, 
PET cannot be used to assess measurable disease. The methods used for prestudy 
assessments should be used throughout the study. If possible, the same equipment 
should be used each time.  
14. Determine if FFPE tissue block (or 20 slides) is available for analysis and storage, 
prior to registration. Collection and shipment of tumor sample (new biopsy or 
archived tissue) to designated lab (check CTI) should occur as soon as possible and 
no later than Day -1.   
15. Review of toxicity assessments, including assessment of peripheral neuropathy, must 
be performed within 4 weeks prior to registration.
Note: Information from procedures that may have been previously performed as part of the 
patient’s routine disease care (prior to enrolling in the trial) is allowed to be used to satisfy 
inclusion criteria as long as the procedures were performed within 28 days of registration. 
3.9.2     Assessments during treatment 
The following evaluations will be performed during therapy at the start of each cycle, unless 
otherwise specified. There is a window (up to 3 business days prior to the scheduled 
time; ± 7 business days for radiologic assessments) for assessments during the study. 


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Cycle 2 and subsequent cycles, only, there is a window of +3 business days (after the 
scheduled time) for treatment administration during the study. Any delay within this 
window is NOT a deviation. 
Note: Cycle 1 only, the baseline values for those assessments that are to be done prior to 
every cycle may be used for Cycle 1 assessments as long as they are completed within 3 
business days prior to the patient receiving their first dose of study drug. If more than 3 
business days have elapsed since the baseline assessment, the assessment must be 
repeated. 
Assessments that are to be done on days when study drug is administered must be done 
prior to dosing as these assessments (CBC, CMP, assessment of response, PS, etc.) may 
determine whether or not drug is administered, or if a dose reduction is necessary. 
1. A brief medical history must be done to capture events that have occurred since the 
last cycle. Events that were not captured in the baseline complete medical history, 
specifically those that have occurred since baseline, should be recorded on the AE 
page of the eCRF. 
2. A brief physical examination, including vital signs and body weight 
*Note: Patients randomized to the paclitaxel and alisertib arm will be seen for Cycle 
1 on days 1, 8 and 15 to have a brief physical exam, review of AEs, concomitant 
medications, vitals, weight (day 1 of each cycle only), and performance status (day 1 
of each cycle only).  Cycle 2 on days 1 and 15 to have a brief physical exam, review 
of AEs, concomitant medications, vitals, weight (day 1 of each cycle only), and 
performance status (day 1 of each cycle only).  And cycles 3 and subsequent cycles, 
patients will have a brief physical exam, review of AEs, concomitant medications, 
and vitals, weight, and performance status on day 1 of each cycle.  Patients receiving 
paclitaxel alone will be seen day 1 of each cycle to have a brief physical exam, 
review of AEs, concomitant medications, vitals, weight, and performance status. 
3. Assessment of PS on the ECOG scale (Appendix 4) 
4. Assessment of concomitant medications 
5. A CBC with differential and platelet count* 
*Note: CBCs are to be done within 3 business days prior to scheduled dosing on Day 
1 of each Cycle for both treatment arms; CBCs also need to be done on Days 8 and 
15 of each cycle. Results of the CBC must be known prior to dosing the patient on 
days when these assessments are done.  
6. Serum chemistries (CMPs)* 
*Note: CMP are to be done within 3 business days prior to scheduled dosing on Day 
1 of each Cycle for both treatment arms.   
7. Tumor response by clinical assessment of the patient’s disease (specifically, by 
physical examination) must be performed Day 1 of each cycle. 
8. Radiological assessment of tumors to follow measurable disease will be performed 
for prestudy assessments should be used throughout the study. If possible, the same 
equipment should be used each time. Under RECIST criteria, PET cannot be used 
to assess measurable disease.  


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z
Chest and abdominal CT imaging will then be performed every 8 weeks after 
initiation of treatment for the first 32 weeks of treatment and every 12 weeks 
thereafter for the duration of the treatment period. Pelvic imaging will be 
continued at subsequent tumor assessments only if pelvic metastases are 
identified at screening.  Note: Patients who have a PET/CT scan do not need 
to have a dedicated CT scan if they have disease measurable on the CT part 
of the PET/CT scan. This applies throughout the study 
z
Bone lesions presented at screening, bone scans will then be repeated every 
12 weeks after initiation of treatment for the first 32 weeks of treatment and 
every 16 weeks thereafter for the duration of the treatment period.  
z
Patients with previously treated brain metastases identified at screening, a 
brain MRI or CT will be performed every 8 weeks after initiation of 
treatment for the first 32 weeks of treatment and every 12 weeks thereafter 
for the duration of the treatment period. . 
9. Assessments of other sites of disease, (full staging CT scan), must be performed only 
to confirm a CR.  
10. A toxicity assessment, including assessment of peripheral neuropathy, must be 
performed.  
11. Review of patient oral medication diary (Appendix 8). 
For details on required assessments, please refer to Schedule of Events. 
3.9.3     End of Treatment assessments  
This is a single assessment that will be performed when a patient finishes treatment, either 
due to PD or toxicity that places patients off treatment, or in cases of MD decision or where 
patient withdraws consent. Patients who withdraw consent may not want any further 
assessment; however, they should be encouraged to have these final assessments done. 
There is a window (up to 7 business days) following determination that patient is “off 
treatment” for assessments following last treatment. Any delay within this window is NOT a 
deviation. 
The following evaluations will be performed following the last treatment: 
1. A brief medical history should be done to capture events that have occurred since the 
last cycle. Events that were not captured in the baseline complete medical history 
should be recorded on the AE page of the eCRF. 
2. A brief physical examination, including vital signs and body weight 
3. Assessment of PS on the ECOG scale (Appendix 4) 
4. Assessment of concomitant medications 
5. A CBC with differential and platelet count 
6. A CMP  


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7. A tumor clinical assessment of the patient’s disease (specifically, by physical 
examination) 
8. Radiological assessment of tumors.  There is a window (± 7 business days for 
radiologic assessments) for end of treatment. Any delay within this window is NOT 
a deviation. 
z
Chest and abdominal CT imaging will then be performed at End of 
Treatment. Pelvic imaging will be continued at subsequent tumor 
assessments only if pelvic metastases are identified at screening. The 
methods used for prestudy assessments should be used throughout the study.   
If possible, the same equipment should be used each time. Under RECIST 
criteria, PET cannot be used to assess measurable disease. 
* Note* For patients who come off-study treatment for reasons other than 
progression, imaging assessments should be performed per standard of care 
for the practice until progressive disease is documented.  Progression free 
survival and overall survival dates will be collected from patient’s chart until 
progressive disease is documented.   
z
Bone scan is required only if the patient has bone metastases present at 
screening, or has developed progressive disease in the bone during study 
treatment.  
z
Brain MRI or CT is required only for patients with historically treated brain 
metastases present at screening, or have developed brain metastases as part of 
their progressive disease during study treatment. 
z
Skin lesion assessments are required only for patients with a documented 
history of skin lesions, or for patients who developed skin using a digital 
camera (color photography).  
9. A toxicity assessment  
10. Review of patient oral medication diary (Appendix 8) 
11. Survival status 
For details on required assessments, please refer to Schedule of Events. 
3.9.4     Follow-up assessments  
After the end of treatment visits, all patients will be followed for safety up to 30 days after 
the last dose of study treatment with paclitaxel and/or alisertib. There is a +/- 7 business day 
window for follow up visit assessments. Any delay within this window is NOT a deviation. 
All patients who discontinue from study treatment due to disease progression must have 
their progression clearly documented according to the criteria specified in RECIST 1.1 
(Appendix 6). 
If a patient did not discontinue study treatment due to disease progression, death, adverse 
event, start of new anti-neoplastic therapies, lost to follow-up, or withdrawal of consent for 
efficacy follow-up then tumor assessments should continue to be performed per standard of 


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care until the start of new anti-cancer therapy, disease progression, death, lost to follow-up 
or withdrawal of consent for efficacy follow-up. 
All patients will be followed for survival every 3 months from last date of treatment 
regardless of treatment discontinuation reason (except if consent is withdrawn or patient is 
lost to follow-up) until death or for up to 2 years from date of registration. Survival 
information can be obtained via phone and information will be documented in source 
document. 
3.10    Discontinuation of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from study treatment at any 
time for any reason, without prejudice to their medical care.   
3.10.1    Reasons Off Treatment 
Patients will be taken off treatment if any of the following occur: 
1. Disease progression 
2. Intolerable toxicity 
Note: If patients go off study treatment due to any adverse event, regardless 
of grade, the reason off treatment will be documented as “Adverse event” in 
eDC; the toxicity (regardless of grade) must be documented in the toxicity 
section of eDC with the action code entered that is appropriate for 
discontinuation of study treatment. 
3. Treatment is interrupted for more than 3 consecutive weeks for any reason 
(Note: Delays do not count scheduled weeks of rest). 
4. An intercurrent illness, which would in the judgment of the Investigator, 
affect assessments of clinical status to a significant degree or require 
discontinuation of study treatment 
5. Non-protocol therapy (chemotherapy, radiation therapy, hormonal therapy, 
immunotherapy, or surgery) is administered during study treatment 
6. Noncompliance with protocol or treatment 
7. Becomes pregnant 
8. Refuses to continue treatment (patient will continue to be followed for 
survival) 
9. Physician decision 
10. Other 


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The date of and reason for discontinuation must be noted on the Change of Status page of 
the electronic Case Report Form (eCRF). Every effort should be made to complete the 
appropriate assessments.  
3.10.2    Reasons Off Treatment 
Patients will be considered off study if any of the following occur:  
1. Termination of study by Delta and/or Millennium Pharmaceuticals, Inc. 
2. Withdrawal of consent for study participation (patient will not be contacted and no 
further information will be collected); patient must sign a change in status of consent 
form  
Note: If the patient withdraws consent, then no additional data will be collected 
without her explicit consent; all data collected prior to withdrawal of consent may be 
used in the data analysis. The only exception to the collection of data after 
withdrawal of consent is collection of date of death and cause of death (if available) 
when the endpoint of the study is mortality. 
Note: Patients who decide to stop study therapy before progression of disease will be 
considered to have withdrawn consent for study therapy but not to have withdrawn 
consent for study participation and follow-up. 
3. Lost to follow-up (3 attempts should be documented in the patient’s source 
document before the site considers the patient as LFU.) 
4. Death 
The appropriate information must be completed on the Change of Status page of the eCRF. 
3.11    Efficacy, Correlative Studies, and Safety Measurements 
3.11.1    Efficacy Measurements 
Tumor response will be assessed locally according to Response Evaluation Criteria in Solid 
Tumors (RECIST), based on RECIST Version 1.1 (Appendix 6). The local investigator’s 
assessment will be used for all endpoint analyses and for treatment decision making. 
The following imaging assessments will be performed: 
z
CT of chest, abdomen, and pelvis at screening. Chest and abdominal CT imaging 
should then be performed every 8 weeks after initiation of treatment for the first 32 
weeks, then every 12 weeks thereafter for the duration of the treatment period, and at 
End of Treatment. Pelvic imaging should be continued at subsequent tumor 
assessments if pelvic lesions are identified at screening, or as clinically indicated. 


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z
A whole body TC-99 bone scan at screening for bone lesions according to 
institutional guidelines. If bone lesions are present at screening, bone scans should be 
repeated every 12 weeks after initiation of treatment for the first 32 weeks, then 
every 16 weeks thereafter for the duration of the treatment period, and at End of 
Treatment (only patients with bone metastases at baseline or those who develop bone 
metastases as part of their disease progression), using the same methodology used at 
screening. Patients whose first follow-up bone scan is read as progressive disease 
may stay on study therapy if the treating physician does not think the patient’s 
disease has progressed clinically, ie, no new bone pain or deterioration in 
performance status and no progression of disease in other sites.  Subsequent bone 
scans that are read as demonstrating progressive disease will lead to termination of 
study therapy. 
z
A baseline brain MRI is necessary for patients with a documented history of treated 
brain metastases (CT is allowed if MRI is contraindicated). A baseline brain MRI or 
CT scan is not required if patients do not have a documented history of brain 
metastases. Brain MRI or CT will be obtained at each tumor assessment only in 
patients with a documented history of treated brain metastases. Imaging will then be 
performed every 8 weeks after initiation of treatment for the first 32 weeks, then 
every 12 weeks thereafter for the duration of the treatment period, and at End of 
Treatment (only patients with documented history of brain metastases at baseline or 
those who develop brain metastases as part of their disease progression). 
z
Skin lesions should be documented at screening using a digital camera (color 
photography) in clear focus including a ruler or calipers in such a way that the size of 
the lesion(s) can be determined from the photograph. Skin photographs should be 
continued at subsequent tumor assessments for any lesions that were photographed at 
screening. Skin lesion assessments should be performed every 8 weeks after 
initiation of treatment for the first 32 weeks, then every 12 weeks thereafter for the 
duration of the treatment period, and at End of Treatment (only for patients with skin 
lesions at baseline or those who develop skin lesions as part of their disease 
progression). 
3.11.2    Correlative Biomarker Study 
One formalin fixed paraffin embedded tumor block (or 20 unstained slides if tumor block is 
not available) from the primary breast cancer, and will be stored for future analysis of 


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potential biomarkers of benefit from paclitaxel plus alisertib, including but not limited to 
FOXM1 and AURKA expression, p53 mutation status, and genomic instability. A metastatic 
lesion is preferred for FFPE analysis if the lesion was resected (no core biopsies). If resected 
metastatic lesion is unavailable, an FFPE block from the primary breast cancer may be 
submitted (from definitive surgery unless diagnostic core biopsy had more cancer than the 
definitive breast surgery specimen). 
Since the archived sample may not be located at the institution where the original diagnosis 
was rendered, the investigational sites will be responsible for locating it. For all tumor 
samples, the sample collection information must be captured on the relevant eCRF page(s) 
and laboratory requisition form(s). 
Tumor samples will be sent to a designated lab (check CTI) for storage and future analysis. 
See Collection of Shipping Information provided by sponsor for more detailed instructions 
on sample preparation and submission information (see Appendix 7). 
3.11.3    Safety Measurements 
Safety assessments will consist of the following: monitoring and recording of all adverse 
events and serious adverse events; regular monitoring of hematology, and blood chemistry; 
regular measurement of vital signs, physical examination (including weight); and 
performance status. 
These assessments should be performed periodically throughout the study, as indicated in 
the Schedule of Events, except for adverse events which will be evaluated continuously. 
All patients who receive at least one dose of study drug will be evaluated for safety. 
Toxicities will be graded and reported from the start of treatment according to the NCI 
CTCAE Version 4.03 (Appendix 2). Incidence and type of adverse events will be tabulated 
and summarized using descriptive statistics. 
3.12    Study Drug Administration 
Alisertib will be administered PO at a dosage of 40 mg BID on days 1-3, 8-10, and 15-17 of 
each 28-day cycle. 
Patients will be instructed to take each oral dose of alisertib with 8 ounces (1 cup, 240 mL) 
of water.  For BID dosing, the doses must be taken at least 6 hours apart. 


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Alisertib will be supplied as 10 mg ECT, with the dose strength expressed as milligrams of 
active drug (free acid); higher strengths may be supplied depending on the observed MTD.  
All tablets are to be ingested whole; patients who have difficulty swallowing tablets will be 
excluded from the study.  Antiemetic agents may be administered at the discretion of the 
investigator.  Although not prohibited, the use of benzodiazepines for the prophylaxis or 
treatment of nausea or vomiting is strongly discouraged because of the potential 
benzodiazepine-like effects of alisertib. 
Study drug will be administered only to eligible patients under the supervision of the 
investigator or identified sub-investigator(s). 
3.13    Description of Investigational Agents 
Alisertib drug product is supplied as the ECT dosage form in 10 mg strengths with dose 
strength expressed as the milligrams of active drug (free acid); other strengths may be 
supplied based on the observed MTD.  The key formulation excipients of the alisertib tablet 
formulation that aid in the in vivo absorption of the drug are the buffer (sodium 
bicarbonate), the surfactant (sodium lauryl sulfate), and the enteric coating. 
3.14    Preparation, Reconstitution, and Dispensation 
Alisertib ECT are packaged (10 tablets to a bottle) in a 60-cc high-density polyethylene 
(HDPE) bottle with a child-resistant cap. 
Alisertib is an anticancer drug, and as with other potentially toxic compounds, caution 
should be exercised when handling alisertib.   
3.15    Packaging and Labeling 
The packaged and labeled study drug, alisertib ECT, will be provided by Millennium and 
will be handled at the investigative site as open-label material.  The labels on the study drug 
will fulfill all requirements specified by governing regulations.  Ten alisertib ECT are 
packaged into each 60-cc HDPE bottle.  Alisertib will be supplied as ECT in 10 mg strength.  
The bottles will have a child-resistant cap and be labeled for take-home use.  Patients will 
receive instructions for home use of alisertib, including the requirement that alisertib be 
administered as intact tablets. 
As required by local regulations, any modifications to the plan for drug supply or storage 
will be communicated to the investigator and detailed in the Study Manual. 


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3.16    Storage, Handling, and Accountability 
Tablets should remain in the bottle provided until use.  The container should be stored at the 
investigative site at controlled room temperature (20-25°C; 68-77°F; excursions are 
permitted from 15-30C; 59-86F) and used before the retest expiry date provided by 
Millennium.  Containers should be kept closed during storage. 
Because alisertib is an investigational agent, it should be handled with due care. In case of 
contact with broken tablets, raising dust should be avoided during the cleanup operation. 
The product may be harmful by inhalation, ingestion, or skin absorption.  If tablets are 
broken or crushed, gloves and protective clothing should be worn during the cleanup 
operation.  The area should be ventilated and the site washed after material pick-up is 
complete.  The broken/crushed material should be disposed of as hazardous medical waste 
in compliance with federal, state, and local regulations. 
In case of contact with the powder (e.g., from a broken tablet), skin should be washed 
immediately with soap and copious amounts of water for at least 15 minutes. In case of 
contact with the eyes, copious amounts of water should be used to flush the eyes for at least 
15 minutes.  Medical personnel should be notified. 
Patients are to be instructed on proper storage, accountability, and administration of 
alisertib, including that alisertib is to be taken as intact tablets. 


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4.    ADVERSE EVENTS 
4.1.1    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. 
For this protocol 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. 
4.1.2    Serious Adverse Event Definition 
Serious adverse event (SAE) means any untoward medical occurrence that at any dose: 
z
Results in death. 
z
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). 
z
Requires inpatient hospitalization or prolongation of an existing hospitalization
(see clarification below on planned hospitalizations in Section 4.2). 
z
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). 
z
Is a congenital anomaly/birth defect. 
z
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, 


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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 (e.g., prion protein 
transmitting Transmissible Spongiform Encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.   
z
Clarification should be made between a serious AE (SAE) and an AE that is 
considered severe in intensity (Grade 3 or 4), because the terms serious and severe 
are NOT synonymous.  The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively 
minor medical significance (such as a Grade 3 headache).  This is NOT the same as 
serious, which is based on patient/event outcome or action criteria described above, 
and is usually associated with events that pose a threat to a patient’s life or ability to 
function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered 
serious.  For example, a white blood cell count of 1000/mm3 to less than 2000 is 
considered Grade 3 (severe) but may not be considered serious.  Seriousness (not 
intensity) serves as a guide for defining regulatory reporting obligations. 
4.2    Procedures for Reporting Serious Adverse Events (SAEs) 
AEs may be 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.  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 one comprehensive event.  AEs which are serious 
must be reported to Delta Pharmaceuticals Drug Safety and Epidemiology Department from 
the first dose of alisertib up to and including 30 days after administration of the last dose of 
alisertib.  Any SAE that occurs at any time after completion of alisertib treatment or after the 
designated follow-up period that the sponsor-investigator and/or sub-investigator considers 
to be related to any study drug must be reported to Delta Central Safety Department.  
Planned hospital admissions or surgical procedures for an illness or disease that existed 
before the patient was enrolled in the trial are not to be considered AEs unless the condition 
deteriorated in an unexpected manner during the trial (e.g., surgery was performed earlier or 


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later than planned).  All 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). 
Instructions for Reporting SAEs to Delta Central Safety Department 
The investigator has the obligation to report all serious adverse events to the IRB and the 
sponsor, (Delta Pharmaceuticals Drug Safety and Epidemiology Department (DS&E)). 
Serious adverse events should also be reported to the FDA and IRB in accordance with 
regulations and IRB policy. 
The investigator must complete the FDA MedWatch 3500A form and Delta SAE coversheet 
in English, assess the relationship to study treatment and send the initial completed 
MedWatch form and Delta SAE coversheet by Fax to (877) 571-8934 within 24 hours to the 
local Delta Drug Safety & Epidemiology (DS&E) Department.  The investigator must then 
ensure that the form and coversheet are accurately and fully completed with follow-up 
information and fax those to Delta DS&E Department within 2 to 3 calendar days for deaths 
or life-threatening events and 4 calendar days for other serious adverse events. The original 
and the duplicate copies of the FDA MedWatch form, Delta SAE coversheet, and the fax 
confirmation sheet should be kept with the site’s regulatory binder.   
In addition, all SAEs will be reported by telephone to the Delta Central Safety Department 
as soon as study personnel become aware of the SAE. The SAEs should be reported by 
facsimile within 24 hours to the Delta Central Safety Department. The site will supply as 
much information as is available at the time of the initial Fax to the Delta Central Safety 
Department (study number, subject initials, subject study number, event), during both 
business and non-business hours, to: 
Delta Clinical Research Safety Department
10101 Woodloch Forest 
The Woodlands, TX 77380 
SAE Hotline: (281) 863-6503 
Safety Fax: (877) 571-8934 
Follow-up information should describe whether the event has resolved or continues, if and 
how it was treated, and whether the patient continued or discontinued study participation. 
The MedWatch form, Delta SAE coversheet, and fax confirmation sheet must be retained by 
the investigator.   


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Pregnancy follow-up should describe the outcome of the pregnancy, including any voluntary 
or spontaneous termination, details of the birth, and the presence or absence of any 
congenital abnormalities or birth defects.   
Adverse events will be recorded for the duration of a patient’s study treatment. All AEs, 
regardless of causal relationship, are to be recorded in the source documentation. The 
Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. The diagnosis should be documented as the AE/SAE and 
not the individual signs/symptoms. 
All AEs will be graded and reported according to the NCI CTCAE (version 4.03). The 
relationship of each event to the study drug will be assessed by the Investigator and recorded 
on the eCRF. Additional information about each event, such as treatment required, whether 
or not the study drug had to be discontinued, and eventual outcome will also be recorded on 
the eCRF.  
4.3    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 must permanently discontinue 
study drug(s).  The sponsor-investigator must fax a completed Pregnancy Form to the 
Millennium Department of Pharmacovigilance or designee (or designee; see Section 4.2 for 
contact information) immediately.  The pregnancy must be followed for the final pregnancy 
outcome (ie, delivery, still birth, miscarriage) and Millennium Pharmacovigilance will 
request this information from the investigator. 
4.4    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), as well as Delta Clinical Research, LLC, and report the event.  
Whenever possible, the associated product should be maintained in accordance with the 
label instructions pending further guidance from a Millennium Quality representative. 
For Product Complaints, 
call MedComm Solutions at 
877-674-3784 (877 MPI DRUG) 
(US and International) 


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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 the Delta Central Safety Department 
(refer to Section 8.2). 


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5.    STATISTICAL PROCEDURES 
5.1    Study Design and Overview of Primary and Secondary Endpoints
This is a Phase II, multicenter, randomized, parallel group study to demonstrate the 
superiority of alisertib plus paclitaxel compared to paclitaxel alone in PFS in two cohorts of 
patients with metastatic or locally recurrent breast cancer, one with ER+/HER2- disease and 
the other with  TN disease. It is estimated that the median PFS time with paclitaxel alone 
treatment will be 3.5 months in TN patients and 6 months in ER+/HER2- patients. With the 
addition of alisertib to paclitaxel, the primary endpoint of this study hypothesizes that the 
median PFS times will increase to 5.8 months and to 10 months, respectively, with a PFS 
hazard ratio (HR) of 0.6 in these two cohorts. OS, ORR, CBR and toxicities are the 
secondary objectives. Molecular analyses of patients’ archival breast cancer tissue to 
investigate potential predictive markers will be proposed and it is also the one of secondary 
endpoints.  
5.2    Sample Size Estimation/Accrual Rate 
In the pivotal trial of ECOG 2100, first-line weekly paclitaxel resulted in a median PFS of 
4.6 months in TN patients, and of approximately 9 months in ER+ patients.8 In this trial the 
first-line and second-line patients will be enrolled and we estimate that the median PFS in 
patients with paclitaxel alone will be 3.5 months in the TN cohort and 6 months in the 
ER+/HER2- cohort. To demonstrate a HR of 0.6 with 80% power and one-sided alpha = 5% 
with the addition of alisertib to paclitaxel in each of the two cohorts, 104 TN and 118 
ER+/HER2 patients would be required for a single final analysis of each cohort.   
However, a 2-stage sequential design with futility boundaries for each group is employed for 
this study. Using ADDPLAN, 112 patients with 103 events (progressions or deaths) are 
needed for the TN population. The first analysis will be performed when the cumulative 
events are 34 with a corresponding accumulative information of 33% and an approximate 
sample size of 64. The statistics resulting from the first stage will be compared with 
acceptance and rejection boundaries given for the first stage. That is, using the Log-rank test 
for PFS between two groups in the first stage, if the Z-value is greater than 2.808, 
superiority of alisertib/paclitaxel can be declared compared to paclitaxel alone. If the Z-
value is less than 0, futility of the combination compared to paclitaxel alone will be 
declared. The study for the TN cohort will be stopped if either superiority or futility is 
declared. Otherwise, the trial for the TN cohort will continue to the second stage. 


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The first-stage analysis for the ER+/HER2- cohort will be performed independently of 
analysis in the TNBC cohort. The 2-stage sequential design for the ER+/HER2- cohort 
requires a total of 113 events and 140 patients, with 23 events and approximately 68 patients 
for the first analysis. The corresponding accumulative information is 20% and the rejection 
boundary is 3.482 for this stage. Similar to the TN cohort, using the Log-rank test, the 
superiority or the futility will be declared if Z-value is greater than 3.482 or less than 0, 
respectively, and the study for this cohort will be stopped. Otherwise, the trial for the 
ER+/HER2- cohort will continue to the second stage.  
The total sample size for the evaluable patient population is 252 (ER+/HER2-: n=140; TN: 
n=112), of which 126 patients will receive alisertib. If the study stops after stage I in each 
cohort, then the total sample size will be reduced to 132 (ER+/HER2-, n=68; TR, n=64), of 
which 66 patients will be treated with alisertib. 
An accrual rate of 12-15 patients per month is anticipated with similar distribution between 
cohorts; thus the accrual phase will be approximately 24 months. The last patient will be 
followed for approximately 12 months after enrollment, until disease progression or 
treatment-limiting toxicity occurs. Therefore, the anticipated total length of the study is 
approximately 36 months. 
5.3    Randomization and Stratification Factors 
Patients in each cohort will be randomly assigned to alisertib/paclitaxel or paclitaxel alone 
arms and stratified by the number of previous chemotherapy regimens for metastatic or 
locally recurrent breast cancer (0 vs. 1 previous chemotherapy regimen) as well as by 
previous (neo)adjuvant paclitaxel (yes or no). 
5.4    Evaluation of Efficacy 
The primary efficacy endpoint is progression-free survival (PFS).  PFS is defined as the time 
from the date of the randomization to the date of first documented disease progression or 
death from any cause. Patients who do not exhibit progression or death at the date of the 
analysis cut-off will be censored at the date of last contact. In patients with lytic bone-only 
disease at study entry, progressive disease will be defined as documentation of progressive 
lytic/destructive disease on CT scan, MRI, or X-ray.  
PFS will be estimated using Kaplan-Meier method with 95% confidence intervals (CI) in 
Intent-to-treat (ITT) population, which includes all patients registered on the study (eligible 


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and ineligible). The stratified logrank test will be used for comparing the distributions of the 
two treatment arms. A Cox proportional hazards analysis will be performed to assess the 
association of potential prognostic factors with PFS and to adjust the treatment comparisons 
for those factors. The results will be presented in terms of adjusted hazard ratios together 
with associated 95% CI and p-values. 
Secondary efficacy endpoints include OS, ORR, CBR, toxicities and molecular analyses of 
patients’ archived breast cancer tissue to investigate potential predictive markers (see 
Correlative Study Section). 
OS will be measured from the date of the randomization to the date of death for patients who 
die. If a patient is still alive or is lost to follow up, the patient will be censored at the last 
contact date. OS in each arm will also be summarized using the Kaplan-Meier method in the 
ITT population. 
ORR, defined as the percentage of CR plus PR, and CBR, defined as the percentage of ORR 
plus SD greater than 6 months, will be examined using univariate and multivariate 
approaches in the evaluable population, which includes all eligible patients who received at 
least 1 dose of study drug. Fisher’s exact test will be employed in the univariate comparison 
of treatment arms with each outcome rate. Logistic regression will be performed to assess 
the association of potential risk factors with each outcome rate and to adjust the treatment 
comparisons for those factors. The results will be presented in terms of adjusted risk ratios 
together with associated 95% CI and p-values. Time to response and duration of response 
will be calculated in each group. 
In addition, patient characteristics including demographics and pre-treatment characteristics 
such as race, sex, ECOG PS, and age will be described and compared between the two arms 
in each cohort. Disease histology at baseline, medical history, and prior therapies will be 
summarized and compared, too. Mean, standard deviation, median, minimum and maximum 
values will be presented for continuous variables, and frequency tables showing numbers 
and percentages will be presented for categorical variables. 
5.5    Evaluation of Safety 
The safety profile of the treatment will be assessed through dose exposure, summaries of 
adverse events, serious adverse events, adverse events leading to study therapy 
discontinuation, and treatment-related deaths. Toxicity events will be reported using the 
worst NCI CTCAE grade adverse event per patient. Safety population, defined as all patients 


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who received at least 1 dose of study treatment, will be included in the analysis for safety. 
The safety evaluation will summarize numbers and frequencies of all study related adverse 
events, as well as dose interruptions, dose reductions, and treatment discontinuations due to 
toxicities. 
A Bayesian continuous interim monitoring rule for toxicity will be applied to the first 40 
patients in the experimental arm beginning after the first five patients have been randomized 
to this arm, using the methodology by Thall, Simon, and Estey.45 We will monitor the 
probability of a 30% toxicity rate, where toxicity is defined as patients who require 2 or 
more dose reductions or delays due to toxicity during Cycles 1 and 2. If there is more than a 
95% chance that this toxicity rate is greater than 30% in the experimental arm, accrual will 
be suspended and appropriate modifications will be discussed by the Delta safety team and 
Millenium Pharmaceuticals, Inc.  
The stopping boundaries corresponding to this monitoring rule are:  
# Patients Randomized 
to Experimental Arm 
Suspend Accrual if there are this many Patients with toxicity  
(2 or more dose reductions or delays in first two cycles) 
1-4 
Never stop with this many patients 
5 
4-5 
6-8 
5-8 
9-10 
6-10 
11-12 
7-12 
13-15 
8-15 
16-18 
9-18 
19-20 
10-20 
21-23 
11-23 
24-25 
12-25 
26-28 
13-28 
29-31 
14-31 
32-34 
15-34 
35-36 
16-36 
37-39 
17-39 
40 
18-40 


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The operating characteristics of this rule are summarized below. If the true toxicity rate is 
very high at 50% or 60%, the chances of stopping early for toxicity are 90% and 99%, 
respectively. With this rule, if the true toxicity rate is 30%, there is a 16% chance of 
stopping early for toxicity.  
True toxicity rate 
Early stopping probability 
Average number of patients 
treated  
0.10 
0.0008 
40+  
0.20 
0.0207 
40+ 
0.30 
0.1622 
38 
0.40 
0.5500 
28 
0.50 
0.8980 
17 
0.60 
0.9932 
10 
This rule incorporates a prior beta (0.6, 1.4) for the experimental toxicity rate, corresponding 
to a 30% toxicity rate, and a constant 30% rate was assumed for the comparison to the 
standard treatment. These stopping boundaries and operating characteristics were obtained 
using the publically available software Multc Lean Desktop version 2.1.0 developed by the 
Biostatistics Department of the University of Texas M.D. Anderson Cancer Center.  
5.6    Correlative Studies 
The objectives of this correlative study include the measurement of FOXM1 and AURKA in 
the primary or metastatic tumor, which will be assessed by RT-PCR expression levels on 
tumor FFPE sections. High coordinate expression of both FOXM1 and AURKA will be the 
main biomarkers correlated with PFS obtained with paclitaxel plus alisertib vs. paclitaxel 
alone in the combined analyses of the ER+/HER2- and TN cohorts, as well as in the 
ER+/HER2- and TN cohorts separately. PFS with paclitaxel plus alisertib vs. paclitaxel 
alone will also be evaluated in patients with FOXM1 and/or AURKA levels below the 
median for ER+/HER2- and TN disease cohorts evaluated together and separately.  
5.7    Interim Analysis  
The interim analysis will be performed when the number of PFS events is 34 with a 
corresponding accumulative information of 33% and an approximate sample size of 64 for 


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the TN cohort. For the ER+/HER2- cohort, the interim analysis will be initiated when the 
number of PFS events is 23 with an approximate sample size of 68 patients in the first stage.  
6.    ADMINISTRATIVE REQUIREMENTS 
6.1    Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s).  The investigator will be thoroughly familiar with the appropriate use of the 
drug as described in the protocol and Investigator’s Brochure.  Essential clinical documents 
will be maintained to demonstrate the validity of the study and the integrity of the data 
collected.  Master files should be established at the beginning of the study, maintained for 
the duration of the study and retained according to the appropriate regulations.   
6.2    Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration 
of Helsinki (see Appendix 1).  The IRB/IEC will review all appropriate study documentation 
in order to safeguard the rights, safety and well-being of the patients.  The study will only be 
conducted at sites where IRB/IEC approval has been obtained.  The protocol, Investigator’s 
Brochure, informed consent, 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.  Informed consent 
documents will be reviewed by Delta and/or Millennium or designee prior to IRB/IEC 
submission.   
6.3    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 prior to study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
will comply with ICH-GCP and all applicable regulatory requirement(s). 
6.4    Patient Confidentiality 
In order to maintain patient privacy, all data capture records, drug accountability records, 
study reports and communications will identify the patient by initials and the assigned 
patient number.  The investigator will grant monitor(s) and auditor(s) from Delta, 


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Millennium or its designees and regulatory authority(ies) access to the patient’s original 
medical records for verification of data gathered on the data capture records and to audit the 
data collection process.  The patient’s confidentiality will be maintained and will not be 
made publicly available to the extent permitted by the applicable laws and regulations. 
6.5    Protocol Compliance 
The investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authority(ies).  
Changes to the protocol will require approval from Delta, Millennium and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed 
to eliminate an immediate hazard(s) to patients.  The IRB/IEC may provide, if applicable 
regulatory authority(ies) permit, expedited review and approval/favorable opinion for minor 
change(s) in ongoing studies that have the approval /favorable opinion of the IRB/IEC.  The 
investigator will submit all protocol modifications to Delta, Millennium and the regulatory 
authority(ies) in accordance with the governing regulations.  
Any departures from the protocol must be fully documented in the source documents.   
6.6    On-site Audits 
Regulatory authorities, the IEC/IRB, Delta, and/or Millennium’s clinical quality assurance 
group may request access to all source documents, data capture records, 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. 
6.7    Drug Accountability 
Accountability for alisertib at all study sites is the responsibility of the Principal 
Investigator.  The investigator will ensure that the drug is used only in accordance with this 
protocol.  Drug accountability records indicating the drug’s delivery date to the site (if 
applicable), inventory at the site (if applicable), use by each patient, and return to Delta 
and/or Millennium or disposal of the drug (if applicable and if approved by Millennium) 
will be maintained by the clinical site.  Accountability records will include dates, quantities, 
lot numbers, expiration dates (if applicable), and patient numbers.   
Drug compliance should be recorded in the eCRF. Patients on the paclitaxel plus alisertib 
arm should be given a copy of the Oral Medication Patient Diary (Appendix 8), and 
adherence to therapy should be reviewed at each office visit. 


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6.8    Premature Closure of the Study 
This study may be prematurely terminated, if in the opinion of the investigator, Delta, or 
Millennium, there is sufficient reasonable cause.  Written notification documenting the 
reason for study termination will be provided to the investigator, Delta, or Millennium by 
the terminating party.   
Circumstances that may warrant termination include, but are not limited to: 
z
Determination of unexpected, significant, or unacceptable risk to patients 
z
Failure to enter patients at an acceptable rate 
z
Insufficient adherence to protocol requirements 
z
Insufficient complete and/or evaluable data 
z
Plans to modify, suspend or discontinue the development of the drug 
Should the study be closed prematurely, all study materials must be returned to Millennium. 
6.9    Record Retention 
The investigator will maintain all study records according to ICH-GCP and applicable 
regulatory requirement(s).   


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7.    
USE OF INFORMATION 
All information regarding alisertib supplied by Delta and/or Millennium to the investigator 
is privileged and confidential information.  The investigator may use this information to 
accomplish the study, but may not use it for other purposes without consent from Delta and 
Millennium.  In accordance with the agreement between Delta, Millennium and the 
investigator sponsor, complete study data must be provided to Delta and Millennium.  This 
data and other information obtained from the clinical study may be used by Millennium for 
the development of alisertib and may be disclosed by Delta and/or Millennium to regulatory 
authority(ies), other investigators, corporate partners, or consultants as deemed necessary by 
Delta and/or Millennium. 
Upon completion of the clinical study and evaluation of results by Delta and Millennium, 
the hospital or institution and/or investigator may publish or disclose the clinical trial results 
pursuant to the terms contained in the applicable Clinical Trial Agreement. 


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2006;107(9):3669-75. 
22 Katayama H, Brinkley WR, Sen S. The Aurora kinases: role in cell transformation and 
tumorigenesis. Cancer & Metastasis Reviews 2003;22(4):451-64. 
23 Marumoto T, Honda S, Hara T, Nitta M, Hirota T, Kohmura E, et al. Aurora-A kinase 
maintains the fidelity of early and late mitotic events in HeLa cells. Journal of 
Biological Chemistry 2003;278(51):51786-95. 
24 Glover DM, Leibowitz MH, McLean DA, Parry H. Mutations in aurora prevent 
centrosome separation leading to the formation of monopolar spindles. Cell 
1995;81(1):95-105. 
25 Katayama H, Zhou H, Li Q, Tatsuka M, Sen S. Interaction and feedback regulation 
between STK15/BTAK/Aurora-A kinase and protein phosphatase 1 through mitotic 
cell division cycle. Journal of Biological Chemistry 2001;276(49):46219-24. 


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26 Hoar K, Chakravarty A, Rabino C, Wysong D, Bowman D, Roy N, et al. MLN8054, a 
small-molecule inhibitor of Aurora A, causes spindle pole and chromosome 
congression defects leading to aneuploidy. Molecular & Cellular Biology 
2007;27(12):4513-25. 
27 Marumoto T, Hirota T, Morisaki T, Kunitoku N, Zhang D, Ichikawa Y, et al. Roles of 
aurora-A kinase in mitotic entry and G2 checkpoint in mammalian cells. Genes to 
Cells 2002;7(11):1173-82. 
28 Honda R, Korner R, Nigg EA. Exploring the functional interactions between Aurora B, 
INCENP, and survivin in mitosis. Molecular Biology of the Cell 2003;14(8):3325-
41. 
29 Giet R, McLean D, Descamps S, Lee MJ, Raff JW, Prigent C, et al. Drosophila Aurora A 
kinase is required to localize D-TACC to centrosomes and to regulate astral 
microtubules. Journal of Cell Biology 2002;156(3):437-51. 
30 Melichar B, DeMichele A, Adenis A, et al. Phase 2 study of single agent MLN8237 
(alisertib), an investigational aurora A kinase (AAK) inhibitor, in patients (pts) with 
relapsed/refractory breast cancer (BrC). 2013 San Antonio Breast Cancer 
Symposium. Abstract PD5-5. Presented December 13, 2013.
31 Taxol (paclitaxel) (package insert). Princeton, NJ : Bristol-Meyers Squibb Company; 
2011. 
32 Nabholtz JM, Gelmon K, Bontenbal M, et al. Multicenter, randomized comparative study 
of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol. 
1996 Jun;14(6):1858-67. 
33 Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel 
compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 
20;23(24):5542-51. 
34 Paridaens R, Biganzoli L, Bruning P, et al. Paclitaxel versus doxorubicin as first-line 
single-agent chemotherapy for metastatic breast cancer: a European Organization for 
Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol. 
2000 Feb;18(4):724-33.  
35 Sledge GW, Neuberg D, Bernardo P, et al. Phase III trial of doxorubicin, paclitaxel, and 
the combination of doxorubicin and paclitaxel as front-line chemotherapy for 
metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 
15;21(4):588-92. 
36 Bishop JF, Dewar J, Toner GC, et al. Initial paclitaxel improves outcome compared with 
CMFP combination chemotherapy as front-line therapy in untreated metastatic breast 
cancer. J Clin Oncol. 1999 Aug;17(8):2355-64.  


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37 Seidman AD, Berry D, Cirrincione C, et al. Randomized phase III trial of weekly 
compared with every-3-weeks paclitaxel for metastatic breast cancer, with 
trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or 
not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B 
protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. 
38 Sparano JA, Wang M, Martino S, et al. Weekly paclitaxel in the adjuvant treatment of 
breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. 
39 Falchook GS, Goff BA, Kurzrock R, et al. Oral MLN8237 with weekly paclitaxel in 
patients with recurrent epithelial ovarian, fallopian tube, primary peritoneal (OC) or 
breast cancer (BRC): Phase I results. 18th International Meeting of the European 
Society of Gynaecological Oncology (ESGO). October 19-22, 2013. Liverpool, UK.
40 Venkatakrishnan K, Zhou X, Ecsedy J, et al. Recommended phase (Ph) II dose (RP2D) 
selection for investigational Aurora A kinase (AAK) inhibitor MLN8237 (Alisertib; 
A) combined with paclitaxel (P): Clinical pharmacokinetics (PK), drug-drug 
interaction (DDI) assessment, and translational exposure-efficacy modeling. J Clin 
Oncol 2013;31(suppl; abstr 2598).
41 Laoukili J, Kooistra MR, Brás A, et al. FoxM1 is required for execution of the mitotic 
programme and chromosome stability. Nat Cell Biol. 2005 Feb;7(2):126-36. 
42 Barsotti AM, Prives C. Pro-proliferative FoxM1 is a target of p53-mediated repression. 
Oncogene. 2009 Dec 3;28(48):4295-305. 
43 Yang G, Chang B, Yang F, et al. Aurora kinase A promotes ovarian tumorigenesis 
through dysregulation of the cell cycle and suppression of BRCA2. Clin Cancer Res. 
2010 Jun 15;16(12):3171-81. 
44 U.S. Department of Health and Human Services, National Institutes of Health National 
Cancer Institute. Common Terminology Criteria for Adverse Events(CTCAE). 
Version 4.03. 14 June 2010. 
45 Thall, PF, Simon, R, and Estey, EH. Bayesian sequential monitoring 
designs for single-arm clinical trials with multiple outcomes. Statistics in Medicine 
14:357-379, 1995. 


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9.    APPENDICES 
9.1    Appendix 1: Declaration of Helsinki 
World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects 
Adopted by the 18th WMA General Assembly Helsinki, Finland, June 1964 and amended 
by the 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 48th WMA General Assembly, Somerset West, Republic of South Africa, 
October 1996 and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
A. INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a 
statement of ethical principles to provide guidance to physicians and other participants in 
medical research involving human subjects.  Medical research involving human subjects 
includes research on identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people.  The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with 
the words, "The health of my patient will be my first consideration," and the 
International Code of Medical Ethics declares that, "A physician shall act only in the 
patient's interest when providing medical care which might have the effect of weakening 
the physical and mental condition of the patient." 
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease.  Even the best proven prophylactic, diagnostic, 
and therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights.  Some research populations are vulnerable and 
need special protection.  The particular needs of the economically and medically 
disadvantaged must be recognized.  Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the research and for 
those for whom the research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements.  No national ethical, legal or regulatory requirement should be allowed to 


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reduce or eliminate any of the protections for human subjects set forth in this 
Declaration. 
B. BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
1. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
2. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and on adequate laboratory and, where appropriate, 
animal experimentation. 
3. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
4. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol.  This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
investigator, the sponsor or any other kind of undue influence.  This independent 
committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed.  The committee has the right to monitor ongoing 
trials.  The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events.  The researcher should also submit to 
the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
5. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration. 
6. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person.  
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given 
consent. 
7. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others.  This does not preclude the participation of healthy volunteers in 
medical research.  The design of all studies should be publicly available. 
8. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and can 
be satisfactorily managed.  Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 
9. Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject.  This is 
especially important when the human subjects are healthy volunteers. 
10. Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
11. The subjects must be volunteers and informed participants in the research project. 
12. The right of research subjects to safeguard their integrity must always be respected.  


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Every precaution should be taken to respect the privacy of the subject, the confidentiality 
of the patient's information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
13. In any research on human beings, each potential subject must be adequately informed of 
the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail.  The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal.  After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing.  If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
14. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress.  In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
15. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law.  
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
16. When a subject deemed legally incompetent, such as a minor child, is able to give assent 
to decisions about participation in research, the investigator must obtain that assent in 
addition to the consent of the legally authorized representative. 
17. Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population.  The 
specific reasons for involving research subjects with a condition that renders them 
unable to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee.  The protocol should state that 
consent to remain in the research should be obtained as soon as possible from the 
individual or a legally authorized surrogate. 
18. Both authors and publishers have ethical obligations.  In publication of the results of 
research, the investigators are obliged to preserve the accuracy of the results.  Negative 
as well as positive results should be published or otherwise publicly available.  Sources 
of funding, institutional affiliations and any possible conflicts of interest should be 
declared in the publication.  Reports of experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication. 
C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
1. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value.  
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 


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2. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods.  This does 
not exclude the use of placebo, or no treatment, in studies where no proven prophylactic, 
diagnostic or therapeutic method exists. 
3. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study. 
4. The physician should fully inform the patient which aspects of the care are related to the 
research.  The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
5. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the patient, must be free to use unproven or new prophylactic, diagnostic and therapeutic 
measures, if in the physician's judgement it offers hope of saving life, re-establishing 
health or alleviating suffering.  Where possible, these measures should be made the 
object of research, designed to evaluate their safety and efficacy.  In all cases, new 
information should be recorded and, where appropriate, published.  The other relevant 
guidelines of this Declaration should be followed. 


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9.2    Appendix 2: Common Terminology Criteria for Adverse Events Version 4.03 
NCI COMMON TERMINOLOGY CRITERIA 
FOR ADVERSE EVENTS (CTCAE) 
Version 4.0 
Published: May 28, 2009 (v4.03: June 14, 2010) 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf
DO NOT USE CTC VERSION 2.0 OR 3.0 TO GRADE TOXICITIES IN THIS STUDY! 


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9.3    
Appendix 3: New York Heart Association Classification of Cardiac Disease 
The following table presents the NYHA 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. 


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9.4    
Appendix 4: Eastern Cooperative Oncology Group Scale for Performance 
Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all predisease performance without restriction 
1 
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work) 
2 
In bed < 50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed > 50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead. 
Source: Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.


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9.5    
Appendix 5: Body Surface Area and Creatinine Clearance Calculations 
Body surface area (BSA) should be calculated using a standard nomogram that yields the 
following results in meters squared (m2): 
BSA = 
3131
)
(
)
(
lbs
Wt
inches
Ht
w
or 
BSA = 
3600
)
(
)
(
kg
Wt
cm
Ht
w
Creatinine clearance (CrCl) can be calculated using the Cockroft-Gault equation as follows: 
 
CrCl (ml/min) = [(140-age) (body weight in kg) / (72 × serum creatinine in mg/dL)]
OR
[(140-age)(body weight in kg) / (0.81 x serum creatinine in mol/L)]
For females, use 85% of calculated CrCl value. 
Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 
1976;16(1):31-41. 
Note:  In markedly obese patients, the Cockroft-Gault formula will tend to overestimate the 
creatinine clearance.  (Adipose tissue tends to contribute little creatinine requiring renal 
clearance.) 


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9.6    
Appendix 6: Response Evaluation Criteria in Solid Tumors (RECIST) v1.1  
New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1)  Eisenhauer EA, Therasse P, Bogaerts J, et al. Eur J Cancer. 2009 Jan;45(2):228-
47. 
http://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf 


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9.7    
Appendix 7: Collection and Shipping Instructions for Tumor Blocks 
Collection of FFPE archival tissue from patients’ resected breast cancer (metastasis or 
primary breast cancer) will be tested for potential biomarkers of benefit from 
paclitaxel plus alisertib, including but not limited to FOXM1 and AURKA expression, 
p53 mutation status, and genomic instability.   
An FFPE TUMOR BLOCK WILL BE COLLECTED in the following order of 
priority:  
1. Resected metastatic lesion (not a core biopsy or FNA of metastatic lesion);  
2. Primary breast cancer resection (unless diagnostic core biopsy has more cancer 
than the definitive breast surgery specimen). If a tumor block is not available, 
20 unstained slides cut at standard 4-5 microns will be submitted.  
The following materials must be submitted for each patient entered on the study. 
z
One paraffin block from a representative area of the tumor Surgical Pathology 
Report 
z
Specimen Requisition Form 
Ship all samples directly to the designated lab (check CTI).The Specimen Requisition Form 
must be completed and submitted even if the patient pathology specimens are not available 
for submission. Please place a copy of the Specimen Requisition Form in the patient study 
record. To maintain uniform sample handling, samples should not be shipped on Fridays. 
Please indicate on the package “PATHOLOGY SPECIMENS ENCLOSED”. 


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9.8    
Appendix 8: Oral Medication Patient Diary 
Make copies of the following page and give to patients who are randomized to the paclitaxel 
plus alisertib arm, to track oral medication compliance. 


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Drug Administration Record – to be completed by patient and returned at 
each visit 
Please begin entries by checking the appropriate box that corresponds to the date treatment 
was started (Calendar Date). For example: If the patient starts treatment on January 24, 2014, 
check the box next to “24” under Calendar Date and continue entries from that date forward.
Patient Initials
Arm
Patient ID #
Month
Year
Please return all copies of this  
form to the Clinical Research 
Coordinator at each clinic visit. 
Calendar
Drug Taken
Date
Yes
No
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
US Oncology, Inc                                                 Study# 13-033