Conditions: Advanced Solid Tumors Ovarian Cancer Small Cell Lung Cancer
Keywords: Drug therapy Dose escalation Dose expansion
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 9
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and tolerability and determine the MTD to subsequently define an RP2D of alisertib in combination with weekly paclitaxel in East Asian participants with advanced solid tumors.

Detailed description:
The drug being tested in this study was called alisertib. Alisertib in combination with paclitaxel was tested to find a safe and well-tolerated dose in East Asian participants. The study consisted of 2 parts: a dose escalation phase to determine the maximum tolerated dose (MTD) and define the recommended phase 2 dose (RP2D) of the alisertib plus paclitaxel combination in East Asian participants with advanced solid tumors; the second part is an expansion cohort at the RP2D of the alisertib plus paclitaxel in East Asian participants with either ovarian cancer or small cell lung cancer. This study looked at safety (lab results and side effects) and pharmacokinetic properties (how the drugs move throughout the body).

This open label study enrolled 9 participants. Dose Escalation Phase: Alisertib tablets at a starting dose of 15 mg, orally, twice daily, 3 days on/4 days off for 3 weeks in 28 day cycle in combination with paclitaxel, 60 mg/m\^2 intravenous on days 1, 8, and 15 in 28-day cycles in Cohort 1 escalated to a dose of 25 mg alisertib, orally, twice daily 3 days on/4 days off for 3 weeks in 28 day cycles in Cohort 2. If ≥ 2 participants experience a dose limiting toxicity (DLT) the dose of alisertib decreased to 20 mg. Expansion Cohort: alisertib tablets at the determined RP2D dose orally, twice daily 3 days on/4 days off for 3 weeks in 28 day cycles in combination with paclitaxel, 60 mg/m\^2 intravenous. Treatment was continued until disease progression or unacceptable toxicity.

* Alisertib 15 mg to 25 mg tablets
* Paclitaxel 60 mg/m\^2 intravenous solution

This multi-centre trial was conducted in Japan and Korea. The overall time to participate in this study was up to 24 months.

The study was terminated early because of the sponsor's decision. Enrollment was completed in the dose escalation cohort, but no participants were enrolled in the dose expansion cohort.

Arms:
arm 1: Alisertib 15 mg, tablet, orally, twice daily, (3 days on/4 days off for 3 weeks) on Days 1 to 3, 8 to 10 and 15 to 17 in 28 day cycles in combination with Paclitaxel 60 mg/m\^2, intravenous (IV), on Days 1, 8, and 15 in a 28-day cycle until disease progression or unacceptable toxicity (Up to 22 Cycles). arm 2: Alisertib 25 mg, tablet, orally, twice daily, (3 days on/4 days off for 3 weeks) on Days 1 to 3, 8 to 10 and 15 to 17 in 28 day cycles in combination with Paclitaxel 60 mg/m\^2, intravenous (IV), on Days 1, 8, and 15 in 28-day cycle until disease progression or unacceptable toxicity. Dose of alisertib will be de-escalated to 20 mg if ≥ 2 participants experience a dose limiting toxicity (DLT). arm 3: Alisertib, MTD/RP2D determined in Dose Escalation Phase, orally, twice daily, (3 days on/4 days off for 3 weeks) on Days 1 to 3, 8 to 10 and 15 to 17 in 28 day cycles in combination with Paclitaxel 60 mg/m\^2, IV on Days 1, 8, and 15 in 28-day cycle until disease progression or unacceptable toxicity.

Interventions: intervention 1: Alisertib intervention 2: Paclitaxel
Intervention descriptions: intervention 1: Alisertib tablets intervention 2: Paclitaxel intravenous solution

Protocol document:
Prot_001.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Phase 1b Study of Alisertib (MLN8237) in Combination With Weekly Paclitaxel in 
East Asian Patients With Advanced Solid Tumors
NCT Number: NCT02367352
Protocol Approve Date: 01 June 2015
Certain information within this protocol has been redacted (ie, specific content is masked 
irreversibly from view with a black bar) to protect either personally identifiable information or 
company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.


Alisertib (MLN8237)
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CLINICAL STUDY PROTOCOL C14022 AMENDMENT 01
Alisertib (MLN8237)
A Phase 1b Study of Alisertib (MLN8237) in Combination With Weekly Paclitaxel in East
Asian Patients With Advanced Solid Tumors
Protocol Number:
C14022
Indication:
Advanced solid tumors (dose escalation)
Ovarian cancer or small cell lung cancer (dose expansion)
Phase:
1b
Sponsor:
Millennium Pharmaceuticals, Inc.
Therapeutic Area:
Oncology
Protocol History
Original
30 September 2014
Amendment 01
01 June 2015
Millennium Pharmaceuticals, Inc.
40 Landsdowne Street
Cambridge, MA  USA  02139
Telephone:  +1 (617) 679-7000
Approved by:
Note:  If this document was approved electronically, the electronic approval signatures may 
be found at the end of the document.
Signature
Date DD Month YYYY
Signature
Date DD Month  YYYY
Confidentiality Statement
The information contained herein is confidential and the proprietary property of Millennium 
Pharmaceuticals and any unauthorized use or disclosure of such information without the prior 
written authorization of Millennium Pharmaceuticals is expressly prohibited.
PPD
PPD


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Rationale for Amendment 01
The major purposes for this amendment are to add dose adjustment guidance for 
management of oral mucositis and to provide the updated dose interruption rule during a 
cycle. This amendment also includes other clarifications and corrections to address the 
feedback received from the health authority and for accuracy and consistency.
Purposes for Amendment 01
The purposes of this amendment are to:

Remove visit windows of 2 days from footnotes to remove repetition.

Allow body temperature to be measured according to local practice at study time points 
other than at Screening and Cycle 1; all Screening and Cycle 1 measurements must be 
taken orally.

Clarify the timing of CA-125 level assessments (for patients with ovarian cancer).

Clarify the screening requirements for HBV and HCV, and to add details of monitoring 
for patients who test HBcAbat Screening.

Adjust the requirement for disease evaluation so that patients will be evaluated up to 
progressive disease.

Clarify that paclitaxel and alisertib should be administered 1 hour apart on Cycle 1,
Day 1.

Allow a longer window for adjusting dosing and study assessments due to safety 
concerns (3 days, rather than 2 days, allowed for administrative reasons). 

Clarify the timing for the predose paclitaxel PK sample collection on Day 1.

Correct errors in percents reported for adverse events in the pooled data from single-
agent studies of alisertib.

Allow for expansion of dose escalation cohort(s) to enable a better understanding of 
safety and/or PK, if needed.

Clarify that there will be approximately 2 to 3 study centers in the escalation part of 
the study.

Redefine adequate renal function (Inclusion Criterion 8) by either creatinine levels or 
estimated creatinine clearance.

Add details to clarify Inclusion Criterion 9 regarding previous chemotherapy regimen 
allowance.

Revise Exclusion Criterion 11 to specify that there must be no use of proton pump 
inhibitors within 5 days (rather than 4 days) of the first dose of alisertib.

Revise Exclusion Criterion 19 to specify uncontrolled cardiac arrhythmias.

Add an exclusion criterion (Exclusion Criterion 21) for patients with another 
malignancy within the past 3 years.

Add details to the instructions for patients regarding the timing of study medication
dosing, and add a statement that the study medication should be swallowed whole and 
not chewed. 


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
Revise paclitaxel dosing instructions to specify that the length of paclitaxel infusion on 
Cycle 1, Day 1 and Cycle 2, Day 1 should be 60 minutes (it must not be less than 
60 minutes, but may be up to 70 minutes maximum, where necessary), while paclitaxel 
should be infused over at least 1 hour (but not more than 90 minutes) at all other dosing 
time points.

Allow prophylactic antiemetics during Cycle 1 and allow modifications to
premedications without the requirement for project clinician approval.

Clarify that thrombocytopenia with clinically significant bleeding is a DLT if it is 
greater than or equal to Grade 3 in the dose-limiting toxicity definitions.

Clarify actions at Dose Level 3 (20-mg BID alisertib).

Specify that PK exposure data will be used to support the determination of the 
recommended phase 2 dose (RP2D).

Extend the minimum rest period between cycles from 10 days to at least 11 days and a 
maximum of 21 days.

Revise the criteria for dose interruption during a cycle.

Revise the dose modification instructions for dose-limiting hematologic toxicities.

Add specific dose adjustment requirements due to occurrence of oral 
mucositis/stomatitis/mouth ulcers.

Clarify that alternative therapy or medicine(s) are not allowed.

Prohibit the use of pancreatic enzyme during the study.

Permit premedication with corticosteroids, diphenhydramine, or histamine-2 receptor 
antagonists before each treatment with paclitaxel.

Correct the definition of women of childbearing potential.

Clarify that radiographic images will be provided to the sponsor if necessary.

Clarify when patients who are withdrawn in Cycle 1 should be replaced.

Add clarification to DLT-evaluable population.

Update the TEAE definition to the current template. 

Remove final study analysis description from interim analysis section.

Remove administrative language regarding study closure that was intended for a 
European regulatory system and is not applicable to this study.

Correct typographical errors, punctuation, grammar, and formatting.
For specific examples of changes in text and where the changes are located, see 
Section 14.5.


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PROTOCOL SUMMARY
Study Title:  A Phase 1b Study of Alisertib (MLN8237) in Combination With Weekly Paclitaxel in 
East Asian Patients With Advanced Solid Tumors
Number of Patients:  Approximately 30 patients will be enrolled in this study, including a 
minimum of 12 patients with epithelial ovarian cancer (OC) and small cell lung cancer (SCLC)
(combined) in the expansion cohort.
Study Objectives
Primary

To evaluate the safety and tolerability and determine the maximum tolerated dose 
(MTD) to subsequently define a recommended phase 2 dose (RP2D) of alisertib in 
combination with weekly paclitaxel in East Asian patients with advanced solid 
tumors

To characterize the pharmacokinetics (PK) of alisertib and paclitaxel in the 
combination setting in East Asian patients with advanced solid tumors
Secondary (For Expansion Only)

To identify initial signs of antitumor activity in patients with relapsed/refractory OC 
or SCLC
Overview of Study Design:  This is an open-label, multicenter, phase 1b study to evaluate 
the safety, tolerability, and PK of alisertib in combination with weekly paclitaxel in East 
Asian patients.  The study is in 2 parts: the first part is a dose escalation to determine the 
MTD and define the RP2D of the alisertib plus paclitaxel combination in East Asian patients 
with advanced solid tumors; the second part is an expansion cohort at the RP2D of the 
alisertib plus paclitaxel combination in East Asian patients with either OC or SCLC.
Alisertib will be administered orally 3 days on/4 days off for 3 weeks on Days 1 through 3, 
8 through 10, and 15 through 17 in 28-day cycles.  Paclitaxel 60 mg/m2 IV will be 
administered on Days 1, 8, and 15 in 28-day cycles.  The paclitaxel dose will remain 
constant throughout the dose escalation and expansion parts of this study.  
Enrolled patients may receive study drug until observed progression, need of discontinuation 
because of toxicity, lost to follow-up, study is terminated by the sponsor, protocol violation, 
unsatisfactory therapeutic response, or voluntary withdrawal by the patient from the study.  
Patients may discontinue therapy at any time.  Patients will attend the End of Treatment visit 
30 days after receiving their last dose of study drug.
A dose escalation (3 + 3 schema) will be used to determine the MTD and the RP2D of the 
combination (as detailed in Section 6.4), which will be further evaluated in the expansion 
part of the study.  The starting dose will be 15 mg BID alisertib (dose level [DL] 1); the next 
planned dose level is 25 mg BID alisertib (DL2).  If ≥ 2 patients experience a DLT at 25 mg, 
alisertib will be de-escalated, and an intermediate dose level of alisertib 20 mg BID (DL3-
intermediate) will be explored.  The MTD/RP2D will require first-cycle DLTs in not more 
than 1 in 6 DLT-evaluable patients enrolled in a given dose level.  If ≥2 of the first 
6 patients experience a DLT at DL1, depending on the overall safety profile, the type of 


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AEs/DLTs observed, and the available PK data, a decision will be made either to expand the 
15 mg BID alisertib (DL1) cohort with 6 additional patients, or to de-escalate the alisertib 
dose to 10 mg BID (DL-1), or to terminate the study.  In the case of an expansion of the 
DL1 cohort, a tolerable dose will then require first-cycle DLTs in no more than 3 of 
12 DLT-evaluable patients to confirm the MTD.  If alisertib exposures in the combination 
setting in the East Asian population are unexpectedly lower than anticipated from single-
agent experience in East Asian patients, and no DLTs have occurred in the DL2 cohort 
(alisertib 25 mg BID plus 60 mg/m2 paclitaxel), the alisertib dose may be escalated further 
following discussion between the investigator and the sponsor pending PK and safety 
assessment.  Should more data be needed to better understand the observed safety and/or 
PK, with the agreement of the sponsor’s project clinician (or designee), cohort(s) at any dose 
level may be expanded.  Intrapatient dose escalation will not be permitted in this study.  It is 
planned that at least 1 Japanese patient will be included in each of the dose levels explored.
The effect of concomitant administration of alisertib on paclitaxel PK will be evaluated in 
this study.  To this effect, alisertib doses will be held on Days 1 through 3 in Cycle 2 so that 
paclitaxel PK can be evaluated, in the absence of alisertib, following paclitaxel dose 
administration on Cycle 2, Day 1.  Paclitaxel PK data on Cycle 2, Day 1 will serve as a 
reference for comparison with paclitaxel PK, evaluated at Cycle 1, Day 1 in the presence of 
alisertib.  During the dose escalation and expansion part, for Cycle 2 only, patients will 
receive 12 doses of alisertib, administered BID on Days 8 through 10 and 15 through 17.  
The effect of alisertib on paclitaxel PK will be assessed in a minimum of 12 patients 
(inclusive of the expansion part) who complete protocol-specified dosing and PK 
measurements in the first 2 treatment cycles at the RP2D of the combination.  Blood draws 
will be taken as detailed in the Schedule of Events and Section 7.4.17.
Pharmacokinetics of alisertib will be evaluated on Days 1 and 3 in Cycle 1 for both the dose 
escalation and expansion parts of the study.  Blood draws will be taken as detailed in the 
Schedule of Events and Section 7.4.17.
An MTD should be established and then an RP2D will be defined based on all relevant 
considerations/parameters (eg, safety, tolerability, and PK).
After dose escalation has completed, patients with relapsed/refractory OC or SCLC will be 
enrolled into the dose expansion part of the study.  During dose expansion, safety, 
tolerability, and initial signs of activity at the RP2D will be evaluated.
Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010.(1)  
Dose-limiting toxicities are defined in Section 6.3.
Adverse events will be assessed, and laboratory values, vital signs, and electrocardiograms 
(ECGs) will be obtained to evaluate the safety and tolerability of alisertib in combination 
with paclitaxel.
Patients cannot have received antineoplastic therapy or radiotherapy within the 21 days
before enrollment (14 days for regimens with recovery expected within 7-14 days).  
For all patients, scans (ie, CT and/or MRI) will be read locally. The investigator-assessed 
CR + PR (based on RECIST 1.1 criteria) will be used for efficacy assessment.


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Study Population:  The study population will consist of male or female East Asian patients 
aged 18 years or older who have an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1; adequate hepatic, renal, and hematologic function; and who 
have been treated with no more than 2 previous chemotherapy regimens in the metastatic 
setting. Patients in the dose escalation part will have advanced solid tumors. Patients in the 
expansion part will have relapsed/refractory ovarian cancer or small cell lung cancer with 
measurable disease. Patients in the expansion part must not have received more than 2 prior 
taxane-containing regimens.
Duration of Study:  It is anticipated that this study will last for approximately 24 months.  
The study will be closed once all the enrolled patients in the expansion part complete or 
discontinue from the study.


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STUDY OVERVIEW DIAGRAM
Dose 
incremental will 
be discussed 
based on the 
PK/Safety
(DL1)
15mg
3 + 3
(DL2)
25mg
3+3
3 + 3
(DL3 interm.)
20mg
Unexpected  lower exposure
than anticipated from single –agent 
and no DLTs
≥ 2 DLTs / 6 patients
Achieve RP2D
(DL-1)
10mg
Stop
Expand 
to 12 
patients
≥ 2 DLTs / 6 patients
Ovarian 
Cancer 
Cohort
Small Cell 
Lung 
Cancer 
Cohort
Escalation Phase
Expansion Phase
Alisertib dose will be 
escalated, paclitaxel dose 
will be held at 60 mg/m2
Abbreviations:  DL = dose level; DLT = dose limiting toxicity; RP2D = recommended phase 2 dose; PK = pharmacokinetic


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SCHEDULE OF EVENTS
Escalation (Patients With Advanced Solid Tumors) and Expansion (Patients With Relapsed/Refractory OC or SCLC)
Procedure
Screena
Cycle 1 (28-Day Cycle)
Subsequent 28-Day Cycles
EOTd
Day
Day
1b
2
3
8
9
10
15
21
1
2
3
8
15
21c
Informed consente
X
Inclusion/Exclusiona
X
Demographics
X
Complete medical historyf
X
Complete physical 
examination with neurological 
examination
X
Symptom-directed physical 
examinationg
Xb
X
X
X
X
X
X
Xc
X
Vital signsh
X
Xb
X
X
X
X
X
X
Xc
X
Height
X
Weighti
X
Xb
X
X
ECOG performance statusj
X
Xb
X
X
Electrocardiogramk
X
Xb
Hematologyl
X
Xb
X
X
X
X
X
X
Xc
X
Serum chemistry and TSHm
X
Xb
X
X
Urinalysisn
X
Xb
X
Serum pregnancy testo
X
Xo
CA-125p
X
X
X
X
X
HBV and HCV testingq
X
HBV DNA should be monitored every 2 months if HBcAb is identified at Screening
Extent of disease evaluation by 
RECIST, version 1.1r
X
Xr
X


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Escalation (Patients With Advanced Solid Tumors) and Expansion (Patients With Relapsed/Refractory OC or SCLC)
Procedure
Screena
Cycle 1 (28-Day Cycle)
Subsequent 28-Day Cycles
EOTd
Day
Day
1b
2
3
8
9
10
15
21
1
2
3
8
15
21c
Concomitant medications and 
procedures
Recorded from 28-days before the first dose of study drug through 30 days after the last dose of study drug or until the start of 
subsequent antineoplastic therapy, whichever occurs first
Adverse event reporting
Recorded from the first dose of study drug through 30 days after the last dose of study drug or until the start of 
subsequent antineoplastic therapy, whichever occurs first
Serious adverse events will be reported from signing of the informed consent form through 30 days after the last dose of 
study drug (see Section 9)s
Paclitaxel PK samplest
X
X
X
In Cycle 2 only
Alisertib PK samplesu
X
X
Administration of weekly 
paclitaxelv
X
X
X
X
X
X
Administration of alisertibw
Days 13, 810, 1517
Cycle 2 only:  Days 810, 15-17 
(no dosing on Days 1-3)
Cycle 3 and beyond: same as 
Cycle 1 dosing
Abbreviations:  -hCG = beta-human chrionic gonadotropin; CXDY = Cycle X, Day Y; D = day; ECOG PS = Eastern Cooperative Oncology Group 
Performance Status; EOS = End of Study visit; EOT = End of Treatment visit; FU = Follow-up; h = hour(s); min = minute(s); PD = progressive disease;
PFS = progression-free survival; PK = pharmacokinetics; RECIST = Response Evaluation Criteria in Solid Tumors; TSH = thyroid-stimulating hormone.
Each treatment cycle is 28-days in length.  Tests and procedures should be done on schedule, but visit windows of 2 days are allowed (except as otherwise 
specified) occasionally for holidays, vacations, and other administrative reasons.  A dosing windows of + 3 days is allowed due to safety concerns. If 
extenuating circumstances prevent a patient from beginning treatment or completing a scheduled assessment within this time frame, the patient may 
continue in the study only with written permission of the project clinician.
a Within 28-days before the Cycle 1, Day 1 dose of study drug, unless otherwise specified.
b Cycle 1, Day 1 is baseline.  Cycle 1, Day 1 evaluations and procedures are to be performed within the 4 days before the first dose of any study drug, unless 
otherwise specified.  A repeat of the procedure is not required on Cycle 1, Day 1 if screening procedures were performed within 4 days of the Cycle 1, Day 1 
dose of study drug.  The exception is the CA-125, as 2 CA-125 values are required to be collected before dosing on Cycle 1, Day 1.
c In patients who tolerate study treatment through multiple cycles, the Day 21 evaluation can be done by telephone contact, with or without laboratory testing
and vital signs, at the discretion of the investigator, if in the prior 2 cycles the patient tolerated study treatment (ie, without the requirement for dose reduction 
or without ≥Grade 3 treatment-related toxicity evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI 


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Escalation (Patients With Advanced Solid Tumors) and Expansion (Patients With Relapsed/Refractory OC or SCLC)
Procedure
Screena
Cycle 1 (28-Day Cycle)
Subsequent 28-Day Cycles
EOTd
Day
Day
1b
2
3
8
9
10
15
21
1
2
3
8
15
21c
CTCAE], version 4.03).
d For all patients, the EOT visit will be conducted 30 (+ 10) days after the last dose of study drug for all patients.  
e Informed consent may be obtained earlier and must be obtained before performance of any study-specific procedures.
f
Including history of prior treatment for cancer.
g The Cycle 1, Day 1 (baseline) symptom-directed physical examination is not required if the screening complete physical examination was conducted within 
the 4 days before administration of the Cycle 1, Day 1 dose of study drug.  A symptom-directed physical examination will be repeated within 3 days before 
the beginning (Day 1) of each new treatment cycle; on Day 8, Day 15, and Day 21 of each treatment cycle; and at the EOT visit.
h Vital signs (blood pressure, heart rate, and temperature) measurements will be obtained during screening; at Cycle 1, Day 1 (baseline); within 3 days before 
the beginning (Day 1) of each treatment cycle; on Day 8, Day 15, and Day 21; and at the EOT visit.  Blood pressure should be determined with the patient in 
a seated position after the patient has been sitting quietly for 5 minutes.  If the screening assessment was done within 4 days before Cycle 1, Day 1, an 
assessment at Cycle 1, Day 1 is not necessary.  During Screening and Cycle 1, temperature should be oral measurements only; temperature measurements in 
all other cycles may be taken based on local practice.  
i
Weight will be measured at screening; at Cycle 1, Day 1 (baseline); within 3 days before the beginning (Day 1) of each treatment cycle; and at the EOT visit.  
If the screening assessment was done within 4 days before Cycle 1, Day 1, an assessment at Cycle 1, Day 1 is not necessary.
j
ECOG performance status will be assessed during screening; at Cycle 1, Day 1 (baseline); within 3 days before the beginning (Day 1) of each treatment 
cycle; and at the EOT visit.  Refer to Section 14.1.  If the screening assessment was done within 4 days before Cycle 1, Day 1, an assessment at Cycle 1, Day 
1 is not necessary.
k A 12-lead electrocardiogram (ECG) will be obtained at screening and at Cycle 1, Day 1 (baseline).  If the screening ECG was obtained within the 4 days 
before the Cycle 1, Day 1 dose of study drug, a repeat ECG at Cycle 1, Day 1 is not necessary.  Additional ECGs may be obtained if clinically indicated.  
Electrocardiogram assessments are to be performed with the patient supine and rested for 5 minutes and before any closely timed blood collection.
l
A blood sample for hematology will be obtained during screening; at Cycle 1, Day 1 (baseline); within 3 days before the beginning (Day 1) of each treatment 
cycle; on Day 8 (2 days), Day 15 (2 days), and Day 21 (2 days); and at the EOT visit.  In patients who tolerate study treatment through multiple cycles, 
the Day 21 clinical laboratory assessment can become optional, at the discretion of the investigator, if in the prior 2 cycles the patient tolerated study 
treatment (ie, without the requirement for dose reduction or without ≥ Grade 3 treatment-related toxicity evaluated according to NCI CTCAE, version 4.03).  
If screening values were obtained within the 4 days before Cycle 1, Day 1, repeat hematology testing at Cycle 1, Day 1 is not necessary.  If a patient has an 
absolute neutrophil count (ANC) less than 500/mm3 or a platelet count less than 25,000/mm3, or both, the complete blood count (CBC) with differential 
should be repeated at least every 2 to 3 days until the ANC or platelet count (or both, if both were decreased) have exceeded these values on at least 
2 occasions.
m A blood sample for serum chemistries will be obtained during screening; at Cycle 1, Day 1 (baseline); within 3 days before the beginning (Day 1) of each 
treatment cycle; and at the EOT visit.  Thyroid stimulating hormone (TSH) level will be measured at screening or Cycle 1, Day 1 (baseline) and at the EOT 
visit; this test should be repeated during the treatment period as clinically indicated.  If screening values were obtained and acceptable within the 4 days 


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Escalation (Patients With Advanced Solid Tumors) and Expansion (Patients With Relapsed/Refractory OC or SCLC)
Procedure
Screena
Cycle 1 (28-Day Cycle)
Subsequent 28-Day Cycles
EOTd
Day
Day
1b
2
3
8
9
10
15
21
1
2
3
8
15
21c
before Cycle 1, Day 1, repeat clinical chemistry testing at Cycle 1, Day 1 is not necessary.
n A urine sample for urinalysis will be obtained during screening, at Cycle 1, Day 1 (baseline), and at the EOT visit.  If urine protein by dipstick changes to 3+ 
(or 2+ that is reconfirmed at least 1 day later), then a 24-hour urine collection should be done for protein and creatinine clearance.  The screening or Cycle 1, 
Day 1 (baseline) urinalysis should include microscopic examination of the sediment.  If screening values were obtained and acceptable within the 4 days 
before the Cycle 1, Day 1 dose of study drug, a repeat urinalysis at Cycle 1, Day 1 is not necessary.
o A serum -hCG pregnancy test will be performed only for patients of childbearing potential during screening and again at Cycle 1, Day 1 (baseline) if the 
screening test was performed more than 4 days before the first dose of any study drug.  The results must be negative within 4 days before the first dose of any 
study drug (alisertib or paclitaxel) is administered (ie, within the 4 days before Cycle 1, Day 1), or as otherwise required by local regulations.  Additional 
pregnancy testing may be performed during the study at the discretion of the investigator, as per request of IEC/IRB, or if required by local regulations.
p For OC patients, CA-125 levels will be obtained according to standard of care within 9 days of screening and sufficient time after prior therapy, or during 
screening period; and within 4 days prior to the dose at Cycle 1, Day 1; and at the end of every treatment cycle, within the week prior to the start of new 
treatment cycle; and at the EOT visit. The investigator’s determination of response by CA-125 is required at the end of every 2 cycles.   
q HBV and HCV screening must be conducted during the Screening period. HBV screening will include testing for hepatitis B surface antigen and hepatitis B 
core antibody (HBcAb). For patients who test positive for HBcAb, HBV DNA will also be assessed at screening.  HCV screening will include testing for the 
anti-HCV antibody (HCVAb).  Patients who test positive for HCVAb will also be tested for HCV-RNA at screening.  Patients who are HBVcAb positive at 
the screening will be monitored by assessment of DNA titers every 2 months.
r
Patients will undergo an evaluation of their disease with standard clinical examinations (eg, CT/MRI) to determine the extent of disease evaluation by the 
Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (see Section 7.4.15).  Magnetic resonance imaging (MRI) scans may be used to assess 
sites of disease not adequately imaged by CT.  If the patient has had appropriate scans performed within 28-days before the Cycle 1, Day 1 dose of alisertib, 
then those scans may be used for tumor lesion measurement during screening.  Repeat CT (with IV contrast) or MRI scans, or both, are to be performed at the 
completion of Cycle 2 and at the completion of every 2 cycles (approximately every 8 weeks, between Days 21 and 28 of every even cycle) thereafter until 
PD is documented (except as permitted per agreement with the investigator and project clinician; see Section 7.4.15).  The same imaging modality should be 
used throughout the study for each site of disease.  For responders, radiographic images will be read locally but will be collected and, if necessary, will be 
provided to the sponsor for subsequent review.  Scans are required at the EOT visit only if PD has not been documented previously and it has been 8 weeks or 
more since the previous evaluation.  Other procedures, such as physical examinations and other scintigraphic examinations (eg, bone scans for patients with 
known or suspected bone metastases) should be taken into consideration also when evaluating the extent of malignant disease.  
s Only those serious events that occur after the first dose of any study drug will be entered in the eCRF, although all serious adverse events and serious 
pretreatment events must be reported to the Millennium Department of Pharmacovigilance or designee.
t
Blood samples to measure plasma concentrations of paclitaxel will be collected at the following time points on Day 1 of both Cycles 1 and 2:  within 1 h 
before the start of the paclitaxel infusion; at the end of the paclitaxel infusion (immediately before switching off the infusion pump); at 5 (± 1) min, 15 (± 3) 
min, 0.5 h (± 5 min), 1 h (± 10 min), 2 h (± 20 min), 3 h (± 20 min), 7 h (± 30 min), 10 h (± 30 min), 23 (± 2) h, and 47 (± 4) h after completion of the 


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Escalation (Patients With Advanced Solid Tumors) and Expansion (Patients With Relapsed/Refractory OC or SCLC)
Procedure
Screena
Cycle 1 (28-Day Cycle)
Subsequent 28-Day Cycles
EOTd
Day
Day
1b
2
3
8
9
10
15
21
1
2
3
8
15
21c
paclitaxel infusion.  The 23- and 47-h blood samples will be collected before alisertib dosing (see Section 7.4.17.1 and the Alisertib and Paclitaxel PK 
Sampling Schedule).
u Blood samples to measure plasma concentrations of alisertib will be collected at the following time points on Days 1 and 3 in Cycle 1:  immediately before 
the morning dose of alisertib, and at 1 h (± 10 min), 2 h (± 20 min), 3 h (± 20 min), 4 h (± 20 min), 5 h (± 20 min), 9 h (± 30 min), and 12 (± 1) h after the 
alisertib morning dose on Days 1 and 3. (See Section 7.4.17.2 and Alisertib and Paclitaxel PK Sampling Schedule)
v Paclitaxel will be administered as a 1-hour intravenous (IV) infusion on Days 1, 8, and 15 of each 28-day treatment cycle (Section 6.2.1).  Premedication may 
be administered in accordance with the recommendations described in the product label.
w During Cycle 1, and Cycle 3 and beyond, alisertib dosing will begin on Day 1; subsequent dosing will occur on Days 2, 3, 8, 9, 10, 15, 16, and 17.  During 
Cycle 2 only, alisertib dosing will begin on Day 8 and will continue on Days 9 and 10, and on Days 15, 16, and 17.  Refer to Table 6-1 for alisertib dose 
administration and titration schema.  On Cycle 1 Day 1 when both paclitaxel and alisertib are administered, alisertib should be administered 1 hour before the 
start of the paclitaxel infusion.  Alisertib will be dispensed to the patient on Day 1.  If the study schedule is shifted, both assessments and dosing must be 
shifted to ensure collection of assessment is completed before dosing.   If extenuating circumstances prevent a patient from beginning treatment or completing 
a scheduled procedure or assessment within this time, the patient may continue the study only with the permission of the sponsor/designee clinician


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ALISERTIB AND PACLITAXEL PK SAMPLING SCHEDULE
Day
Dosing
Paclitaxel PK
(Cycle 1 and Cycle 2)
Alisertib PK
(Cycle 1)
Alisertib
Paclitaxel
Timepoint
Sample
Timepoint
Sample
1
X
Predose
Xa
Predose
Xb,g
X (start)
1 h (± 10 min)
Xd
X (end) c
End of infusion
Xe
2 h (± 20 min)
Xd
5 (± 1) min
Xf
15 (± 3) min
Xf
0.5 h (± 5 min)
Xf
1 h (± 10 min)
Xf
3 h (± 20 min)
Xd
2 h (± 20 min)
Xf
4 h (± 20 min)
Xd
3 h (± 20 min)
Xf
5 h (± 20 min)
Xd
7 h (± 30 min)
Xf
9 h (± 30 min)
Xd
10 h (± 30 min)
Xf
12 (± 1) h
Xd
2
X
23 (± 2) h
Xf
3
X
47 (± 4) h
Xf
Predose
Xb,g
1 h (± 10 min)
Xd
2h (± 20 min)
Xd
3 h (± 20 min)
Xd
4 h (± 20 min)
Xd
5 h (± 20 min)
Xd
9 h (± 30 min)
Xd
12 (± 1) h
Xd
Abbreviations: h = hour(s); min = minute(s); PK = pharmacokinetics.
a Within 1 h before the start of the paclitaxel infusion.
b Immediately before the morning dose of alisertib.  On the day when both paclitaxel and alisertib are 
administered, alisertib should be administered 1 h before the start of the paclitaxel infusion.
c Paclitaxel should be infused over 60 (10) minutes (Section 6.2.1).
d After the morning dose of alisertib.
e Immediately before switching off the infusion pump.
f
After the completion of the paclitaxel infusion (ie, from the time the infusion pump is switched off).
g The predose sample for alisertib PK on Days 1 and 3 can be timed to coincide with the predose sample for 
paclitaxel PK on Day 1 and the 47-h paclitaxel PK sample depending on the timing of alisertib dosing.


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TABLE OF CONTENTS
LIST OF TABLES.............................................................................................................16
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ..........................................17
1. BACKGROUND AND STUDY RATIONALE..............................................................20
1.1 Scientific Background ..............................................................................................20
1.1.1 Study Drug ........................................................................................................20
1.2 Nonclinical Experience.............................................................................................20
1.2.1 In Vitro Pharmacology.......................................................................................20
1.2.2 In Vivo Pharmacology .......................................................................................20
1.2.3 Safety Pharmacology and Toxicology................................................................21
1.3 Clinical Experience ..................................................................................................22
1.4 Disease Under Treatment..........................................................................................24
1.4.1 Epithelial Ovarian Cancer Epidemiology and Treatment ....................................24
1.4.2 Small Cell Lung Cancer.....................................................................................25
1.5 Study Rationale ........................................................................................................25
1.6 Dose Rationale .........................................................................................................26
1.7 Potential Risks and Benefits .....................................................................................27
2. STUDY OBJECTIVES ..................................................................................................28
2.1 Primary Objectives ...................................................................................................28
2.2 Secondary Objective (For Expansion Only)..............................................................29
3. STUDY ENDPOINTS....................................................................................................29
3.1 Primary Endpoints....................................................................................................29
3.2 Secondary Endpoint..................................................................................................29
4. STUDY DESIGN...........................................................................................................30
4.1 Overview of Study Design........................................................................................30
4.2 Number of Patients...................................................................................................32
4.3 Duration of Study.....................................................................................................32
5. STUDY POPULATION.................................................................................................33
5.1 Inclusion Criteria......................................................................................................33
5.2 Exclusion Criteria.....................................................................................................35
6. STUDY DRUG..............................................................................................................37
6.1 Study Drug Administration.......................................................................................37
6.2 Reference/Control Therapy.......................................................................................38
6.2.1 Paclitaxel...........................................................................................................38
6.2.2 Premedication for Paclitaxel-Associated Hypersensitivity or Other Acute 
Reactions ....................................................................................................38
6.3 Definitions of Dose-Limiting Toxicity......................................................................39
6.4 Dose Escalation Rules ..............................................................................................40
6.5 Dose-Modification Guidelines..................................................................................42
6.5.1 Criteria for Beginning a Subsequent Treatment Cycle ........................................42
6.5.2 Criteria for Dose Interruption During a Cycle ....................................................43
6.5.3 Dose Modifications............................................................................................44
6.6 Excluded Concomitant Medications and Procedures.................................................48
6.7 Permitted Concomitant Medications and Procedures.................................................49
6.8 Precautions and Restrictions .....................................................................................50


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6.9 Management of Clinical Events................................................................................51
6.9.1 Nausea and Vomiting.........................................................................................51
6.9.2 Diarrhea.............................................................................................................52
6.9.3 Central Nervous System Effects.........................................................................52
6.9.4 Hypersensitivity Reactions Associated With Paclitaxel ......................................52
6.10 Blinding and Unblinding ........................................................................................52
6.11 Description of Investigational Agents .....................................................................52
6.12 Preparation, Reconstitution, and Dispensation ........................................................53
6.13 Packaging and Labeling..........................................................................................53
6.14 Storage, Handling, and Accountability....................................................................53
6.15 Other Protocol-Specified Materials.........................................................................54
7. STUDY CONDUCT ......................................................................................................54
7.1 Study Personnel and Organizations...........................................................................54
7.2 Arrangements for Recruitment of Patients ................................................................55
7.3 Treatment Group Assignments .................................................................................55
7.4 Study Procedures......................................................................................................55
7.4.1 Informed Consent ..............................................................................................55
7.4.2 Patient Demographics ........................................................................................55
7.4.3 Medical History.................................................................................................55
7.4.4 Physical Examination.........................................................................................55
7.4.5 Patient Height and Weight .................................................................................56
7.4.6 Vital Signs .........................................................................................................56
7.4.7 Pregnancy Test ..................................................................................................57
7.4.8 Concomitant Medications and Procedures..........................................................58
7.4.9 Adverse Events..................................................................................................58
7.4.10 Enrollment .......................................................................................................58
7.4.11 Electrocardiogram............................................................................................58
7.4.12 Clinical Laboratory Evaluations.......................................................................58
7.4.13 CA-125 Assessment.........................................................................................60
7.4.14 HBV and HCV Assessment..............................................................................60
7.4.15 Disease Assessment .........................................................................................61
7.4.16 Tumor Biopsies (Not Applicable).....................................................................62
7.4.17 Pharmacokinetic Measurements.......................................................................62
7.4.18 Pharmacodynamic Measurements (Not Applicable) .........................................62
7.5 Completion of Treatment..........................................................................................62
7.6 Completion of Study.................................................................................................63
7.7 Discontinuation of Treatment With Study Drug, and Patient Replacement................63
7.8 Withdrawal of Patients From Study..........................................................................64
7.9 Study Compliance ....................................................................................................65
8. STATISTICAL AND QUANTITATIVE ANALYSES ..................................................65
8.1 Statistical Methods ...................................................................................................65
8.1.1 Determination of Sample Size............................................................................66
8.1.2 Randomization and Stratification .......................................................................66
8.1.3 Populations for Analysis ....................................................................................66
8.1.4 Procedures for Handling Missing, Unused, and Spurious Data...........................66
8.1.5 Demographic and Baseline Characteristics.........................................................66


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8.1.6 Efficacy Analysis...............................................................................................67
8.1.7 Pharmacokinetics/Pharmacodynamics/Biomarkers.............................................67
8.1.8 Safety Analysis ..................................................................................................68
8.1.9 Interim Analysis.................................................................................................69
9. ADVERSE EVENTS .....................................................................................................69
9.1 Definitions................................................................................................................69
9.1.1 Pretreatment Event Definition............................................................................69
9.1.2 Adverse Event Definition...................................................................................69
9.1.3 Serious Adverse Event Definition ......................................................................70
9.2 Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events.................................................................................................71
9.3 Monitoring of Adverse Events and Period of Observation.........................................72
9.4 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events..........72
10. ADMINISTRATIVE REQUIREMENTS .....................................................................73
10.1 Good Clinical Practice............................................................................................73
10.2 Data Quality Assurance ..........................................................................................73
10.3 Electronic Case Report Form Completion...............................................................73
10.4 Study Monitoring ...................................................................................................74
10.5 Ethical Considerations............................................................................................74
10.6 Patient Information and Informed Consent..............................................................75
10.7 Patient Confidentiality............................................................................................75
10.8 Investigator Compliance.........................................................................................75
10.9 On-site Audits ........................................................................................................75
10.10 Investigator and Site Responsibility for Drug Accountability................................76
10.11 Product Complaints ..............................................................................................76
10.12 Closure of the Study .............................................................................................76
10.13 Record Retention..................................................................................................77
11. USE OF INFORMATION............................................................................................77
12. INVESTIGATOR AGREEMENT................................................................................79
13. REFERENCES.............................................................................................................80
14. APPENDICES .............................................................................................................85
14.1 Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status.........85
14.2 List of Strong and Moderate CYP3A Inhibitors ......................................................85
14.3 Cockcroft-Gault Equation.......................................................................................86
14.4 Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1) ...................86
14.5 Amendment 1 Detailed Summary of Changes.........................................................87
LIST OF TABLES
Table 6-1   
Alisertib Combined With Paclitaxel for Phase 1 Dose Escalation ................42
Table 6-2   
Dose Modification Rules:  Hematological Toxicity .....................................46
Table 6-3   
Dose Adjustments for Oral Mucositis (Drug-related)...................................47


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS
Abbreviation
Term
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ASCO
American Society of Clinical Oncology
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the plasma concentration versus time curve
AUC0-inf
area under the plasma concentration versus time curve from zero to infinity
AUC0-tlast
area under the plasma concentration versus time curve zero to the time of the 
last measurement
AUC0-τ
area under the plasma concentration versus time curve from zero to next dose
hCG
beta-human chorionic gonadotropin
BID
bis in die; twice daily
BSA
body surface area
BUN
blood urea nitrogen
CBC
complete blood count
CL
clearance, IV dosing
CL/F
apparent oral clearance
Cmax
single-dose maximum (peak) concentration  
CNS
central nervous system
CO2
carbon dioxide
CR
complete response
CRM
continual reassessment method
CT
computed tomography
CYP
cytochrome P450
DL
dose level
DLT
dose-limiting toxicity
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ECT
enteric-coated tablet


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Abbreviation
Term
EDC
electronic data capture
EOS
End of Study (visit)
EOT
End of Treatment (visit)
ES-SCLC
extensive-stage small cell lung cancer
EU
European Union
FDA
United States Food and Drug Administration
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
GI
gastrointestinal
GLP
Good Laboratory Practices
Hct
hematocrit
HDPE
high-density polyethylene
hERG
human ether-à-go-go related gene
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
independent ethics committee
IRB
institutional review board
ITT
intent-to-treat
IV
intravenous; intravenously
Ki
inhibition constant
LDH
lactate dehydrogenase
LS-SCLC
limited-stage small cell lung cancer
MedDRA
Medical Dictionary for Regulatory Activities
Millennium
Millennium Pharmaceuticals, Inc., and its affiliates
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
OC
ovarian cancer
OS
overall survival


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Abbreviation
Term
PD
progressive disease (disease progression)
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
PR
partial response
QD
quaque die; once daily
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
serious adverse event
SCLC
Small cell lung cancer
SmPC
Summary of Product Characteristics
t1/2
terminal disposition half-life
TGI
tumor growth inhibition
Tmax
first time of occurrence of maximum (peak) concentration
TSH
Thyroid stimulating hormone
UGT
uridine diphosphate-glucuronosyltransferase
ULN
upper limit of the normal range
US
United States
WBC
white blood cell
WHO
World Health Organization


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1.   
BACKGROUND AND STUDY RATIONALE
1.1   
Scientific Background
1.1.1   
Study Drug
Alisertib (International Nonproprietary Name; also known as MLN8237) is an adenosine 
triphosphate (ATP)-competitive and reversible inhibitor of Aurora A kinase.  A selective 
small molecule inhibitor of Aurora A kinase, alisertib is being developed for the treatment of 
advanced malignancies, as Aurora A is expressed in all actively dividing cells.  Aurora A is 
localized to centrosomes and the proximal mitotic spindle during mitosis, where it functions 
in a diverse set of mitotic processes.  It is expected to have potential application across a 
broad range of human tumors, given the central role of mitosis in the progression of virtually 
all malignancies.  Indeed, alisertib has demonstrated activity against a broad range of both 
in vitro and in vivo nonclinical tumor models, as described briefly in Section 1.2.
1.2   
Nonclinical Experience
1.2.1   
In Vitro Pharmacology
Alisertib is an ATP-competitive and reversible inhibitor of Aurora A kinase in vitro with an 
inhibition constant (Ki) of 0.43 nM.(2)  The data from both enzymatic and cell-based assays 
demonstrated that alisertib is a selective and potent inhibitor of Aurora A kinase.(2, 3, 4, 5, 6)  
Alisertib (administered as the salt form MLN8237-004 or as the free acid MLN8237-001) 
inhibited proliferation of a wide variety of tumor cell lines grown in culture.(7)  Moreover, 
treatment of tumor cell lines with alisertib induced phenotypes consistent with Aurora A 
kinase inhibition, including mitotic spindle defects, mitotic delay, and apoptosis.(3, 7, 8, 9, 10, 11, 
12, 13)  For further details, refer to the Investigator’s Brochure (IB).
1.2.2   
In Vivo Pharmacology
Alisertib demonstrated antitumor activity when administered orally on a daily basis for 
approximately 21 days (maximal tumor growth inhibition [TGI] 90%) in several 
experimental solid and hematologic human tumor models grown as xenografts in 
immunocompromised mice.(14, 15, 16, 17, 18, 19, 20)  The maximally efficacious dose 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.(15)  A single oral dose of alisertib 


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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.(21)  The relationship 
between pharmacokinetics (PK), pharmacodynamics, and efficacy was further studied in 
HCT-116 xenografts using oral dosing and subcutaneous osmotic minipumps.(21)  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 1-M 
steady-state plasma concentrations.  Moreover, the maximally efficacious oral dose of 
alisertib in the HCT-116 model (30 mg/kg QD) resulted in plasma concentrations of 1 M 
for 8 to 12 hours postdose.  Plasma concentrations of alisertib associated with saturating 
levels of pharmacodynamic and antitumor activity (1 µM) were exceeded at the 
recommended phase 2 dose of alisertib in patients (50 mg BID).  For further details, refer to 
the IB.
1.2.3   
Safety Pharmacology and Toxicology
Safety pharmacology studies with alisertib did not identify significant adverse effects in 
nonclinical studies, including in the central nervous system (CNS) and cardiovascular 
systems.(22, 23)  No alisertib-related effects on clinical signs or physical examination findings 
indicative of impaired respiratory function (ie, 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.(24, 25, 26, 27)  Alisertib exhibited minimal activity against the human ether-à-go-go-
related gene current (concentration producing 50% inhibition and Ki 100 M).(28)  
Alisertib (administered as the free acid, MLN8237-001) had in vitro activity against the 
gamma aminobutryic acid alpha 1 benzodiazepine binding site (Ki 290 nM).(29)
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.(24, 25, 
26, 27)  Principal findings in toxicology studies in rats and dogs included gastrointestinal (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.(30)  No off-target effects were 
seen in the GLP-compliant toxicology studies.


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When tested for genotoxicity, alisertib was negative for mutagenicity using the bacterial 
reverse mutation assay (Ames assay) both in the absence and presence of Aroclor
1254-induced rat liver S9 fractions.(31)
In a rat bone marrow micronucleus assay, alisertib was considered to be equivocal for 
clastogenicity.(32)  For further details, refer to the IB.
1.3   
Clinical Experience
Clinical experience to date includes 20 company-sponsored clinical studies of alisertib that 
are in progress or have been completed, as follows:  11 single-agent phase 1 studies (Studies 
C14001, C14002, C14003, C14010, C14013, C14014, C14015, C14017, C14019, 
TB-MA010030, and TB-MA010033); 3 single-agent phase 2 studies (Studies C14004, 
C14005, and C14006); 1 single-agent phase 1/2 study (Study C14007); 1 single-agent 
phase 3 study (Study C14012); and 4 combination studies (Studies C14008 [phase 1/2] with 
paclitaxel, C14009 [phase 1] with docetaxel, C14011 [phase 1/2] with either rituximab or 
rituximab + vincristine, and C14018 [phase 2] with paclitaxel).
As of 29 March 2014, a total of 1103 patients have received alisertib in company-sponsored 
studies.  The clinical safety data include experience from patients who received multiple 
cycles followed by treatment-free periods between each cycle, and experience from patients 
who reduced or discontinued treatment.  Drug abuse, dependency, and drug withdrawal 
effects were not observed in the available clinical data.
Adverse events (AEs) observed as of 29 March 2014 are generally reversible, dose 
dependent, and consistent with the pharmacologic profile of alisertib as an antimitotic agent 
with predominant effects in proliferative tissues.  Adverse events were generally 
manageable with standard medical intervention and dose reduction as needed.  The more 
commonly observed (30% incidence) treatment-emergent AEs (TEAEs) from pooled data 
across the alisertib single-agent studies include neutropenia (47%), fatigue (46%), anemia 
(45%), diarrhea (42%), alopecia (35%), nausea (32%), and stomatitis (31%).  The more 
commonly observed (30% incidence) treatment-emergent AEs (TEAEs) from Study
C14008 of alisertib plus paclitaxel include neutropenia (71%), diarrhea (69%), 
fatigue (63%), stomatitis (57%), anemia (52%), nausea (51%), alopecia (47%), constipation 
(34%), vomiting (32%), leucopenia (31%), and abdominal pain (30%).  When compared to 
patients treated with alisertib alone, patients treated with alisertib plus paclitaxel 
experienced a greater frequency of Grade 3 treatment-related neutropenia, stomatitis, and 


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diarrhea.  For alisertib plus paclitaxel the frequency was: neutropenia (62%), stomatitis
(19%), and diarrhea (7%), and for alisertib alone the frequency was: neutropenia (38%), 
stomatitis (9%), and diarrhea (3%). No unanticipated toxicities were reported, and no 
increased rate of peripheral neuropathy when alisertib was added to paclitaxel.
The predominant toxicities reflect the mechanism of action in proliferating tissues (bone 
marrow, gastrointestinal epithelium, and hair follicles).  The suggested management of these 
toxicities is based on standard clinical paradigms for an antiproliferative chemotherapeutic 
agent.  Using a treatment-free period for recovery between each cycle of drug 
administration, the clinical experience from multiple phase 1 through 2 studies indicates that 
major toxicities can be managed to allow repeat treatment cycles over periods extending 
beyond 12 to 24 months.  Except for alopecia, the predominant toxicities are largely 
reversible, can be monitored by routine clinical examinations, and are manageable by dose 
reduction or supportive care.
Central nervous system effects, including transient dose-dependent somnolence and 
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 in recent studies that administered alisertib with divided 
doses (eg, BID), a schedule designed to reduce peak plasma levels while maintaining overall 
area under the plasma concentration versus time curve (AUC).  Overall, CNS effects were 
generally reversible and manageable by dose delay or reduction, and some patients have 
been managed by dose reduction of other sedative medications.
Following oral administration of alisertib as the enteric-coated tablet (ECT) formulation, 
peak concentrations of alisertib were generally achieved by 3 hours postdose.  The terminal 
half-life (t1/2) 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.  Alisertib is 
metabolized by multiple cytochrome P450 (CYP) isozymes (CYP3A4, 2C8, 2C9, 2C19, and
1A2) and uridine diphosphate-glucuronosyltransferase (UGT) isozymes (UGT1A1, 1A3, 
and 1A8). Based on preliminary results of a population PK analysis in 363 adult cancer 


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patients, the apparent oral clearance (CL/F) of alisertib was unaffected by age, body weight, 
body surface area (BSA), or UGT1A1 genotype (number of *28 alleles).
In Study C14008 the effect of alisertib on paclitaxel PK was assessed at the Western
recommended phase 2 dose (RP2D) of 40 mg BID of alisertib plus 60 mg/m2 of paclitaxel.
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-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.
Pharmacokinetic data are available from 3 completed single-agent, phase 1 studies designed 
to evaluate the safety, tolerability, and PK of alisertib in Asian patients (22 Japanese patients 
[TB MA010030 and TB-MA010033], and 34 East Asian patients [C14013]).  Across a total 
of 56 patients from these 3 phase 1 studies in Asian patients, the geometric mean dose-
normalized steady-state AUC was 67% higher than the corresponding geometric mean dose-
normalized steady-state AUC in the Western population (N = 363). Consistent with these 
PK results, the maximum tolerated dose (MTD) of single-agent alisertib in East Asian 
patients was determined to be 30 mg BID and is 40% lower than the Western MTD of 50 
mg BID.
Further details on alisertib clinical experience are provided in the IB.
1.4   
Disease Under Treatment
1.4.1   
Epithelial Ovarian Cancer Epidemiology and Treatment
Ovarian cancer (OC) continues to be the leading cause of death from gynecological 
malignancies and ranks as the fourth most common cause of cancer mortality in women.  In 
2010, more than 9900 new cases of OC were reported in Japan, with over 4600 deaths 
estimated by Center for Cancer Control and Information Services, National Cancer Center, 
Japan.(33)  Unfortunately, in most patients, OC is diagnosed at advanced stages, indicating 
spread beyond the pelvis at the time of diagnosis.  Disease dissemination results in 
significant morbidity and impaired survival in comparison with those who have disease 
diagnosed while it is still confined to the ovaries (Stage I), in whom over 90% survival can 


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be achieved largely with surgical intervention.  Patients with advanced-stage disease have 5-
year overall survival (OS) rates ranging from 20% to 30%.
Systemic treatments commonly employ a combination of platinum and taxane 
chemotherapy.  Strategies incorporating biological and targeted agents continue to evolve.  
Unfortunately, most (up to 70%) patients who present with advanced-stage disease exhibit 
recurrent or persistent disease following primary treatment.  
1.4.2   
Small Cell Lung Cancer
The annual estimation of lung cancer incidence in Japan is about 107,000.(33)  Small cell 
lung cancer (SCLC) accounts for approximately 13% to 15% of all lung cancers diagnosed, 
representing around 15,000 in Japan.(34, 35, 36)  This is a devastating disease where patients 
are rarely cured and the long-term survival rate (beyond 5 years) is dismal at less than 
5%.(37)
SCLC is an aggressive malignant disease. At the time of diagnosis, 70% of patients will 
have extensive-stage (ES)-SCLC, and for these patients the prognosis is poor, with a median 
survival of 8 to 10 months and less than 10% surviving 2 years after standard first-line 
treatment.(34)
Platinum-based combinations are the accepted first-line therapy for SCLC.  Despite being 
initially chemosensitive with response rates of around 60% to 80%, relapse is almost 
universal; of the limited-stage (LS)-SCLC patients, approximately 85% will relapse, and for 
the ES-SCLC patients, almost all patients will relapse.  Topotecan is the accepted standard 
treatment for relapsed patients worldwide and is the only drug that has regulatory approval 
in the EU and the US for second-line therapy.  Paclitaxel has also shown activity in the 
resistant relapse population and its use as an active agent for this disease is supported by the 
NCCN and ESMO guidelines. (38, 39, 40, 41)
1.5   
Study Rationale
In experimental system, modulation of Aurora kinase activity in ovarian or other cancer 
models has been studied, including work with taxane combination treatments with tumor
cells in vitro and in vivo xenografts.(42) These experiments generally demonstrated tumor 
cell apoptosis and delay or regression in xenograft models. Blockade of Aurora kinase 
signaling enhanced the antitumor activity of chemotherapy, including taxanes in OC 
models.(43, 44, 45) Targeting the mitotic apparatus by 2 complementary mechanisms of action 


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by combining alisertib with a known active agent such as paclitaxel is a rational approach to 
treating patients.
The phase 1 dose ranging portion of Study C14008, a phase 1/2 study of the combination of 
alisertib and paclitaxel in patients with advanced ovarian and breast cancer, has been 
completed.  The combination was found to be tolerable, with manageable toxicity and 
without occurrence of unknown or unexpected toxicities.  A RP2D of alisertib 40 mg BID 
(3 days on/4 days off for 3 weeks) on Days 1 through 3, 8 through 10, 15 through 17 plus 
paclitaxel 60 mg/m2 on Days 1, 8, and 15 in a 28-day cycle was determined.  Preliminary 
results in 49 patients enrolled in the phase 1 portion showed objective responses in 17 
(44%) patients (11 with OC and 6 with breast cancers), including 1 complete response (CR)
and 16 partial responses (PR). This combination is being investigated in 2 randomized 
phase 2 studies including the phase 2 portion of Study C14008 in relapsed/refractory OC 
patients and Study C14018 in relapsed/refractory SCLC patients.
The present study is an open-label, phase 1b, dose-finding study of alisertib combined with 
60 mg/m2 weekly paclitaxel to be conducted in East Asian patients (ie, patients from 
countries including but not limited to Japan, Taiwan, and South Korea) with advanced solid 
tumors.  The MTD/RP2D of alisertib combined with weekly paclitaxel was determined in 
Western patients in Study C14008.  As discussed in the following section, single-agent 
phase 1 studies of alisertib in East Asian/Japanese patient populations have indicated that 
systemic exposures of alisertib are approximately 70% higher than in Western patient 
populations, translating to a 40% lower single-agent MTD in East Asian patients compared 
to Western patients.  The MTD of alisertib in combination with 60 mg/m2 weekly paclitaxel 
in East Asian patients has not yet been determined.  Based on the observed PK and dose 
differences between East Asian/Japanese and Western populations for single-agent alisertib, 
it can be expected that the MTD of alisertib in combination with paclitaxel would be lower 
than that determined for this combination in Western patients in Study C14008.  
Accordingly, this study is intended to characterize the PK, safety, and tolerability and to 
determine the MTD/RP2D of alisertib in combination with 60 mg/m2 weekly paclitaxel in 
East Asian patients to support global clinical development.
1.6   
Dose Rationale
In Study C14008, the RP2D of alisertib combined with weekly paclitaxel in Western 
patients was alisertib 40 mg BID on Days 1-3, 8-10, and 15-17 plus paclitaxel 60 mg/m2 on 
Days 1, 8, and 15 in a 28-day cycle.  While no new or unanticipated toxicities were reported 


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in the combination arm, there was an increased incidence for some AEs, including 
neutropenia, diarrhea, and stomatitis with a higher incidence of Grade 3 or higher treatment 
related AEs of neutropenia and stomatitis.
Preliminary alisertib PK data in Japanese/East Asian patients across 3 phase 1 studies 
(TB-MA010030 and TB-MA010033 in Japanese patients; C14013 in East Asian patients of 
Chinese and Korean races) have indicated approximately 70% higher dose-normalized 
systemic exposure to single-agent alisertib when compared with exposures in Western 
patients.  Therefore, an alisertib dose of 20 or 25 mg BID in East Asian patients is expected 
to achieve exposures comparable to the range of exposures achieved in the Western 
population at the MTD/RP2D of the combination (ie, 40 mg BID alisertib plus 60 mg/m2
paclitaxel).  Escalation beyond 25 mg BID is not expected to be necessary in the dose 
escalation part of this combination study as higher alisertib doses in the East Asian patient 
population would be expected to result in systemic exposures higher than those observed at 
the Western MTD/RP2D of 40 mg BID.  However, if alisertib exposures in the combination 
setting in the East Asian population are unexpectedly lower than anticipated from 
single-agent experience in East Asian patients, and no DLTs have occurred in the dose level
(DL) 2 cohort (alisertib 25 mg BID plus 60 mg/m2 paclitaxel), the alisertib dose may be 
escalated further following discussion between the investigator and the sponsor pending PK 
and safety assessment.
The dose of paclitaxel will remain constant throughout the study and will be administered 
IV at a dose of 60 mg/m2 on Days 1, 8, and 15 in 28-day cycles.  In Study C14008, 
escalation beyond 10 mg BID alisertib was limited by overlapping antiproliferative 
mechanistic toxicities (eg, myelosuppression) when alisertib was added to 80 mg/m2 weekly 
paclitaxel.  Based on preliminary PK results, exposures of alisertib achieved at 10 mg BID 
in combination with 80 mg/m2 weekly paclitaxel (administered on Days 1, 8, and 15 in 28-
day cycles) were below the pharmacodynamically active range of exposures based on prior 
understanding of the exposure-tumor pharmacodynamics relationship for single-agent 
alisertib.  Based on these considerations, a dose of 60 mg/m2 weekly paclitaxel will be used 
in this study.
1.7   
Potential Risks and Benefits
In company-sponsored studies as of 29 March 2014, 1103 patients have been treated with 
alisertib.  The clinical safety data include experience from patients who received multiple 
cycles followed by treatment-free periods between each cycle, and experience from patients 


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who reduced or discontinued treatment.  Drug abuse, dependency, and drug withdrawal 
effects were not observed in the available clinical data.
To date, the observed risks associated with alisertib treatment, as detailed in Section 6 and 
the Safety Management Attachment to the IB, include (1) reversible myelosuppression, 
including leukopenia, neutropenia, febrile neutropenia, lymphopenia, thrombocytopenia, and 
anemia; (2) GI toxicity, including stomatitis/mucositis/oral pain, nausea, vomiting, anorexia, 
abdominal pain, dyspepsia, diarrhea, and dehydration; (3) sedation, somnolence, confusional 
state, disorientation (and associated memory loss), and gait disturbances; (4) alopecia; 
(5) asthenia/fatigue; (6) fever; (7) infection; (8) abnormal liver function tests, including 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, alkaline 
phosphatase (ALP), and gamma glutamyl transferase (GGT); and (9) skin disorders 
(eg, rash, which may include bullous dermatitis) and palmar-plantar erythrodysaesthesia 
syndrome.  One case of hepatic veno-occlusive disease has also been observed.
To mitigate the inherent risks in clinical studies of alisertib, patients are evaluated frequently 
while they are receiving treatment.
For details regarding management of specific clinical events, refer to Section 6.5.
2.   
STUDY OBJECTIVES
2.1   
Primary Objectives
The primary objectives are:

To evaluate the safety and tolerability and determine the MTD to subsequently 
define an RP2D of alisertib in combination with weekly paclitaxel in East Asian 
patients with advanced solid tumors

To characterize the PK of alisertib and paclitaxel in the combination setting in East
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2.2   
Secondary Objective (For Expansion Only)
The secondary objective is:

To identify initial signs of antitumor activity in patients with relapsed/refractory OC 
or SCLC
3.   
STUDY ENDPOINTS
3.1   
Primary Endpoints
The primary endpoints are:

AEs, serious adverse events (SAE)s, assessment of clinical laboratory values and 
vital sign measurements – dose escalation and dose expansion

PK parameters of alisertib, including but not limited to, maximum plasma 
concentration (Cmax), first time of occurrence of maximum (peak) concentration
(Tmax) and area under the plasma concentration versus time curve zero to the next 
dose (AUC0-τ); PK parameters of paclitaxel, including but not limited to, Cmax, area 
under the plasma concentration versus time curve zero to the time of the last 
measurement (AUC0-tlast), area under the plasma concentration versus time curve
from zero to infinity(AUC0-inf) (if data permit), and t1/2 (if data permit), when 
administered alone and during concomitant administration of alisertib – dose 
escalation and dose expansion
3.2   
Secondary Endpoint
The secondary endpoint is:

Disease response based on the Response Evaluation Criteria in Solid Tumors 
(RECIST) version 1.1 overall response rate (ORR) (CR + PR) - dose expansion only


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4.   
STUDY DESIGN 
4.1   
Overview of Study Design
This is an open-label, multicenter, phase 1b study to evaluate the safety, tolerability, and PK 
of alisertib in combination with weekly paclitaxel in East Asian patients.  The study is in 
2 parts: the first part is a dose escalation to determine the MTD and define the RP2D of the 
alisertib plus paclitaxel combination in East Asian patients with advanced solid tumors; the 
second part is an expansion cohort at the RP2D of the alisertib plus paclitaxel combination 
in East Asian patients with either OC or SCLC.
It is expected that approximately 30 patients will be enrolled into this study.  Alisertib will 
be administered orally 3 days on/4 days off for 3 weeks on Days 1 through 3, 8 through 10, 
and 15 through 17 in 28-day cycles.  Paclitaxel 60 mg/m2 IV will be administered on 
Days 1, 8, and 15 in 28-day cycles.  The paclitaxel dose will remain constant throughout the 
dose escalation and expansion parts of this study.  
Enrolled patients may receive study drug until observed progression, need of discontinuation 
because of toxicity, lost to follow-up, study is terminated by the sponsor, protocol violation, 
unsatisfactory therapeutic response, or voluntary withdrawal by the patient from the study.  
Patients may discontinue therapy at any time.  Patients will attend the End of Treatment visit 
30 days after receiving their last dose of study drug.
A dose escalation (3 + 3 schema) will be used to determine the MTD and the RP2D of the 
combination (as detailed in Section 6.4), which will be further evaluated in the expansion 
part of the study.  The starting dose will be 15 mg BID alisertib (DL1); the next planned 
dose level is 25 mg BID alisertib (DL2).  If ≥ 2 patients experience a DLT at 25 mg, alisertib 
will be de-escalated, and an intermediate dose level of alisertib 20 mg BID (DL3-
intermediate) will be explored.  The MTD/RP2D will require first-cycle DLTs in not more 
than 1 in 6 DLT-evaluable patients enrolled in a given dose level.  If ≥2 of the first 6
patients experience a DLT at DL1, depending on the overall safety profile, the type of
AEs/DLTs observed, and the available PK data, a decision will be made either to expand the 
15 mg BID alisertib (DL1) cohort with 6 additional patients, or to de-escalate the alisertib 
dose to 10 mg BID (DL-1), or to terminate the study.  In the case of an expansion of the 
DL1 cohort, a tolerable dose will then require first-cycle DLTs in no more than 3 of 12 
DLT-evaluable patients to confirm the MTD.  If alisertib exposures in the combination 
setting in the East Asian population are unexpectedly lower than anticipated from single-
agent experience in East Asian patients, and no DLTs have occurred in the DL2 cohort 


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(alisertib 25 mg BID plus 60 mg/m2 paclitaxel), the alisertib dose may be escalated further 
following discussion between the investigator and the sponsor pending PK and safety 
assessment. Should more data be needed to better understand the observed safety and/or 
PK, with the agreement of the sponsor’s project clinician (or designee), cohort(s) at any dose 
level may be expanded. Intrapatient dose escalation will not be permitted in this study. It is 
planned that at least 1 Japanese patient will be included in each of the dose levels explored.
The effect of concomitant administration of alisertib on paclitaxel PK will be evaluated in 
this study.  To this effect, alisertib doses will be held on Days 1 through 3 in Cycle 2 so that 
paclitaxel PK can be evaluated, in the absence of alisertib, following paclitaxel dose 
administration on Cycle 2, Day 1.  Paclitaxel PK data on Cycle 2, Day 1 will serve as a 
reference for comparison with paclitaxel PK, evaluated at Cycle 1, Day 1 in the presence of 
alisertib.  During the dose escalation and expansion part, for Cycle 2 only, patients will 
receive 12 doses of alisertib, administered BID on Days 8 through 10 and 15 through 17.  
The effect of alisertib on paclitaxel PK will be assessed in a minimum of 12 patients who 
complete protocol-specified dosing and PK measurements in the first 2 treatment cycles at 
the RP2D of the combination (dose escalation and expansion part).  Blood draws will be 
taken as detailed in the Schedule of Events and Section 7.4.17.
Pharmacokinetics of alisertib will be evaluated on Days 1 and 3 in Cycle 1 for both the dose 
escalation and expansion parts of the study.  Blood draws will be taken as detailed in the 
Schedule of Events and Section 7.4.17.
An MTD should be established and then a RP2D will be defined based on all relevant 
considerations/parameters (eg, safety, tolerability, and PK).
After dose escalation has completed, a minimum of 12 patients with relapsed/refractory OC 
or SCLC will be enrolled into the dose expansion part of the study.  During dose expansion, 
safety, tolerability, and initial signs of activity at the RP2D will be evaluated.
Toxicity will be evaluated according to National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), version 4.03, effective date 14 June 2010.(1)  
Dose-limiting toxicities (DLTs) are defined in Section 6.3.
Adverse events will be assessed, and laboratory values, vital signs, and electrocardiograms 
(ECGs) will be obtained to evaluate the safety and tolerability of alisertib in combination 
with paclitaxel.


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Patients cannot have received antineoplastic therapy or radiotherapy within the 3 weeks 
before enrollment (14 days for regimens with recovery expected within 7-14 days).  
For all patients, scans (ie, CT and/or MRI) will be read locally. The investigator-assessed 
CR + PR (based on RECIST 1.1 criteria) will be used for efficacy assessment.
4.2   
Number of Patients
Approximately 30 patients will be enrolled in this study, including a minimum of 12 patients 
with epithelial OC and SCLC (combined) in the expansion cohort.  
There will be approximately 2 to 3 study centers in the escalation part and approximately 10 
study centers in the expansion part.  All study centers will be in East/North Asia and will 
include 2 sites in Japan.  A patient is considered enrolled in the study when the patient 
receives the first dose of alisertib.
For MTD assessment, patients who are withdrawn from treatment during Cycle 1 for 
reasons other than DLTs will be replaced.
4.3   
Duration of Study
Patients, including those who achieve a CR, may receive alisertib plus paclitaxel until they 
experience disease progression.  Patients will discontinue treatment if they have an 
unacceptable alisertib plus paclitaxel-related toxicity.  The maximum duration of treatment, 
however, will be 12 months unless it is determined that a patient would derive benefit from 
continued therapy beyond 12 months.
Patients will be followed for 30 days after the last dose of alisertib plus paclitaxel or the start 
of subsequent anticancer therapy to permit the detection of any delayed treatment-related 
AEs.  The pharmacokinetic analyses will be conducted after all patients enrolled in the study 
have had the opportunity to complete 2 cycles of treatment with alisertib plus weekly 
paclitaxel. The final analysis for the clinical study report will be conducted after all patients 
enrolled in the study have had the opportunity to complete 1 year of treatment with alisertib 
plus weekly paclitaxel or discontinue the study treatment.
It is anticipated that this study will last for approximately 24 months.  The study will be 
closed once all the enrolled patients in the expansion part complete or discontinue from the 
study.


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5.   
STUDY POPULATION
5.1   
Inclusion Criteria
Each patient must meet all of the following inclusion criteria to be enrolled in the study:
1. Male or female patients 18 years or older (or minimum age of legal consent 
consistent with local regulations) at the time written study informed consent is
obtained.
2. Patients of East Asian ethnicity (eg, Chinese, Japanese, or Korean).
3. Patients must have a diagnosis of a solid tumor malignancy (escalation part) or
relapsed or refractory OC or SCLC (expansion part).

Patients in the expansion cohort must have a pathologically (histology or 
cytology) confirmed diagnosis of either OC (including recurrent epithelial 
ovarian, fallopian tube, or primary peritoneal cancer) or SCLC, which is 
measurable disease as per RECIST, version 1.1.

Patients in the expansion cohort must not have received more than 2 prior taxane-
containing regimens.
4. No antineoplastic therapy (eg, drugs, biologicals, monoclonal antibodies, etc) or 
radiotherapy within the 3 weeks before enrollment (14 days for regimens with 
recovery expected within 7 to 14 days).  The patient must have recovered 
(ie, Grade 1 toxicity or patient’s baseline status, except alopecia) from all 
treatment-related toxicities.  
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Section 
14.1).
6. Adequate bone marrow function as defined by:

Absolute neutrophil count (ANC) ≥1,500 cells/mm3 (without need for growth 
factor support).

Platelet count ≥100,000 cells/mm3 (without need for transfusion or growth factor 
support).


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
Hemoglobin level ≥9 g/dL.
7. Adequate liver function as defined by:  

Bilirubin < 1.5 times the upper limit of normal (ULN)

ALT and AST ≤ 2.5 ULN (≤ 5 x ULN if due to liver metastases)

Serum albumin equal to or greater than the lower limit of normal 
8. Adequate renal function as defined by:  

Creatinine < 1.5 × institutional ULN or estimated creatinine clearance using the 
Cockcroft-Gault formula ≥ 30 mL/minute for patients with creatinine levels 
above institutional ULN (can be calculated using serum creatinine value; see 
Section 14.3).
9. Patients must have received at least 1 prior chemotherapy regimen, but no more than 
2 previous chemotherapy regimens for the advanced and/or metastatic stage disease.
The neo-adjuvant chemotherapy or post-surgical adjuvant chemotherapy for 
early-stage disease would not be counted.
10. Female patients who:

Are postmenopausal for at least 1 year before the screening visit, OR

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception, at the same time, from the time of signing the informed consent 
through 30 days after the last dose of study drug

Adhere to any treatment-specific pregnancy prevention guidelines for paclitaxel
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment 
period and through 4 months after the last dose of study drug

Adhere to any treatment-specific pregnancy prevention guidelines for paclitaxel.


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11. Voluntary written consent must be given before performance of any study-related 
procedure not part of standard medical care, with the understanding that consent may 
be withdrawn by the patient at any time without prejudice to future medical care.
12. Suitable venous access for the study-required blood sampling, including PK.
13. Ability to swallow tablets.
5.2   
Exclusion Criteria
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Patients with carcinomatous meningitis.
2. Patients with symptomatic and/or progressive brain metastases or treatment with 
brain edema.
3. Known hypersensitivity to Cremophor® EL, paclitaxel, alisertib or their components.
4. Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent, 
including alisertib in any setting.
5. Prior history of ≥ Grade 2 neurotoxicity or any toxicity requiring discontinuation 
from taxane chemotherapy that is not resolved to ≤Grade 1.
6. Patients who received prior weekly taxane-based therapy with early disease 
progression during or within 1 month of completing therapy (refractory disease).
7. Any comorbid condition or unresolved toxicity that would preclude administration of 
weekly paclitaxel.
8. Systemic treatment with moderate or strong CYP3A inhibitors must be discontinued 
at least 14 days before the first dose of alisertib, and the use of these agents is not 
permitted during the study.
9. Known GI abnormality (including recurrent nausea or vomiting) or GI procedure that 
could interfere with or modify the oral intake, absorption, or tolerance of alisertib.
10. Patients requiring treatment with clinically significant enzyme inducers, such as the 
enzyme-inducing antiepileptic drugs phenytoin, carbamazepine, phenobarbital, 
oxcarbazepine, primidone, rifampin, rifabutin, rifapentine, or St. John’s wort within 


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14 days before the first dose of alisertib or requiring the use of these medications 
during the study.
11. Requirement for administration of proton pump inhibitor (PPI), H2 antagonist
(premedication for paclitaxel allowed), or pancreatic enzymes.  Use of any PPI in 
either continued or intermittent use will be prohibited during the conduct of the study 
and patients must not use a PPI within 5 days of the first dose of alisertib.
12. Life-threatening or severe CNS, pulmonary, renal, or hepatic disease unrelated to 
cancer, or any serious medical or psychiatric illness that could, in the investigator’s 
opinion, potentially interfere with the completion of treatment according to this 
protocol.
13. Treatment with any investigational products within 5 half-lives before the first dose 
of study drug.
14. Treatment with fully human or chimeric monoclonal antibodies within 42 days 
before the first dose of study drug (21 days if clear evidence of progression).
15. Major surgery within 14 days before the first dose of study drug.
16. Infection requiring systemic intravenous (IV) antibiotic therapy within 14 days 
preceding the first dose of study drug, or other severe infection.
17. Known human immunodeficiency virus (HIV) positive.
18. Known hepatitis B surface antigen seropositive or detectable hepatitis C infection 
viral load. Note: Patients who have positive hepatitis B core antibody can be enrolled 
but must have an undetectable hepatitis B viral load. Patients who have positive 
hepatitis C antibody must have an undetectable hepatitis C viral load.
19. History of myocardial infarction, unstable symptomatic ischemic heart disease, 
uncontrolled hypertension despite appropriate medical therapy, or cardiac 
arrhythmias, thromboembolic events (eg, deep vein thrombosis, pulmonary 
embolism, or symptomatic cerebrovascular events), or any other cardiac condition 
(eg, pericardial effusion or restrictive cardiomyopathy) within 6 months before 
receiving the first dose of study drug.  Chronic stable atrial fibrillation on stable 
anticoagulant therapy is allowed.  Patients with a pacemaker may be enrolled in the 
study upon discussion with the project clinician.


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20. Female patients who are in the lactation period or have a positive serum pregnancy 
test during the Screening period or a positive urine pregnancy test on Day1 before
the first dose of study drug.  
21. Diagnosed with or treated for another malignancy within 3 years before the first dose 
of study drug, or previously diagnosed with another malignancy and have any 
evidence of residual disease.  Patients with non-melanoma skin cancer or carcinoma 
in situ of any type may be enrolled in the study if they have undergone complete 
resection and no evidence of active disease is present.  
6.   
STUDY DRUG
6.1   
Study Drug Administration
All protocol-specific criteria for administration of study drug must be met and documented 
prior to drug administration.  Study drug will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s).
Alisertib will be administered orally 3 days on/4 days off for 3 weeks on Days 1 through 3, 8
through 10, and 15 through 17 in 28-day cycles.  Alisertib dosing during Cycle 1 will begin 
at Cycle 1, Day 1, the same day as the first dose of paclitaxel; alisertib will be administered 
1 hour before the start of the paclitaxel infusion.  In Cycle 2, alisertib doses will be held on 
Days 1 through 3.  During the dose escalation and expansion part, for Cycle 2 only, patients 
will receive 12 doses of alisertib, administered BID on Days 8 through 10 and 15 through 17
to permit PK assessment of paclitaxel alone up to 48 hours (Alisertib and Paclitaxel PK 
Sampling Schedule).  Alisertib dosing in all subsequent cycles (Cycle 3 and beyond) will 
begin on Day 1.  
Patients will be instructed to take each PO dose of alisertib with 8 ounces (1 cup, 240 mL) of 
water.  The 2 daily doses must be taken at least 6 hours apart.  Alisertib should be 
administered on an empty stomach in the first 3 days of Cycle 1 (no food from 2 hours 
before the dose until 1 hour after the dose). Patients should be instructed to take their 
alisertib study medication at approximately the same time each day, approximately 12 hours 
apart (eg, 08:00 and 20:00) but not less than 6 hours apart, and not to take more than the 
prescribed dose at any time.  Patients should swallow the study medication whole and not 
chew it before swallowing.  


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Alisertib will be supplied as 10- and 15-mg ECTs with the dose strength expressed as 
milligrams of active drug (free acid); other 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.  Anti-emetogenic 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 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 subinvestigator(s).
6.2   
Reference/Control Therapy
6.2.1   
Paclitaxel
Paclitaxel will be administered as an IV infusion over at least 1 hour (but not more than 
90 minutes) with a dose of 60 mg/m2 on Days 1, 8, and 15 in 28-day cycles. On Cycle 1, 
Day 1 and Cycle 2, Day 1, the paclitaxel dose should be administered over 60 minutes (it 
must not be less than 60 minutes, but may be up to 70 minutes maximum, where necessary).
The paclitaxel dose will remain constant throughout the study.  The paclitaxel infusion time 
is 1 hour; the infusion time may be modified if required after review and agreement by the 
project clinician.  Refer to the paclitaxel product label for further details regarding paclitaxel 
administration.
6.2.2   
Premedication for Paclitaxel-Associated Hypersensitivity or Other Acute 
Reactions
Premedication to prevent paclitaxel-associated (hypersensitivity or other) reactions is 
recommended according to institutional guidelines or local practices.  Premedications that 
may be used in this setting can include:  corticosteroid (eg, dexamethasone, as a 20-mg 
single dose, which can be reduced with subsequent paclitaxel cycles); diphenhydramine; a 
5-hydroxytryptamine 3 (5-HT3) serotonin receptor antagonist antiemetic administered at its 
labeled dose.  Benzodiazepines are to be avoided.  Brief administration of histamine-2 
antagonists (such as a single dose of cimetidine or ranitidine) is allowed if required on the 
day of paclitaxel administration, but prolonged administration of a histamine-2 antagonist 
(or any other agent that can alter stomach pH or drug absorption) is to be avoided (see 
Section 6.6).  Modifications to paclitaxel administration are allowed upon agreement by the 
project clinician and will be documented in the electronic case report form (eCRF).


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6.3   
Definitions of Dose-Limiting Toxicity
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective 
14 June 2010.(1)  These criteria are provided in the Study Manual.  Dose-limiting toxicity
will be defined as any of the following events that are considered by the investigator to be at 
least possibly related to therapy with alisertib plus paclitaxel.  See also Section 6.5.3 for 
toxicities considered to be DLTs if they occur during the dosing period in the first cycle.
1. Grade 4 neutropenia (ANC 500 cells/mm3) lasting more than 7 consecutive days.
2. Grade 4 neutropenia associated with coincident fever (where fever is defined as an 
oral temperature ≥38.5°C).
3. Grade 4 thrombocytopenia lasting more than 7 consecutive days.
4. A platelet count 10,000/mm3 at any time.
5. Greater than or equal to Grade 3 thrombocytopenia with clinically significant 
bleeding.
6. Greater than or equal to Grade 3 nonhematological toxicity, with the following 
exceptions:

Grade 3 or greater nausea or emesis, or both, that occurs in the absence of 
optimal antiemetic therapy (5-HT3 serotonin receptor antagonist).

Grade 3 or greater diarrhea that occurs in the absence of optimal supportive 
therapy with loperamide.

Grade 3 fatigue that lasts less than 1 week.

Grade 3 nonhematological toxicity that can be controlled to Grade 2 or less with 
appropriate treatment (eg, Grade 3 hypertension will be considered a DLT only if 
the hypertension is unmanageable by standard approved pharmacological agents 
or if symptomatic sequelae are identified despite appropriate medical 
intervention).
7. Greater than or equal to Grade 2 nonhematological toxicities that are considered by 
the investigator to be related to study drug and in the opinion of the investigator 
require dose reduction.


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8. Delay in the initiation of the subsequent cycle of therapy by more than 10 days due 
to treatment-related toxicity. 
Although DLTs may occur at any point during treatment, only DLTs occurring during 
Cycle 1 of treatment during the dose escalation part of this study will necessarily influence 
decisions regarding dose escalation, expansion of a dose level, or evaluation of intermediate 
dose levels or alternative schedules.  
Patients experiencing DLTs in Cycle 1 may continue in the study provided they are deriving 
clinical benefit but will have doses of alisertib and/or paclitaxel reduced as appropriate.
6.4   
Dose Escalation Rules
The dose escalation will follow the 3 + 3 traditional rules and dose intervals will follow the 
outline provided in Table 6-1.  Should more data be needed to better understand the 
observed safety and/or PK, with the agreement of the sponsor’s project clinician (or 
designee), cohort(s) at any dose level may be expanded. Intrapatient dose escalation is not 
planned and will not be permitted in this study. Patients who do not meet the DLT-
evaluable criteria in the dose-escalation part of the study will be replaced.  
Accrual and treatment will proceed according to the following rules:
1. The initial cohort will start with the treatment of 3 patients at DL1 (15-mg BID 
alisertib): 
-
If 0 of 3 patients experience a DLT, dose escalation will proceed to the next 
planned dose level (DL2 / 25-mg BID alisertib), at which 3 patients will be 
enrolled.
-
If 1 of 3 patients experiences a DLT, 3 more patients will be enrolled at that same 
dose level. Escalation will continue if no more than 1 of 6 patients experiences a 
DLT. 
-
If 2 or more patients experience DLT at DL1, depending on the overall safety 
profile and the type of AEs/DLTs observed, a decision will be made to either 
expand the 15-mg BID alisertib cohort with 6 additional patients, to de-escalate 
the alisertib dose to 10 mg BID (DL-1), or to terminate the study.  In the case of 
an expansion of the DL1 cohort, a tolerable dose will then require first-cycle 
DLTs in no more than 3 out of 12 DLT-evaluable patients to confirm MTD.


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2. At DL2 (25-mg BID alisertib):
-
If 0 of 6 patients experience a DLT AND if alisertib exposures in the 
combination setting in the East Asian population are unexpectedly lower than 
anticipated from single-agent experience in East Asian patients, the alisertib dose 
may be escalated further following discussion between the investigator and the 
sponsor. 
-
MTD declaration will require first-cycle DLTs in no more than 1 out of 6 DLT 
evaluable patients 
-
If 2 of 6 patients experience a DLT, alisertib will be de-escalated and an 
intermediate dose level of alisertib 20 mg BID (DL3-intermediate) will be 
explored.
3. At DL3 (20-mg BID alisertib)
-
MTD declaration will require first cycle DLTs in no more than 1 out of 6 DLT 
evaluable patients.  
-
If 2 or more of 6 patients experience a DLT, alisertib will be de-escalated to the 
DL1 (15-mg BID alisertib) and 3 additional patients will be enrolled at that dose 
level if there are not yet 6 patients enrolled.  
The RP2D regimen will be established following evaluation of the available data from the
dose escalation portion of the trial which will include, but is not limited to, DLTs, toxicity 
characterization (Grade 3/4 AEs, SAEs, toxicities leading to early dose reduction and 
treatment discontinuation).  For the purpose of the RP2D regimen, Cycle 1 PK data from 6 
evaluable patients will be used in addition to the available clinical data. AEs that meet DLT 
criteria in Cycle 2 and beyond will not necessarily influence dose escalation but will be 
considered when determining the RP2D regimen. Following discussions between the 
sponsor and the investigators, expansion of an existing dose level to confirm the safety of 
the dosing regimen is permissible if the nature of the DLTs and AEs allows further 
exploration. Upon review of available data and agreement on the RP2D by the sponsor and 
investigators, enrollment in the expansion portion of the study may begin. The dose 
expansion part of the study will further investigate the safety and tolerability of the RP2D 
that was determined during dose escalation.


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Table 6-1   
Alisertib Combined With Paclitaxel for Phase 1 Dose Escalation 
Cohort
Target Alisertib (PO) Dose and Schedule
Target Paclitaxel (IV)
Dose and Schedule
Starting Dose Level
1
15 mg BID for 3 days on/4 days off repeated 
weekly ×3 weeks in 28-day cycle
60 mg/m2 on Days 1, 8, 15
2
25 mg BID for 3 days on/4 days off repeated 
weekly ×3 weeks in 28-day cycle
60 mg/m2 on Days 1, 8, 15
3-intermediate
20 mg BID for 3 days on/4 days off repeated 
weekly ×3 weeks in 28-day cycle
60 mg/m2 on Days 1, 8, 15
-1
10 mg BID for 3 days on/4 days off repeated 
weekly ×3 weeks in 28-day cycle
60 mg/m2 on Days 1, 8, 15
Abbreviations:  IV = intravenous; PO = orally, by mouth.
6.5   
Dose-Modification Guidelines
Toxicity will be evaluated according to the NCI CTCAE, version 4.03, effective as of 
14 June 2010.  These criteria are provided in the Study Manual and are available online at 
ctep.cancer.gov/reporting/ctc.html.
NOTE:  Dose reductions for all events are permanent and should be for all subsequent 
cycles (ie, once a dose has been reduced, it cannot be re-escalated to a higher dose).
6.5.1   
Criteria for Beginning a Subsequent Treatment Cycle
For a new cycle of therapy to begin the following criteria must be met: 

ANC must be ≥ 1,500/mm3  

Platelet count must be ≥ 75,000/mm3

All other toxicity considered by the investigator to be related to therapy with alisertib 
(except alopecia) or paclitaxel must have resolved to ≤ Grade 1, or to a level 
considered acceptable by the physician, or to the patient’s baseline values before a 
new cycle of therapy may begin.

There has been a minimum rest period of 11 days and a maximum of 21 days since 
the last dose of study drug.


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6.5.2   
Criteria for Dose Interruption During a Cycle
If a patient experiences any of the following toxicities during the dosing period, dosing will 
be discontinued for the remainder of that cycle, or until recovery sufficient for completion of 
the cycle or the start of a new treatment cycle.  

Grade 3 neutropenia (ANC 1,000 cells/mm3)

Febrile neutropenia

Grade 3 thrombocytopenia (platelet count < 50,000/mm3) 

Greater than or equal to Grade 3 nonhematological toxicity, with the following 
exceptions:
o
Grade 3 or greater nausea, emesis, or both that occurs in the absence of optimal 
antiemetic therapy (5-HT3 serotonin receptor antagonist)
o
Grade 3 or greater diarrhea that occurs in the absence of optimal supportive 
therapy with loperamide
o
Grade 3 nonhematological toxicity that can be controlled to Grade 2 or less with 
appropriate treatment (eg, Grade 3 hypertension only if the hypertension is 
manageable by standard approved pharmacological agents) 

Greater than or equal to Grade 2 nonhematological toxicities that are considered by 
the investigator to be related to study drug and in the opinion of the investigator 
require dose interruption
Once the criteria for retreatment (Section 6.5) have been met (ANC>1000/mm3, platelet 
count>50,000/mm3), the patient may resume therapy for completion of the cycle.  If the Day 
8 or Day 15 doses of paclitaxel and alisertib (or paclitaxel alone if applicable) have been 
delayed through 2 additional days or less (eg, Monday delayed to Wednesday, but restart 
possible on Thursday), dosing should resume after the delay without omitting doses, and 
without dose reduction.  The subsequent dose of the cycle should preserve the same minimal 
days between doses within the cycle originally planned; thus, if the planned Day 8 dose is 
delayed but restarted on Thursday, then the next planned “Day 15” dose would be 
administered on the following Thursday to preserve a 7-day period between the Day 8 and 
Day 15 doses.


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If the Day 8 or Day 15 doses of paclitaxel and alisertib have been delayed through additional 
days due to lack of adequate recovery (eg, dosing originally planned for Monday delayed 
through Thursday, and restart only possible on Friday or later), both the paclitaxel dose and 
the 3 associated alisertib doses should be omitted within that cycle.  If the doses started on 
Day 15 are omitted, the cycle should preserve a minimum 2-week treatment-free period 
between the last dose of protocol treatment and the start of the new cycle.  When paclitaxel 
and alisertib are resumed, either on Day 15 or with the subsequent cycle, the doses of 
paclitaxel and/or alisertib should be modified with incremental reductions if appropriate (see 
Section 6.5.3).
6.5.3   
Dose Modifications
Patients who continue to experience any toxicity (hematologic or nonhematologic) of a 
severity that requires additional dose reductions after 1 dose reduction of paclitaxel and 
1 dose reduction of alisertib, given administration of appropriate supportive care, should 
discontinue protocol treatment.  However, if the patient has evidence of clinical benefit and 
would be considered to benefit from continued protocol treatment, the patient may continue 
protocol treatment with further dose reductions, upon review and written approval by the 
project clinician.  These circumstances should be discussed on a case-by-case basis.  
As a general rule, if a patient requires dose reduction due to a study drug-related toxicity, the 
drug dose may not be re-escalated. Similarly, if a patient requires elimination of alisertib on 
the last 3 days (Days 15, 16, and 17) (Table 6-2), as described previously, alisertib will only 
be dosed on the earlier cycle days as planned for all subsequent cycles. 
To manage hematologic or nonhematologic toxicities that require dose reductions, the dose 
modifications planned for this protocol will include the following:
Paclitaxel:  10-mg/m2 increment reductions from planned starting dose, administered on 
Cycle Days 1, 8, and 15.  An option for an additional dose reduction (40 mg/m2) may be 
possible in some situations described in the following.
Alisertib:  Either a 5-mg reduction from planned starting dose, administered on Cycle 
Days 1 through 3, 8 through 10, and 15 through 17, or an omission of doses on Days 15 
through 17, depending on the circumstance for adjustment (Table 6-2), with the option for 
further dose reduction in some situations described in the following.


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The decision regarding which study drug requires dose reduction will be dependent upon the 
toxicity, its onset, and time course.  For example, neuropathy has been related to paclitaxel,
but it has not been a frequent or dominant toxicity associated with alisertib.  Although 
somnolence can be observed from multiple causes in patients with advanced malignancy, it 
has been observed in some patients as a toxicity associated with high individual doses of 
alisertib, typically within the first few days of drug administration.  Thus, the dose of 
paclitaxel alone will be adjusted for dose-limiting nonhematologic toxicities such as 
neuropathy, and the dose of alisertib alone will be reduced for dose-limiting nonhematologic 
toxicities such as somnolence that is not due to other comorbidities.
Paclitaxel or alisertib will be individually reduced for dose-limiting hematologic toxicities 
that are attributable to both agents, such as sustained Grade 4 neutropenia, 
thrombocytopenia, or febrile neutropenia according to Table 6-2.  As a general approach to 
manage these hematologic toxicities which are also attributable to the taxane, paclitaxel 
should be first delayed and/or reduced before initiation of myeloid growth factors or before 
modification of alisertib, if applicable.  To manage dose-limiting neutropenia attributable to 
paclitaxel alone or to the combination with alisertib, the general goal is to avoid reducing 
alisertib dosing below a range considered to be clinically relevant.  Given these 
considerations, the first intervention will be dose reduction of paclitaxel by 10 mg/m2.  The 
next intervention would be to add myeloid growth factor if appropriate.  Only after 
intervention with myeloid growth factor, if appropriate, and in a situation of a repeat 
occurrence within dosing would the alisertib be reduced by 5 mg/dose. In the situation of a 
repeat occurrence of hematological toxicity after completion of dosing in a cycle, the last 3 
days of alisertib or placebo would be omitted.  If the treating physician (or investigator) 
believes that at a particular occurrence and due to the nature of the event or patient history, 
an intervention treatment that deviates from the described general guidelines is preferred, it 
should be discussed with and approved by the sponsor’s project clinician (or designee).
Prophylactic use of myeloid growth factors are not allowed for patients newly enrolled who 
receive the first cycle, but may be administered for supportive care to manage neutropenia 
events if clinically indicated, according to American Society of Clinical Oncology (ASCO) 
guidelines and/or institutional practices.  Thus, myeloid growth factors are not mandated, 
but if used per investigator discretion, they should be administered according to local 
guidelines, the product label, and Table 6-2.  During the first cycle of patients enrolled to the 
dose escalation part, the use of myeloid growth factors should be avoided unless DLT or 
dose interruption criteria have already been met.  Short acting myeloid growth factors are 


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preferred, and they should be discontinued for an appropriate number of days before restart 
of protocol treatment.
Alternative dose modifications may be recommended after discussion with the investigator 
and project clinician/designee to maximize exposure of study treatment while protecting 
patient safety.
Table 6-2   
Dose Modification Rules:  Hematological Toxicity 
Alisertib + Paclitaxel
First occurrence 
Reduce paclitaxel 1 level 
(eg, 60 mg/m2 to 50 mg/m2)
Repeat occurrence
Add myeloid growth factor without further dose 
modification, if appropriatea
Repeat occurrence within dosing period
(Days 1-17)
Reduce alisertib 1 level
(ie, a 5-mg reduction)a
Or
Repeat occurrence after dosing complete, 
during treatment-free period (Days 18-28)
Omit alisertib in last 3 days of schedule (ie, Days 15, 16, and 
17) but maintain the same alisertib doses for Days 1-3 and 
8-11 as administered on earlier cycles
Repeat occurrence 
Discontinueb 
Paclitaxel 40 mg/m2
AND/OR
Alisertib with 1 dose reduction level, omitting Days 15-17
Abbreviations: BID = twice daily.
a The use of myeloid growth factors is not mandated but is strongly encouraged as an intervention step for 
neutropenia before dose reduction of alisertib or further dose reduction of paclitaxel if appropriate.
b A patient may continue the protocol with further dose reductions (hematologic and nonhematologic 
toxicities) if he or she is deriving clinical benefit, upon review and written approval by the project 
clinician.  The actual doses to be administered in those situations are listed.  The decision to reduce only 
1 of the agents or both should be based on similar considerations regarding the type of adverse event at 
this time.  Note:  If after the first occurrence, the myeloid growth factor was not an option, the patient 
may continue the protocol with myeloid growth factor, if appropriate, before discontinuation.
No more than 1 dose reduction of paclitaxel will be allowed.  However, if the patient has 
clinical benefit and would benefit from continued protocol treatment, the patient may 
continue protocol treatment with further dose reductions, upon review and written approval 
by the project clinician. 
Dose Modifications for Nonhematologic Toxicities

Dose modifications with incremental reductions will be as described previously for 
hematologic toxicities; however, only the drug thought to be responsible for the 
toxicity should be reduced.  If both alisertib and paclitaxel may have contributed, or 


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the investigator is uncertain which drug is responsible, then dose modification will 
be as described above for hematologic toxicities starting with paclitaxel (first 
occurrence).

For both the “within” and “after” dosing regimens at the next repeat occurrence with 
dose modified, drug will be discontinued but with the option to continue under the 
considerations detailed in the last row of Table 6-2.  Specific dose adjustment is 
required for oral mucositis (Table 6-3).
Table 6-3   
Dose Adjustments for Oral Mucositis (Drug-related)
Toxicity
NCI CTCAE 
Grade
Finding
Action on Drug
Mucositis 
oral
Grade 1
Asymptomatic or mild symptoms; 
intervention not indicated
Medical management as 
appropriate, no action on study 
drug.
Grade 2
Moderate pain; not interfering with oral 
intake; modified diet indicated
•
Medical management as 
appropriate.
•
Hold alisertib until 
resolution to Grade ≤ 1 or 
baseline but pursue 
paclitaxel as single agent at 
current dose level.
Upon recovery (at any time 
during the cycle), resume 
alisertib at current dose level.
Grade 3
Severe pain; interfering with oral intake
•
Hold paclitaxel and alisertib.
•
Upon recovery to Grade ≤ 2, 
resume paclitaxel only at 
current dose level. 
Upon recovery to Grade ≤ 1 or 
baseline (at any time during the 
cycle), resume alisertib at the 
next lower dose level.
Grade 4
Life-threatening consequences; urgent 
intervention indicated
Discontinue study drug.
Lack of 
acceptable timely 
recovery
Delay > 21 days in the start of a 
subsequent cycle due to lack of 
recovery of oral mucositis to Grade 2 
for initiation of paclitaxel and/or Grade 
1 for initiation of alisertib
Discontinue study drug. The 
maximum delay before treatment 
should be discontinued is 
3 weeks (Section 6.3.1).
•Abbreviation:  NCI CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Event.


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Suggested Management of Stomatitis
Stomatitis/oral mucositis/mouth ulcers should be treated using local supportive care.  In 
addition to standard oral and dental assessment and hygiene, please consider the paradigm 
below for treatment of stomatitis/oral mucositis/mouth ulcers:
1. PROPHYLAXIS:

Consider prophylaxis with salt water (0.9%) mouthwash or baking soda 
(1 teaspoon per glass of warm water) 2 to 3 times per day to prevent mucositis
starting the day of alisertib for up to 7 days thereafter.
2. ESTABLISHED STOMATITIS:

For mild toxicity (Grade 1), use conservative measures such as nonalcoholic 
mouthwash, artificial saliva, or salt water (0.9%) mouthwash 4 to 6 times daily 
until resolution. Limit to foods that do not require significant chewing, and avoid 
acidic, salty, or dry foods.

For more severe toxicity (Grade 2 in which case patients have pain but are able to 
maintain adequate oral alimentation, or Grade 3 in which case patients cannot 
maintain adequate oral alimentation), use topical analgesic mouth treatments (eg, 
local anesthetics such as benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical corticosteroids, such 
as triamcinolone oral paste 0.1% (Kenalog in Orabase®).
3. AGENTS THAT SHOULD BE AVOIDED: 

Agents containing hydrogen peroxide, iodine, and thyme derivatives may worsen 
mucositis and should be avoided.
6.6   
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Use of any antineoplastic therapy other than study drug (alisertib or paclitaxel) is not 
permitted.

Use of any other investigational therapy is not permitted.


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
Alternative therapy or medicine(s) are not allowed.  Palliative radiation therapy for 
pain management on a lesion not established as progressive and located outside of 
the field of a target/nontarget lesion is allowed.  (Note that radiation therapy should 
occur during the rest period and not while dosing.)

Use of any PPI or pancreatic enzyme is prohibited during the conduct of the study
and within 5 days before the first dose of alisertib.  Patients may be administered 
alternative agents to manage gastric acidity or reflux (eg, H2 receptor antagonists, 
antacids) with exceptions described in the following.
o
Histamine 2 receptor antagonists are to be avoided during the alisertib treatment 
period, but may be used during the rest period if clinically indicated to treat 
mucositis or other GI abnormalities.  Brief administration of histamine-2 
antagonists (such as a single dose of cimetidine or ranitidine) is allowed if 
required on the day of paclitaxel administration.
o
Neutralizing antacids and calcium-containing supplements should be avoided 
within 2 hours before and 2 hours after alisertib administration.

Enzyme-inducing drugs such as phenytoin, carbamazepine, phenobarbital, 
oxcarbazepine, primidone, rifampin, rifabutin, rifapentine, or St. John’s wort are not 
permitted within 14 days before the first dose of alisertib, and the use of these agents 
is not permitted during the study.

Use of moderate or strong CYP3A inhibitors is not permitted within 14 days before 
the first dose of study drug and during the conduct of the study. (see Section 14.2)
6.7   
Permitted Concomitant Medications and Procedures
Myeloid and erythroid growth factors may be used in accordance with the American Society 
of Clinical Oncology guidelines(46) or local institutional policy guidelines.  The use of 
myeloid and erythroid growth factors will be prohibited in the DLT evaluation period as 
detailed in Section 6.5.3.  Antiemetic agents may be administered at the discretion of the 
investigator.  
Anticoagulation is permitted; however, the risks for bleeding in the setting of low platelets 
should be carefully assessed.  Platelet counts may require more frequent monitoring per 


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clinical practice standards, and doses of anticoagulants should be adjusted or held in the 
setting of thrombocytopenia to mitigate the risk of bleeding.  
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 structural 
and pharmacological similarity between alisertib and benzodiazepines, concomitant therapy 
with benzodiazepines is discouraged but not prohibited.
Premedication with corticosteroids, diphenhydramine, or histamine-2 receptor antagonists is 
permitted before each treatment with paclitaxel.
All other medical conditions should be treated at the discretion of the investigator in 
accordance with local community standards of medical care.  
6.8   
Precautions and Restrictions
It is not known what effects alisertib has on human pregnancy or development of the embryo 
or fetus.  Therefore, female patients participating in this study should avoid becoming 
pregnant, and male patients should avoid impregnating a female partner.  Nonsterilized 
female patients of reproductive age group and male patients should use effective methods of 
contraception through defined periods during and after study treatment as specified below.
Female patients must meet 1 of the following: 

Postmenopausal for at least 1 year before the screening visit, or

Surgically sterile, or

If they are of childbearing potential, agree to practice 2 effective methods of 
contraception from the time of signing of the informed consent form through 30 days 
after the last dose of study drug, see details in the following.
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and 
through 4 months after the last dose of study drug, see details in the following,


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Barrier Methods (each time the 
subject has intercourse)
Intrauterine Devices (IUDs)
Hormonal Contraceptives
Male condom PLUS 
spermicide
Cap (plus spermicidal cream 
or jelly) PLUS male condom 
and spermicide
Diaphragm (plus spermicidal 
cream or jelly) PLUS male 
condom and spermicide
Copper T PLUS condom or 
spermicide
Progesterone T PLUS 
condom or spermicide
Implants
Hormone injections
Combined pills
Minipills
Patches
Vaginal ring PLUS male 
condom and spermicide
Patients must adhere to any treatment-specific pregnancy prevention guidelines for 
paclitaxel
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 should also become familiar with the effects 
of the study drugs before engaging in such activities.
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 
30 days after the last dose of study drug.  A standard unit of alcohol is defined as 12 ounces 
of beer (350 mL), 1.5 ounces (45 mL) of 80-proof alcohol, or one 6-ounce (175 mL) glass of 
wine.
6.9   
Management of Clinical Events
6.9.1   
Nausea and Vomiting
Prophylactic antiemetic therapy may be used in this study per standard of care.  If 
prophylactic antiemetic therapy is needed, 5-HT3 receptor antagonists should be tried first.  
Because of the potential for benzodiazepines to cause sedation, the use of benzodiazepines 
for anti-emetic prophylaxis should be reserved for patients who cannot be satisfactorily 
managed otherwise.
There is no prohibition against anti-emetic use in the management of a patient who develops 
nausea or vomiting, or both.


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6.9.2   
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.
6.9.3   
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.
6.9.4   
Hypersensitivity Reactions Associated With Paclitaxel
Minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia do 
not require interruption of paclitaxel therapy.  Severe reactions, however, such as 
hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or 
generalized urticaria require immediate discontinuation of paclitaxel and aggressive 
symptomatic therapy.  Patients who have developed severe hypersensitivity reactions should 
not be rechallenged with paclitaxel.  Please refer to the paclitaxel product label for further 
information.
6.10   
Blinding and Unblinding
This is an open-label study.
6.11   
Description of Investigational Agents
Alisertib drug product is supplied as the ECT dosage form in 10- and 15-mg strength, with 
dose strength expressed as the milligrams of active drug (free acid).  
 
 
 
Paclitaxel will be supplied as a solution for injection in a 100 mg/16.7 mL vial labeled as 
investigational material.
CCI


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6.12   
Preparation, Reconstitution, and Dispensation
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.
Please refer to the paclitaxel product label for instructions and precautions regarding 
preparation and handling.
Alisertib and paclitaxel are anticancer drugs, and as with other potentially toxic compounds, 
caution should be exercised when handling alisertib and paclitaxel.  It is recommended that 
gloves and protective clothing be worn during preparation.
6.13   
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.  Alisertib will be supplied as 
ECT in 10- or 15-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 will be labeled as investigational material and provided to the investigative site by 
Millennium; packaging labels will fulfill all requirements specified by governing 
regulations.  Paclitaxel will be supplied as a solution for injection in a 100 mg/16.7 mL vial 
(6 mg/mL).
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.
6.14   
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°C to 25°C; 68°F to 77°F; excursions 
permitted from 15°C to 30°C; 59°F to 86°F) and used before the retest expiry date provided 
by Millennium.  The stability of the drug product will be monitored for the duration of the 
clinical studies.  Tablets are not intended to be broken or manipulated in any way.  
Containers should be kept closed during storage.


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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.  Gloves and 
protective clothing should be worn during the cleanup operation.  The area should be 
ventilated and the spill site washed after material pick-up is complete.  The spilled material 
should be disposed of as hazardous medical waste in compliance with federal, state, and 
local regulations.
In case of contact with the powder (eg, from a broken 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.
Vials of paclitaxel should be stored at 20°C to 25°C (68°F to 77°F), protected from light.  
Please refer to the paclitaxel product label for further information regarding the proper 
storage and handling of paclitaxel.
Procedures for drug accountability at the investigational site are described in Section 10.10.
6.15   
Other Protocol-Specified Materials
This section is not applicable.
7.   
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Conference on Harmonisation (ICH) 
guidelines.
7.1   
Study Personnel and Organizations
The contact information for the project clinician for this study, the central laboratory and 
any additional clinical laboratories, and Quintiles physician may be found in the Study 
Manual.  A full list of investigators is available in the sponsor’s investigator database.


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7.2   
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians.  If advertisements become 
part of the recruitment strategy, they will be reviewed by the institutional review board 
(IRB)/independent ethics committee (IEC).  It is not envisioned that prisoners (or other 
populations that might be subject to coercion or exploitation) will be enrolled into this study.
7.3   
Treatment Group Assignments 
Patient accrual and treatment is discussed in Section 6.4
7.4   
Study Procedures
Refer to the Schedule of Events for timing of assessments.  Additional details are provided 
as necessary in the sections that follow.
7.4.1   
Informed Consent
Each patient must provide written informed consent before any study-required procedures 
are conducted, unless those procedures are performed as part of the patient’s standard care.  
7.4.2   
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during screening.
7.4.3   
Medical History
During the Screening period (within 28-days before the first dose of any study drug), a 
complete medical history will be obtained and a complete physical examination, including 
neurological examination, performed.  Additionally, concomitant medications will be listed 
and will include all medications being taken at the time of screening and within 28 days of 
the first dose.
7.4.4   
Physical Examination
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events.  
The screening physical examination will include the patient’s height (Section 7.4.5) and 
weight (Section 7.4.5) and will also include an assessment of the patient’s ECOG 
performance status (see Section 14.1).


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The symptom-directed physical examination will be performed at Cycle 1, Day 1 (baseline), 
and within 3 days before the beginning of each treatment cycle (Day 1) and on Days 8, 15, 
and 21 of each treatment cycle.  In patients who tolerate study treatment through multiple 
cycles, the Day 21 symptom-directed physical examination can become optional, at the 
discretion of the investigator, if in the prior 2 cycles the patient tolerated study treatment (ie, 
without the requirement for dose reduction or without ≥Grade 3 treatment-related toxicity 
evaluated according to NCI CTCAE, version 4.03).  For patients who have been on study for 
longer than 6 months and/or have discontinued paclitaxel treatment, the Day 8 and Day 15 
physical examinations are optional, at the discretion of the investigator.
The Cycle 1, Day 1 (baseline) symptom-directed physical examination is not required if the 
screening medical history was obtained and the screening complete physical examination 
was conducted within the 4 days before administration of the Cycle 1, Day 1 dose of study 
drug.
During the symptom-directed physical examination, neurotoxicity will be monitored through 
AE reporting and concomitant medication usage.
The symptom-directed physical examination will be repeated at the End of Treatment (EOT) 
visit (see Schedule of Events).  The symptom-directed physical examination will be directed 
toward the identification of new symptoms and signs, and changes in concomitant 
medications (Section 7.4.8).
7.4.5   
Patient Height and Weight
Height will be measured during screening only (within 28 days before the first dose of any 
study drug).
Weight will be measured during screening; at Cycle 1, Day 1 (baseline); and within 3 days 
before the beginning (Day 1) of each subsequent treatment cycle.
If the screening assessment was done within 4 days before Cycle 1, Day 1, an assessment at 
Cycle 1, Day 1 is not necessary.
Weight also will be measured at the EOT visit.
7.4.6   
Vital Signs 
Vital signs (systolic and diastolic blood pressures, heart rate, and temperature) 
measurements will be obtained during screening; at Cycle 1, Day 1 (baseline); within 3 days 


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before the beginning of each treatment cycle (Day 1); and on Days 8, 15, and 21 of each 
treatment cycle.  If the screening assessment was done within 4 days before Cycle 1, Day 1, 
an assessment at Cycle 1, Day 1 is not necessary.  During Screening and Cycle 1,
temperature should be oral measurements only; temperature measurements in all other 
cycles may be taken based on local practice.
For patients who have been on study for longer than 6 months and/or have discontinued 
paclitaxel treatment, the Day 8 and Day 15 vital sign assessments are optional, at the 
discretion of the investigator.
Blood pressure should be determined with the patient in a seated position after the patient 
has been sitting quietly for 5 minutes.
Vital signs measurements also will be obtained at the EOT visit.
7.4.7   
Pregnancy Test
A serum beta-human chorionic gonadotropin (-hCG) pregnancy test will be performed only 
for patients of childbearing potential during screening and again at Cycle 1, Day 1 (baseline) 
if the screening test was performed more than 4 days before the first dose of alisertib or 
paclitaxel.  The results must be negative within 4 days before the first dose of alisertib or 
paclitaxel is administered (ie, within the 4 days prior to Cycle 1, Day 1), or as otherwise 
required by local regulations.
Additional pregnancy testing may be performed during the study at the discretion of the 
investigator, as per request of IEC/IRB, or if required by local regulations.
If a patient becomes pregnant or suspects pregnancy while participating in this study, the 
investigator must be informed immediately (see Section 9.4).
Women of childbearing potential will be defined as sexually mature females who meet the 
following criteria:
1. Those who have not undergone hysterectomy or bilateral oophorectomy, and
2. Those who have not had natural menopause (eg, FSH > 40 IU/L and no menstrual
period for at least 24 consecutive months) for 24 consecutive months or longer (loss 
of menstrual periods following chemotherapy may not rule out childbearing 
potential).


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7.4.8   
Concomitant Medications and Procedures
Concomitant medications and supportive therapies will be recorded from 28 days before the 
first dose of study drug through 30 days after the last dose of study drug or until the start of 
subsequent antineoplastic therapy, whichever occurs first.  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 discouraged but not 
prohibited.  See Section 6.6 and Section 6.7 for a list of excluded and permitted concomitant 
medications and procedures, respectively. 
7.4.9   
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as 
specified in the Schedule of Events.  Refer to Section 9 for details regarding definitions, 
documentation, and reporting of pretreatment events, AEs, and SAEs.  
7.4.10   
Enrollment
A patient is considered to be enrolled in the study when the patient has received the first 
dose of study drug. 
Procedures for completion of the enrollment information are described in the Study Manual.
7.4.11   
Electrocardiogram
A 12-lead ECG will be obtained at screening and at Cycle 1, Day 1 (baseline).  If the 
screening ECG was obtained within the 4 days before the Cycle 1, Day 1 dose of study drug, 
a repeat ECG at Cycle 1, Day 1 is not necessary.  Additional ECGs may be obtained if 
clinically indicated.  Electrocardiogram assessments are to be performed with the patient 
supine and rested for 5 minutes and before any closely timed blood collection.
7.4.12   
Clinical Laboratory Evaluations
Blood samples for analysis of the following hematology and clinical chemistry parameters, 
and urine for urinalysis will be obtained as specified in the Schedule of Events.  Clinical 
laboratory evaluations will be performed by local laboratories.  Handling and shipment of 
clinical laboratory samples will be outlined in the Study Manual.  Clinical laboratory 
evaluations will be performed as outlined in the following.


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If screening values were obtained and acceptable within the 4 days before the Cycle 1, 
Day 1 dose of study drug, repeat clinical laboratory testing (hematology, clinical chemistry, 
or urinalysis) at Cycle 1, Day 1 is not necessary.
A blood sample for hematology (complete blood count [CBC] with differential white blood 
cell [WBC] count) will be obtained during screening; within 3 days before the beginning 
(Day 1) of each treatment cycle; and on Day 8 (- 2 days), Day 15 (- 2 days), and Day 21 
(- 2 days).  In patients who tolerate study treatment through multiple cycles, the Day 21 
clinical laboratory assessments can become optional, at the discretion of the investigator, if 
in the prior 2 cycles the patient tolerated study treatment (ie, without the requirement for 
dose reduction or without ≥Grade 3 treatment-related toxicity evaluated according to NCI 
CTCAE, version 4.03).  If a patient has an ANC less than 500/mm3 or a platelet count less 
than 25,000/mm3, or both, the CBC with differential should be repeated at least every 2 to 
3 days until the ANC or platelet count (or both, if both were decreased) have exceeded these
values on at least 2 occasions.
For patients who have been on study for longer than 6 months and/or have discontinued 
paclitaxel treatment, the Day 8 and Day 15 clinical laboratory assessments are optional, at 
the discretion of the investigator.
A blood sample for CBC with differential also will be obtained at the EOT visit.
Hematology

Hemoglobin

Hematocrit

Platelet (count)

Leukocytes with differential

Neutrophils (absolute neutrophil count [ANC])
A blood sample for clinical chemistry panel will be obtained during screening, within 3 days 
before the beginning (Day 1) of each treatment cycle, and at the EOT visit.
Serum Chemistry

Blood urea nitrogen 
(BUN)

Creatinine

Bilirubin (total)

Urate

Lactate dehydrogenase 
(LDH)

Albumin

Alkaline phosphatase 
(ALP)

Aspartate 
aminotransferase (AST)

Alanine 
aminotransferase (ALT)

Calcium

Chloride

Carbon dioxide 
(CO2) if 
available

Magnesium


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
Gamma glutamyl 
transferase (GGT)

Phosphate

Glucose 

Sodium

Potassium
Thyroid stimulating hormone (TSH) level will be measured at screening or Cycle 1, Day 1 
(baseline) and at the EOT visit; this test should be repeated during the treatment period as 
clinically indicated.
A urine sample for urinalysis will be obtained during screening, at Cycle 1, Day 1 
(baseline), and at the EOT visit.
Urinalysis

Turbidity and color

pH

Specific gravity

Protein

Ketones

Bilirubin

Occult blood

Nitrite

Urobilinogen

Glucose

Leukocytes
If urine protein by dipstick changes to 3+ (or 2+ that is reconfirmed at least 1 day later), then 
a 24-hour urine collection should be done for protein and creatinine clearance.  The 
screening or Cycle 1, Day 1 urinalysis should include microscopic examination of the 
sediment.
7.4.13   
CA-125 Assessment
For patients with ovarian, fallopian tube, or peritoneal cancer, CA-125 levels will be 
obtained according to standard of care within 9 days before screening and sufficient time 
after prior therapy, or within the Screening period; and within 4 days before the dose on
Cycle 1, Day 1; and at the end of every treatment cycle (within the week before the start of a 
new treatment cycle); and at the EOT visit. The investigator’s determination of response by 
CA-125 is required at the end of every 2 cycles. Please refer to the Gynecological Cancer 
Intergroup guideline for the Definition of CA-125 response.(47)
7.4.14   
HBV and HCV Assessment
At screening assessments, HBV surface antigen, HBV core antibody, and HCV antibody
testing are mandatory. If HBcAb is positive, HBV DNA should be assessed.  If HCVAb is 
positive, HCV-RNA should be tested.
For patients who are HBcAb positive screening, DNA titers will be taken every 2 months.  


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
If DNA titers increase (1 log increase of viral load), treat with antivirals medication 
(lamivudine) and continue monitoring. 

If a second 1 log of increase of viral load occurs, stop treatment and discontinue 
from the study.
7.4.15   
Disease Assessment
Patients will undergo computed tomography (CT) with contrast as appropriate, magnetic 
resonance imaging (MRI), x-ray and/or bone scanning to monitor and assess disease 
progression, using RECIST criteria (version 1.1).(48)  Contrast CT scans of the chest, 
abdomen, and pelvis will be obtained at screening.  Specific disease sites that cannot be 
adequately imaged by CT may be documented by MRI.  Anatomical measurements 
(summed across target lesions) will be collected at baseline and each subsequent evaluation 
using an imaging modality consistent with that used at screening.  Objective assessments 
will be performed at each time point as described in the Schedule of Events.  When possible, 
the same qualified physician will interpret results to reduce variability.  Radiographic 
images will be maintained at the site, and test results and physician’s findings will be filed in 
patient source documents.  
Repeat CT (with IV contrast) or MRI scans as appropriate, or both, are to be performed at 
the completion of Cycle 2 and every 2 cycles (approximately every 8 weeks, between 
Days 21 and 28 of every even cycle) thereafter until PD is documented.  The same imaging 
modality should be used throughout the study for each site of disease.  For responders, 
radiographic images will be read locally but will be collected and, if necessary, provided to 
the sponsor for subsequent review.  Scans are required at the EOT visit only if PD has not 
been documented previously and it has been 8 weeks or more since the previous evaluation.
Other procedures, such as physical examinations and other scintigraphic examinations 
(eg, bone scans for patients with known or suspected bone metastases) should be taken into 
consideration also when evaluating the extent of malignant disease.
In the event of antitumor response, the sponsor may request electronic images for those 
patients who demonstrate tumor reduction.


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7.4.16   
Tumor Biopsies (Not Applicable)
7.4.17   
Pharmacokinetic Measurements
7.4.17.1   Paclitaxel Pharmacokinetic Measurements
Paclitaxel PK measurements will be performed on Day 1 of Cycle 1 (weekly paclitaxel 
dosed during concomitant administration of alisertib) and on Day 1 of Cycle 2 (weekly 
paclitaxel administered alone).  Blood samples for the measurement of plasma 
concentrations of paclitaxel will be collected at prespecified time points on Day 1 of both 
Cycles 1 and 2 (see also Alisertib and Paclitaxel PK Sampling Schedule).
7.4.17.2   Alisertib Pharmacokinetic Measurements
Blood samples to measure plasma concentrations of alisertib will be collected at 
prespecified time points on Days 1 and 3 of Cycle 1 (see also the Alisertib and Paclitaxel PK 
Sampling Schedule).
7.4.18   
Pharmacodynamic Measurements (Not Applicable)
7.5   
Completion of Treatment
Treatment with alisertib is to be considered completed for patients meeting any of the 
following criteria:  

12 months of treatment

PD (see below for exception)

Symptomatic deterioration
A patient can be treated for up to 12 months.  If it is determined that a patient tolerates 
protocol treatment and would derive benefit from continued alisertib treatment beyond 
12 months, alisertib treatment may be continued in this or in another extension or rollover 
study, if available, upon request by the investigator and agreement by the project clinician.


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A patient who experiences PD, as defined by imaging results described in the protocol 
(Section 14.4) may continue protocol treatment if tolerated and if the investigator determines 
it is in the patient’s best interest upon review and agreement by the project clinician.  
Criteria for removing patients from the study include the following:
1. Patients with unequivocal evidence of any new metastasis including development of 
peritoneal studding or malignant ascites must be removed from the study.
2. Patients whose disease progression is such that they are at risk for catastrophic 
complications from vital organ compression (eg, spinal cord compression, small 
bowel obstruction, encroachment of major blood vessels, etc) must be removed from 
the study immediately and treated appropriately.
3. Patients with evidence of progression based on RECIST must be removed from the 
study if the subsequent assessment (8 weeks later) demonstrates evidence of 
progressive disease.
4. Patients must be informed of the evidence of progression and the availability of 
alternative treatments.
In addition to the previous criteria, patients who have PD that is symptomatic or leads to 
altered organ function, such as increases in bilirubin by 1 common terminology criteria
severity grade that could represent altered drug clearance, should be removed from study.
7.6   
Completion of Study
Patients will be considered to have completed the study if they complete 1 year of treatment 
with alisertib plus paclitaxel.
7.7   
Discontinuation of Treatment With Study Drug, and Patient Replacement
Treatment with study drug may also be discontinued for any of the following reasons:

Adverse event

Protocol violation

Complete response 

Progressive disease 


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
Symptomatic deterioration 

Unsatisfactory therapeutic response 

Study terminated by sponsor

Withdrawal by subject

Lost to follow-up

Use of antineoplastic therapy other than study drug (alisertib or paclitaxel)

Other
Once study drug has been discontinued, all study procedures outlined for the End of 
Treatment visit will be completed as specified in the Schedule of Events.  The primary 
reason for study drug discontinuation will be recorded on the eCRF.
Patients who are withdrawn from treatment during Cycle 1, either for reasons other than 
DLT, or because they do not meet DLT-evaluable criteria, will be replaced.  
Patients who withdraw from the study for any reason may continue with alternative doses or 
schedules of taxane therapy at the discretion of the treating physician.
7.8   
Withdrawal of Patients From Study
A patient may be withdrawn from the study for any of the following reasons:

Lost to follow-up

Study terminated by sponsor

Withdrawal by subject

Completed study 

Death 

Other

Complete response 


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
Progressive disease 

Initiation of subsequent antineoplastic therapy
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. However, every effort 
will be made to follow all patients for safety.  
7.9   
Study Compliance
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing. including the following:  applicable 
lot numbers and total drug administered in milligrams (mg).  Any discrepancy regarding the 
dose administered and the reason for the discrepancy will be noted in the eCRF.
Paclitaxel will be administered by study personnel.
Patients will receive a sufficient quantity of alisertib for each treatment cycle.  The study 
center staff will check the patient’s diary versus the patient’s supply of remaining alisertib 
tablets at the Day 8, Day 15, and Day 21 visit of each treatment cycle and at the EOT visit to 
ensure proper compliance with dosing.  For patients who do not require a clinic visit on 
Day 21, the medication count may be confirmed verbally with the patient by telephone; 
however, a check of the patient diary versus the patient’s supply of alisertib tablets should 
be performed at the next visit (eg, on Day 1 of the subsequent cycle or at the EOT visit, if 
applicable).  Patients who are not compliant with the dosing schedule may be withdrawn 
from the study.
8.   
STATISTICAL AND QUANTITATIVE ANALYSES
8.1   
Statistical Methods
Statistical analyses will be primarily descriptive and graphical in nature.  No formal 
statistical hypothesis testing will be performed. Summary tabulations will be presented 
displaying the number of observations, mean, standard deviation, median, minimum, and 
maximum for continuous variables, and the number and percentage per category for 
categorical data.  A formal statistical analysis plan will be developed and finalized before 
database lock.


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8.1.1   
Determination of Sample Size
During the study, different doses of alisertib are planned for evaluation when combined with 
a fixed dose of paclitaxel to identify the RP2D.  Dose escalation will be conducted 
according to a traditional dose escalation rule, with 3 to 6 patients evaluated at each dose 
level.  There will be an expansion cohort at the RP2D to of least 12 patients . Including 10% 
of patients who are not evaluable for DLT, it is anticipated that enrollment of approximately 
30 patients is needed.
8.1.2   
Randomization and Stratification  
There is no randomization or stratification; all patients will receive alisertib plus weekly 
paclitaxel.
8.1.3   
Populations for Analysis
The populations used for analysis will include the following:  

Safety population:  The safety population, defined as all patients who receive at least 
1 dose of any study drug, will be used for all safety analyses.

PK population:  The PK population, defined as all patients who have sufficient 
dosing data and plasma concentration-time data to permit calculations of PK 
parameters, will be used for PK analyses.

DLT-evaluable population:  the DLT-evaluable population, defined as all patients 
who either experience DLT during Cycle 1 or complete treatment with at least 15 of 
the planned 18 doses of alisertib and 2 of the planned 3 doses of paclitaxel in Cycle 1 
unless AE/DLTs and have sufficient follow up data to allow the investigators and 
sponsor to determine whether DLT occurred, will be used for analysis of DLT.
8.1.4   
Procedures for Handling Missing, Unused, and Spurious Data
All available data will be included in data listings.  No imputation of values for missing data 
will be performed.  Data that are potentially spurious or erroneous will be examined 
according to standard data management operating procedures.
8.1.5   
Demographic and Baseline Characteristics
The demographic and baseline characteristics will be summarized in a descriptive fashion.  
Data to be evaluated will include age, race, ethnicity, and other parameters, as appropriate.


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8.1.6   
Efficacy Analysis
There is no primary efficacy endpoint in the study.
The secondary efficacy endpoint in the expansion part of the study is the disease response 
based on the RECIST version 1.1 ORR (CR + PR), which will be presented in a listing.
8.1.7   
Pharmacokinetics/Pharmacodynamics/Biomarkers
Pharmacokinetic Analysis
Paclitaxel
Individual and mean plasma concentration data (grouped by alisertib dose level) will be 
plotted over time for paclitaxel alone (Cycle 2, Day 1) and for paclitaxel administered 
concomitantly with alisertib (Cycle 1, Day 1).  Noncompartmental PK analysis will be 
performed on individual concentration-time data to calculate plasma PK parameters, 
including, but not limited to, Cmax, AUC0-tlast, AUC0-inf, and t½, for paclitaxel administered 
alone (Cycle 2, Day 1) and during concomitant administration of alisertib (Cycle 1, Day 1).
Descriptive statistics will be presented for plasma PK parameters grouped by alisertib dose 
level.  Additionally, the ratio of geometric means of paclitaxel Cmax, AUC0-tlast, and AUC0-inf
(when administered with the MTD/RP2D of alisertib in reference to when administered 
alone) and the associated 90% CI will be calculated.
Alisertib
Individual and mean plasma concentration-time data will be plotted for alisertib on Days 1 
and 3 by dose level.  Noncompartmental PK analysis will be performed on individual 
concentration-time data to calculate plasma PK parameters of alisertib, including but not 
limited to, Day 1 and Day 3 Cmax, Tmax, and AUC0-.  Alisertib plasma concentration-time 
data and PK parameters will be summarized descriptively by dose level using the 
PK-evaluable population.
Pharmacodynamic Analysis
This is not applicable to this study.
Biomarkers
This is not applicable to this study.


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8.1.8   
Safety Analysis
Treatment-emergent AEs that occur after administration of the first dose of study drug and 
through 30 days after the last dose of study drug will be tabulated.  
Safety evaluations will be based on the incidence, intensity, and type of AEs; and clinically 
significant changes in the patient’s vital signs, weight, and clinical laboratory results.  Safety 
variables will be tabulated and presented for the safety population.  The incidence of DLT 
will be presented.  Exposure to study drug and reasons for discontinuation of study treatment 
will be tabulated.
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
coding dictionary for the purpose of summarization.  All AEs occurring on study will be 
listed in data listings.  Treatment-emergent AEs will be tabulated, where treatment-emergent 
is defined as any AE that occurs after administration of the first dose of any study drug 
through 30 days after the last dose of any study drug.  AEs are to be tabulated using 
MedDRA system organ class, high-level term, and preferred term, including the following 
treatment-emergent categories:  

Treatment-emergent AEs

Drug-related treatment-emergent AEs

Grade 3 or higher treatment-emergent AEs

Grade 3 or higher drug-related treatment-emergent AEs

Treatment-emergent AEs resulting in study drug discontinuation

SAEs
The most commonly reported treatment-emergent AEs (ie, those events reported by ≥10% 
of all patients in the safety population) will be tabulated by the MedDRA preferred term.  
Tabulation also will be provided that enumerates AEs by maximum intensity.  Deaths, 
SAEs, and AEs resulting in study drug discontinuation will be tabulated.
Clinical laboratory parameters will be summarized at each scheduled time point.  Shift 
tables will be produced for selected laboratory parameters.  These tables will summarize the 


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number of patients with each baseline NCI CTCAE grade and changes to the worst 
NCI CTCAE grade during study.
Descriptive statistics for the actual values of vital signs and weight over time will be 
tabulated by scheduled time point.
All concomitant medications collected from screening through the study period will be 
classified by preferred term according to the World Health Organization drug dictionary.
Additional safety analyses may be determined at any time without prejudice to enumerate 
rates of toxicities and to further define the safety profile of study drugs.
8.1.9   
Interim Analysis
There is no formal interim analysis. 
9.   
ADVERSE EVENTS
9.1   
Definitions
9.1.1   
Pretreatment Event Definition
A pretreatment event is any untoward medical occurrence in a patient or subject who has 
signed informed consent to participate in a study but before administration of any study 
medication; it does not necessarily have to have a causal relationship with study 
participation.
9.1.2   
Adverse Event Definition
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug.


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


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may be of relatively minor medical significance (such as a Grade 3 headache).  This is NOT 
the same as serious, which is based on patient/event outcome or action criteria described 
above, and is usually associated with events that pose a threat to a patient’s life or ability to 
function.  A severe AE (Grade 3 or 4) does not necessarily need to be considered serious.  
For example, a white blood cell count of 1000/mm3 to less than 2000 is considered Grade 3 
(severe) but may not be considered serious.  Seriousness (not intensity) serves as a guide for 
defining regulatory reporting obligations.
9.2   
Procedures for Recording and Reporting Adverse Events and Serious 
Adverse Events
All AEs spontaneously reported by the patient and/or in response to an open question from 
study personnel or revealed by observation, physical examination, or other diagnostic 
procedures will be recorded on the appropriate page of the eCRF (see Section 9.3 for the 
period of observation).  Any clinically relevant deterioration in laboratory assessments or 
other clinical finding is considered an AE.  When possible, signs and symptoms indicating a 
common underlying pathology should be noted as 1 comprehensive event.
Regardless of causality, SAEs and serious pretreatment events (as defined in Section 9.1) 
must be reported (see Section 9.3 for the period of observation) by the investigator to the 
Millennium Department of Pharmacovigilance or designee (contact information provided 
below).  This should be done by faxing the SAE Form within 24 hours after becoming aware 
of the event.  The SAE Form, created specifically by Millennium, will be provided to each 
clinical study site.  A sample of the SAE Form may be found in the Study Manual.  Follow-
up information on the SAE or serious pretreatment event may be requested by Millennium.  
SAE report information must be consistent with the data provided on the eCRF.
SAE Reporting Contact Information
Planned hospital admissions or surgical procedures for an illness or disease that existed
before the patient was enrolled in the trial or before study drug was given are not to be 
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considered AEs unless the condition deteriorated in an unexpected manner during the trial 
(eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the intensity of 
the event and the relationship of the event to study drug administration.  For serious 
pretreatment events, the investigator must determine both the intensity of the event and the 
relationship of the event to study procedures.
Intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010.(1)  The criteria are provided in the 
Study Manual.
Relationship to study drug administration will be determined by the investigator responding 
yes or no to this question:  Is there a reasonable possibility that the AE is associated with the 
study drug?
9.3   
Monitoring of Adverse Events and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows:  

AEs will be reported from first dose through 30 days after administration of the last 
dose of study drug and recorded in the eCRFs.    

Serious pretreatment events will be reported to the Millennium Department of 
Pharmacovigilance or designee from the time of the signing of the ICF up to first 
dose of study drug, but will not be recorded in the eCRF.>>

Related and unrelated SAEs will be reported to the Millennium Department of 
Pharmacovigilance or designee from: the first dose of study drug  through 30 days 
after administration of the last dose of study drug and recorded in the eCRF.  After 
this period, only related SAEs must be reported to the Millennium Department of 
Pharmacovigilance or designee.  SAEs should be monitored until they are resolved 
or are clearly determined to be due to a patient’s stable or chronic condition or 
intercurrent illness(es).
9.4   
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 


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


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eCRFs will be completed for each study patient.  It is the investigator’s responsibility to 
ensure the accuracy, completeness, clarity, and timeliness of the data reported in the 
patient’s eCRF.
The investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.
The investigator must provide through the EDC application formal approval of all the 
information in the eCRFs and changes to the eCRFs to endorse the final submitted data for 
the patients for which he or she is responsible.  The audit trail entry will show the user’s 
identification information and the date and time of the correction.
Millennium, or a designee, will retain the eCRF data and corresponding audit trails.  A copy 
of the final archival eCRF in the form of a compact disk (CD) or other electronic media will 
be placed in the investigator’s study file.
10.4   
Study Monitoring
Monitoring and auditing procedures developed or approved by Millennium will be followed 
to comply with GCP guidelines.
All information recorded on the eCRFs for this study must be consistent with the patient’s 
source documentation.  During the course of the study, the study monitor will make study 
site visits to review protocol compliance, verify eCRFs against source documentation, assess 
drug accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements.  The review of medical records will be performed in a manner that 
ensures that patient confidentiality is maintained.  
10.5   
Ethical Considerations
The study will be conducted in accordance with applicable regulatory requirement(s) and 
will adhere to GCP standards.  The IRB/IEC will review all appropriate study 
documentation to safeguard the rights, safety, and well-being of the patients.  The study will 
be conducted only at sites where IRB/IEC approval has been obtained.  The protocol, IB, 
ICF, advertisements (if applicable), written information given to the patients (including 
diary cards), safety updates, annual progress reports, and any revisions to these documents 
will be provided to the IRB/IEC by the investigator or the sponsor, as allowed by local 
regulations.


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10.6   
Patient Information and Informed Consent
After the study has been fully explained, written informed consent will be obtained from 
either the patient or his/her guardian or legal representative before study participation.  The 
method of obtaining and documenting the informed consent and the contents of the consent 
must comply with the ICH-GCP and all applicable regulatory requirements.
10.7   
Patient Confidentiality
To maintain patient privacy, all eCRFs, study drug accountability records, study reports, and 
communications will identify the patient by initials where permitted and/or by the assigned 
patient number.  The patient’s confidentiality will be maintained and will not be made 
publicly available to the extent permitted by the applicable laws and regulations.
10.8  
Investigator Compliance
The investigator will conduct the trial in compliance with the protocol provided by 
Millennium and given approval/favorable opinion by the IRB/IEC and the appropriate 
regulatory authority(ies).  Modifications to the protocol are not to be made without 
agreement of both the investigator and Millennium.  Changes to the protocol will require 
written IRB/IEC approval/favorable opinion before implementation, except when the 
modification is needed to eliminate an immediate hazard or hazards to patients.  Millennium, 
or a designee, will submit all protocol modifications to the appropriate regulatory 
authority(ies) in accordance with the governing regulations.
When immediate deviation from the protocol is required to eliminate an immediate hazard 
or hazards to patients, the investigator will contact Millennium, or a designee, if 
circumstances permit, to discuss the planned course of action.  Any departures from the 
protocol must be documented.
10.9   
On-site Audits
Regulatory authorities, the IEC/IRB, and/or Millennium may request access to all source 
documents, eCRFs, and other study documentation for on-site audit or inspection.  Direct 
access to these documents must be guaranteed by the investigator, who must provide support 
at all times for these activities.


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10.10   Investigator and Site Responsibility for Drug Accountability
Accountability for the study drug at the trial site is the responsibility of the investigator.  
Drug accountability records indicating the drug’s delivery date to the site, inventory at the 
site, use by each patient, and amount returned to Millennium, or a designee (or disposal of 
the drug, if approved by Millennium) will be maintained by the clinical site.  Millennium or 
its designee will review drug accountability at the site on an ongoing basis.
All material containing study drug will be treated and disposed of in accordance with 
governing regulations.
10.11   Product Complaints
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals 
who identify a potential product complaint situation should immediately contact
(see below) and report the event.  Whenever possible, the associated product 
should be maintained in accordance with the label instructions pending further guidance 
from a Millennium Quality representative.
For Product Complaints,
(US and International)
Product complaints in and of themselves are not AEs.  If a product complaint results in an 
SAE, an SAE form should be completed and sent to Cognizant (refer to Section 9.2).
10.12   Closure of the Study
Study participation by individual sites or the entire study may be prematurely terminated if, 
in the opinion of the investigator or Millennium, there is sufficient reasonable cause.  
Written notification documenting the reason for study termination will be provided to the 
investigator or Millennium by the terminating party.
Circumstances that may warrant termination include, but are not limited to:
!
Determination of unexpected, significant, or unacceptable risk to patients
!
Failure to enter patients at an acceptable rate
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
Insufficient adherence to protocol requirements

Insufficient, incomplete, and/or unevaluable data

Determination of efficacy based on interim analysis

Plans to modify, suspend or discontinue the development of the study drug
Should the study be closed prematurely, the site will no longer be able to access the EDC 
application, will not have a right to use the EDC application, and will cease using the 
password or access materials once their participation in the study has concluded.  In the 
event that any access devices for the EDC application have been provided, these will be 
returned to Millennium once the site’s participation in the study has concluded.
10.13   Record Retention
The investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s).  Records will be retained for at least 2 years after the last 
marketing application approval or 2 years after formal discontinuation of the clinical 
development of the investigational product or according to applicable regulatory 
requirement(s).  If the investigator withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person willing to accept the responsibility and 
Millennium notified.  
11.   
USE OF INFORMATION
All information regarding alisertib supplied by Millennium to the investigator is privileged 
and confidential information.  The investigator agrees to use this information to accomplish 
the study and will not use it for other purposes without consent from Millennium.  It is 
understood that there is an obligation to provide Millennium with complete data obtained 
during the study.  The information obtained from the clinical study will be used toward the 
development of alisertib and may be disclosed to regulatory authority(ies), other 
investigators, corporate partners, or consultants as required.


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Upon completion of the clinical study and evaluation of results by Millennium, the hospital 
or institution and/or investigator may publish or disclose the clinical trial results pursuant to 
the terms contained in the applicable Clinical Trial Agreement.
The Millennium clinical pharmacologist will be the lead and corresponding author on 
abstracts and publications of the data generated from this study; the overall principal 
investigator or lead enroller will be the last author.  Subsequently, individual investigators 
may publish results from their study center in compliance with their agreements with 
Millennium.  Millennium reserves the right to determine which authors are named on 
abstracts and publications and also reserves the right to determine the order in which named 
authors appear.


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12.   
INVESTIGATOR AGREEMENT
I have read Protocol C14022 Amendment 01:  A Phase 1b Study of Alisertib (MLN8237) in 
Combination With Weekly Paclitaxel in East Asian Patients With Advanced Solid Tumors
I agree to conduct the study as detailed herein and in compliance with International 
Conference on Harmonisation Guidelines for Good Clinical Practice and applicable 
regulatory requirements and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
Principal investigator printed name
Principal investigator signature
Date
Investigational site or name of institution and 
location (printed)


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2.2013. 2013 2013.
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Lin YG, Immaneni A, Merritt WM, Mangala LS, Kim SW, Shahzad MM, et al. 
Targeting aurora kinase with MK-0457 inhibits ovarian cancer growth. Clinical 
Cancer Research 2008;14(17):5437-46.
43.
Anand S, Penrhyn-Lowe S, Venkitaraman AR. AURORA-A amplification overrides 
the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell 
2003;3(1):51-62.
44.
Yang H, He L, Kruk P, Nicosia SV, Cheng JQ. Aurora-A induces cell survival and 
chemoresistance by activation of Akt through a p53-dependent manner in ovarian 
cancer cells. International Journal of Cancer 2006;119(10):2304-12.
45.
Scharer CD, Laycock N, Osunkoya AO, Logani S, McDonald JF, Benigno BB, et al. 
Aurora kinase inhibitors synergize with paclitaxel to induce apoptosis in ovarian 
cancer cells. Journal of Translational Medicine 2008;6:79.
46.
Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, et al. 
2006 update of recommendations for the use of white blood cell growth factors: an 
evidence-based clinical practice guideline. Journal of Clinical Oncology 
2006;24(19):3187-205.
47.
Rustin GJ, Vergote I, Eisenhauer E, Pujade-Lauraine E, Quinn M, Thigpen T, et al. 
Definitions for response and progression in ovarian cancer clinical trials 
incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer 
Intergroup (GCIG). International Journal of Gynecological Cancer 2011;21(2):419-
23.


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48.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer 2009;45(2):228-47.
49.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. 
American Journal of Clinical Oncology 1982;5(6):649-55.
50.
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976;16(1):31-41.


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14.   
APPENDICES
14.1   
Eastern Cooperative Oncology Group (ECOG) Scale for Performance Status
Grade
Description
0
Normal activity.  Fully active, able to carry on all predisease performance without restriction
1
Symptoms but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (eg, light housework, office work)
2
In bed < 50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours.
3
In bed > 50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours.
4
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair
5
Dead
Source: Oken MM, et al. 1982.(49)
14.2  
List of Strong and Moderate CYP3A Inhibitors
Strong CYP3A inhibitor
Boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telaprevir, telithromycin, voriconazole
Moderate CYP3A inhibitor 
Amprenavir, aprepitant, atazanavir, ciprofloxacin, darunavir/ritonavir, diltiazem, 
erythromycin, fluconazole, fosamprenavir, imatinib, verapamil


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14.3   
Cockcroft-Gault Equation
For male subjects:
Creatinine clearance = (140 age[years]) weight [kg]
OR
(140 age[years]) weight [kg]
72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
For female subjects:
Creatinine clearance = 0.85 (140 age[years]) weight [kg]
OR 0.85 (140 age[years]) weight [kg]
72 (serum creatinine[mg/dL])
0.81 (serum creatinine[mol/L])
Source: Cockcroft DW, Gault MH.  Prediction of creatinine clearance from serum creatinine.  Nephron 
1976;16(1):31-41.(50)
14.4   
Response Evaluation Criteria in Solid Tumors (RECIST, Version 1.1)
Disease response will be assessed using the Response Evaluation Criteria in Solid Tumor 
(RECIST) guidelines, version 1.1.(48)


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14.5   
Amendment 1 Detailed Summary of Changes
THE PRIMARY SECTION(S) OF THE PROTOCOL AFFECTED BY THE CHANGES 
IN AMENDMENT 1 ARE INDICATED.  THE CORRESPONDING TEXT HAS BEEN 
REVISED THROUGHOUT THE PROTOCOL.
Purpose:  Remove visit windows of 2 days from footnotes to remove repetition.
The primary change occurs in the Schedule of Events:
Deleted 
text:
g The Cycle 1, Day 1 (baseline) symptom-directed physical examination is not required if 
the screening complete physical examination was conducted within the 4 days before 
administration of the Cycle 1, Day 1 dose of study drug.  A symptom-directed physical 
examination will be repeated within 3 days before the beginning (Day 1) of each new 
treatment cycle; on Day 8 (2 days), Day 15 (2 days), and Day 21 (2 days) of each 
treatment cycle; and at the EOT visit.
Sections that also contain this change are:

Schedule of Events footnote h

Section 7.4.4, Physical Examination

Section 7.4.6, Vital Signs
Purpose:  Allow body temperature to be measured according to local practice at study 
time points other than at Screening and Cycle 1; all Screening and Cycle 1 measurements 
must be taken orally.
The primary change occurs in Section 7.4.6, Vital Signs:
Formerly 
read:
Vital signs (systolic and diastolic blood pressures, heart rate, and oral
temperature) measurements will be obtained during screening; at Cycle 1, 
Day 1 (baseline); within 3 days before the beginning of each treatment cycle 
(Day 1); and on Days 8 (± 2 days), 15 (± 2 days), and 21 (± 2 days) of each 
treatment cycle.  If the screening assessment was done within 4 days before 
Cycle 1, Day 1, an assessment at Cycle 1, Day 1 is not necessary.
Now 
reads:
Vital signs (systolic and diastolic blood pressures, heart rate, and temperature) 
measurements will be obtained during screening; at Cycle 1, Day 1 (baseline); 
within 3 days before the beginning of each treatment cycle (Day 1); and on 
Days 8, 15, and 21 of each treatment cycle.  If the screening assessment was 
done within 4 days before Cycle 1, Day 1, an assessment at Cycle 1, Day 1 is 
not necessary.  During Screening and Cycle 1, temperature should be oral 
measurements only; temperature measurements in all other cycles may 
be taken based on local practice.
The Schedule of Events also contains this change.


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Purpose:  Clarify the timing of CA-125 level assessments (for patients with ovarian 
cancer).
The primary change occurs in Section 7.4.13, CA-125 Assessment:
Formerly 
read:
For patients with ovarian, fallopian tube, or peritoneal cancer, CA-125 levels 
will be obtained according to standard of care within 9 days before screening 
and sufficient time after prior therapy within 4 days before the dose on Cycle 
1, Day 1; at the end of every treatment cycle; within the week before the start 
of a new treatment cycle; and at the EOT visit. The investigator’s 
determination of response by CA-125 is required at the end of every 2 cycles. 
Now 
reads:
For patients with ovarian, fallopian tube, or peritoneal cancer, CA-125 levels 
will be obtained according to standard of care within 9 days before screening 
and sufficient time after prior therapy, or within the Screening period; and
within 4 days before the dose on Cycle 1, Day 1; and at the end of every 
treatment cycle (within the week before the start of a new treatment cycle); 
and at the EOT visit. The investigator’s determination of response by 
CA-125 is required at the end of every 2 cycles. Please refer to the 
Gynecological Cancer Intergroup guideline for the Definition of CA-125 
response.(47)
The Schedule of Events also contains this change.
Purpose:  Clarify the screening requirements for HBV and HCV, and to add details of 
monitoring for patients who test HBcAbat Screening.
The primary change occurs in Section 7.4.14, HBV and HCV Assessment:
Added 
text:
At screening assessments, HBV surface antigen, HBV core antibody, and 
HCV antibody testing are mandatory. If HBcAb is positive, HBV DNA 
should be assessed.  If HCVAb is positive, HCV-RNA should be tested.
For patients who are HBcAb positive screening, DNA titers will be taken 
every 2 months.  

If DNA titers increase (1 log increase of viral load), treat with 
antivirals medication (lamivudine) and continue monitoring. 

If a second 1 log of increase of viral load occurs, stop treatment
and discontinue from the study.
Sections that also contain this change are:

Section 5.2, Exclusion Criteria (Criterion #18)

The Schedule of Events


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Purpose:  Adjust the requirement for disease evaluation so that patients will be evaluated 
up to progressive disease.
The primary change occurs in Section 7.4.15, Disease Assessment:
Deleted 
text:
Repeat CT (with IV contrast) or MRI scans as appropriate, or both, are to be 
performed at the completion of Cycle 2 and every 2 cycles (approximately 
every 8 weeks, between Days 21 and 28 of every even cycle) thereafter for up 
to 12 months or until PD is documented.  
The Schedule of Events also contains this change.
Purpose:  Clarify that paclitaxel and alisertib should be administered 1 hour apart on 
Cycle 1, Day 1.
The change occurs in the Schedule of Events:
Formerly 
read:
v During Cycle 1, and Cycle 3 and beyond, alisertib dosing will begin on Day 1; subsequent 
dosing will occur on Days 2, 3, 8, 9, 10, 15, 16, and 17.  During Cycle 2 only, alisertib 
dosing will begin on Day 8 and will continue on Days 9 and 10, and on Days 15, 16, and 
17.  Refer to Table 6-1 for alisertib dose administration and titration schema.  On days
when both paclitaxel and alisertib are administered, alisertib should be administered 1 hour 
before the start of the paclitaxel infusion.  Alisertib will be dispensed to the patient on Day 
1.  Tests and procedures should be performed on schedule, but may be adjusted (+ 2 days) 
for administrative and safety reasons.  If the study schedule is shifted, both assessments 
and dosing must be shifted to ensure collection of assessment is completed before dosing.  
If extenuating circumstances prevent a patient from beginning treatment or completing a 
scheduled procedure or assessment within this time, the patient may continue the study 
only with the permission of the sponsor/designee clinician.
Now 
reads:
w During Cycle 1, and Cycle 3 and beyond, alisertib dosing will begin on Day 1; subsequent 
dosing will occur on Days 2, 3, 8, 9, 10, 15, 16, and 17.  During Cycle 2 only, alisertib 
dosing will begin on Day 8 and will continue on Days 9 and 10, and on Days 15, 16, and 
17.  Refer to Table 6-1 for alisertib dose administration and titration schema.  On Cycle 1 
Day 1 when both paclitaxel and alisertib are administered, alisertib should be administered 
1 hour before the start of the paclitaxel infusion.  Alisertib will be dispensed to the patient 
on Day 1.  If the study schedule is shifted, both assessments and dosing must be shifted to 
ensure collection of assessment is completed before dosing.  If extenuating circumstances 
prevent a patient from beginning treatment or completing a scheduled procedure or 
assessment within this time, the patient may continue the study only with the permission of 
the sponsor/designee clinician
Purpose:  Allow a longer window for adjusting dosing and study assessments due to 
safety concerns (3 days, rather than 2 days, allowed for administrative reasons).
The change occurs in the Schedule of Events:
Added 
text:
Each treatment cycle is 28-days in length.  Tests and procedures should be done on schedule, 
but visit windows of 2 days are allowed (except as otherwise specified) occasionally for 
holidays, vacations, and other administrative reasons.  A dosing windows of + 3 days is
allowed due to safety concerns. If extenuating circumstances prevent a patient from 
beginning treatment or completing a scheduled assessment within this time frame, the 
patient may continue in the study only with written permission of the project clinician.


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Purpose:  Clarify the timing for the predose paclitaxel PK sample collection on Day 1.
The change occurs in the Alisertib and Paclitaxel PK Sampling Schedule:
Added 
text:
g The predose sample for alisertib PK on Days 1 and 3 can be timed to coincide with the
predose sample for paclitaxel PK on Day 1 and the 47-h paclitaxel PK sample 
depending on the timing of alisertib dosing.
Purpose:  Correct errors in percents reported for adverse events in the pooled data from 
single-agent studies of alisertib.
The change occurs in Section 1.3, Clinical Experience:
Formerly 
read:
The more commonly observed (30% incidence) treatment-emergent AEs 
(TEAEs) from pooled data across the alisertib single-agent studies include 
fatigue (48%), neutropenia (48%), anemia (45%), diarrhea (42%), alopecia 
(37%), nausea (32%), and stomatitis (31%). 
Now 
reads:
The more commonly observed (30% incidence) treatment-emergent AEs 
(TEAEs) from pooled data across the alisertib single-agent studies include 
neutropenia (47%), fatigue (46%), anemia (45%), diarrhea (42%), alopecia 
(35%), nausea (32%), and stomatitis (31%).  
Purpose:  Allow for expansion of dose escalation cohort(s) to enable a better 
understanding of safety and/or PK, if needed.
The change occurs in Section 4.1, Overview of Study Design:
Added 
text:
If alisertib exposures in the combination setting in the East Asian population 
are unexpectedly lower than anticipated from single-agent experience in East 
Asian patients, and no DLTs have occurred in the DL2 cohort (alisertib 25 mg 
BID plus 60 mg/m2 paclitaxel), the alisertib dose may be escalated further 
following discussion between the investigator and the sponsor pending PK 
and safety assessment.  Should more data be needed to better understand 
the observed safety and/or PK, with the agreement of the sponsor’s 
project clinician (or designee), cohort(s) at any dose level may be 
expanded. Intrapatient dose escalation will not be permitted in this study.  It 
is planned that at least 1 Japanese patient will be included in each of the dose 
levels explored.
Sections that also contain this change are:

Section 6.4, Dose Escalation Rules

Protocol Summary


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Purpose:  Clarify that there will be approximately 2 to 3 study centers in the escalation 
part of the study.
The change occurs in Section 4.2, Number of Patients,:
Added 
text:
There will be approximately 2 to 3 study centers in the escalation part and 
approximately 10 study centers in the expansion part.  
Purpose:  Redefine adequate renal function (Inclusion Criterion 8) by either creatinine 
levels or estimated creatinine clearance.
The change occurs in Section 5.1, Inclusion Criteria (criterion #8):
Added 
text:
Adequate renal function as defined by:  

Creatinine < 1.5 × institutional ULN or estimated creatinine clearance 
using the Cockcroft-Gault formula ≥ 30 mL/minute for patients with 
creatinine levels above institutional ULN (can be calculated using 
serum creatinine value; see Section 14.3).
Purpose:  Add details to clarify Inclusion Criterion 9 regarding previous chemotherapy 
regimen allowance.
The change occurs in Section 5.1, Inclusion Criteria (criterion #9):
Formerly 
read:
No more than 2 previous chemotherapy regimen in the metastatic setting.
Now 
reads:
Patients must have received at least 1 prior chemotherapy regimen, but
no more than 2 previous chemotherapy regimens for the advanced and/or
metastatic stage disease. The neo-adjuvant chemotherapy or post-surgical 
adjuvant chemotherapy for early-stage disease would be counted.
Purpose:  Revise Exclusion Criterion 11 to specify that there must be no use of proton 
pump inhibitors within 5 days (rather than 4 days) of the first dose of alisertib.
The primary change occurs in Section 5.2, Exclusion Criteria (criterion #11):
Formerly 
read:
Requirement for administration of proton pump inhibitor (PPI), H2 antagonist
(premedication for paclitaxel allowed), or pancreatic enzymes.  Use of any 
PPI in either continued or intermittent use will be prohibited during the 
conduct of the study and patients must discontinue any use of PPI within 4  
days before the first dose of alisertib.
Now 
reads:
Requirement for administration of proton pump inhibitor (PPI), H2 antagonist
(premedication for paclitaxel allowed), or pancreatic enzymes.  Use of any 
PPI in either continued or intermittent use will be prohibited during the 
conduct of the study and patients must not use a PPI within 5 days of the first 


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dose of alisertib.
Purpose:  Revise Exclusion Criterion 19 to specify uncontrolled cardiac arrhythmias.
The primary change occurs in Section 5.2, Exclusion Criteria (criterion #19):
Deleted 
text:
History of myocardial infarction, unstable symptomatic ischemic heart 
disease, uncontrolled hypertension despite appropriate medical therapy, any 
ongoing cardiac arrhythmias of > Grade 2, thromboembolic events (eg, deep 
vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular 
events), or any other cardiac condition (eg, pericardial effusion or restrictive 
cardiomyopathy) within 6 months before receiving the first dose of study 
drug.  Chronic stable atrial fibrillation on stable anticoagulant therapy is 
allowed.  Patients with a pacemaker may be enrolled in the study upon 
discussion with the project clinician.
Purpose:  Add an exclusion criterion (Exclusion Criterion 21) for patients with another 
malignancy within the past 3 years
The change occurs in Section 5.2, Exclusion Criteria (criterion #21):
Added 
text:
21.  Diagnosed with or treated for another malignancy within 3 years 
before the first dose of study drug, or previously diagnosed with another 
malignancy and have any evidence of residual disease.  Patients with non-
melanoma skin cancer or carcinoma in situ of any type may be enrolled 
in the study if they have undergone complete resection and no evidence of 
active disease is present.
Purpose:  Add details to the instructions for patients regarding the timing of study 
medication dosing, and add a statement that the study medication should be swallowed 
whole and not chewed.
The change occurs in Section 6.1, Study Drug Administration:
Added 
text:
Patients will be instructed to take each PO dose of alisertib with 8 ounces (1 
cup, 240 mL) of water.  The 2 daily doses must be taken at least 6 hours apart.  
Alisertib should be administered on an empty stomach in the first 3 days of 
Cycle 1 (no food from 2 hours before the dose until 1 hour after the dose).
Patients should be instructed to take their alisertib study medication at 
approximately the same time each day, approximately 12 hours apart 
(eg, 08:00 and 20:00) but not less than 6 hours apart, and not to take 
more than the prescribed dose at any time.  Patients should swallow the 
study medication whole and not chew it before swallowing.  


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Purpose:  Revise paclitaxel dosing instructions to specify that the length of paclitaxel 
infusion on Cycle 1, Day 1 and Cycle 2, Day 1 should be 60 minutes (it must not be less 
than 60 minutes, but may be up to 70 minutes maximum, where necessary), while 
paclitaxel should be infused over at least 1 hour (but not more than 90 minutes) at all other 
dosing time points.
The change occurs in Section 6.2.1, Paclitaxel:
Added 
text:
Paclitaxel will be administered as an IV infusion over at least 1 hour (but not 
more than 90 minutes) with a dose of 60 mg/m2 on Days 1, 8, and 15 in 
28-day cycles.  On Cycle 1, Day 1 and Cycle 2, Day 1, the paclitaxel dose 
should be administered over 60 minutes (it must not be less than 60 
minutes, but may be up to 70 minutes maximum, where necessary). The
paclitaxel dose will remain constant throughout the study.  The paclitaxel 
infusion time is 1 hour; the infusion time may be modified if required after 
review and agreement by the project clinician.  Refer to the paclitaxel product 
label for further details regarding paclitaxel administration.
Sections that also contain this change are:

Schedule of Events

Alisertib and Paclitaxel PK Sampling Schedule
Purpose:  Allow prophylactic antiemetics during Cycle 1, and allow modifications to 
premedications without the requirement for project clinician approval.
The change occurs in Section 6.2.2, Premedication for Paclitaxel-Associated 
Hypersensitivity or Other Acute Reactions:
Deleted 
text:
Premedication to prevent paclitaxel-associated (hypersensitivity or other) 
reactions is recommended according to institutional guidelines or local 
practices.  Premedications that may be used in this setting can include:  
corticosteroid (eg, dexamethasone, as a 20-mg single dose, which can be 
reduced with subsequent paclitaxel cycles); diphenhydramine; a 
5-hydroxytryptamine 3 (5-HT3) serotonin receptor antagonist antiemetic 
administered at its labeled dose (but prophylactic antiemetic agents should not 
be administered in the first cycle of treatment if nausea or vomiting is not 
observed).  Benzodiazepines are to be avoided.  Brief administration of 
histamine-2 antagonists (such as a single dose of cimetidine or ranitidine) is 
allowed if required on the day of paclitaxel administration, but prolonged 
administration of a histamine-2 antagonist (or any other agent that can alter 
stomach pH or drug absorption) is to be avoided (see Section 6.6).  On days 
when both alisertib and paclitaxel are administered on the same morning, the 
alisertib should be administered 1 hour before the start of the paclitaxel 
infusion.  Modifications to paclitaxel administration or to the premedications
are allowed upon agreement by the project clinician and will be documented 


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in the electronic case report form (eCRF).  
Purpose:  Clarify that thrombocytopenia with clinically significant bleeding is a DLT if it 
is greater than or equal to Grade 3 in the dose-limiting toxicity definitions.
The change occurs in Section 6.3, Definitions of Dose-Limiting Toxicity:
Added 
text:
5. Greater than or equal to Grade 3 thrombocytopenia with clinically 
significant bleeding.
Purpose:  Clarification of actions at DL3 (20-mg BID alisertib).
The change occurs in Section 6.4, Dose Escalation Rules:
Added 
text:
3.    At DL3 (20-mg BID alisertib)
-
MTD declaration will require first cycle DLTs in no more than 1 
out of 6 DLT evaluable patients.  
-
If 2 or more of 6 patients experience a DLT, alisertib will be de-
escalated to the DL1 (15-mg BID alisertib) and 3 additional 
patients will be enrolled at that dose level if there are not yet 6 
patients enrolled.  
Purpose:  Specify that PK exposure data will be used to support the determination of the 
recommended phase 2 dose (RP2D).
The change occurs in Section 6.4, Dose Escalation Rules:
Formerly 
read:
The RP2D regimen will be established following evaluation of the available 
data from the dose escalation portion of the trial which will include, but is not 
limited to, toxicity characterization (Grade 3/4 AEs, SAEs, toxicities leading 
to early dose reduction and treatment discontinuation).  The RP2D will 
require first-cycle DLTs in no more than 1 in 6 DLT-evaluable patients 
enrolled in a given cohort.  For the purpose of the RP2D regimen, Cycle 1 
data from 6 evaluable patients will be used in addition to the available clinical 
data supporting tolerance over multiple treatment cycles.  
Now 
reads:
The RP2D regimen will be established following evaluation of the available 
data from the dose escalation portion of the trial which will include, but is not 
limited to, DLTs, toxicity characterization (Grade 3/4 AEs, SAEs, toxicities 
leading to early dose reduction and treatment discontinuation).  For the 
purpose of the RP2D regimen, Cycle 1 PK data from 6 evaluable patients will 
be used in addition to the available clinical data.


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Purpose:  Extend the minimum rest period between cycles from 10 days to at least 
11 days and a maximum of 21 days.
The change occurs in Section 6.5.1, Criteria for Beginning a Subsequent Treatment Cycle:
Formerly 
read:
For a new cycle of therapy to begin the following criteria must be met: 
…

There has been a minimum rest period of 10 days or longer since the last 
dose of study drug.  
Now 
reads:
For a new cycle of therapy to begin the following criteria must be met: 
…

There has been a minimum rest period of 11 days and a maximum of 
21 days since the last dose of study drug.
Purpose:  Revise the criteria for dose interruption during a cycle.
The change occurs in Section 6.5.2, Criteria for Dose Interruption During a Cycle:
Formerly 
read:

Grade 4 neutropenia (ANC 500 cells/mm3)

Febrile neutropenia

Grade 4 thrombocytopenia (platelet count < 25,000/mm3) 

Grade 3 thrombocytopenia associated with clinically significant 
bleeding
…
Once the criteria for retreatment (Section 6.5) have been met, the patient may 
resume therapy.  If the Day 8 or Day 15 doses of paclitaxel and alisertib (or 
paclitaxel alone if applicable) have been delayed through 2 additional days or 
less (eg, Monday delayed to Wednesday, but restart possible on Thursday), 
dosing should resume after the delay without omitting doses, and without 
dose reduction.  The subsequent dose of the cycle should preserve the same 
minimal days between doses within the cycle originally planned; thus, if the 
planned Day 8 dose is delayed but restarted on Thursday, then the next 
planned “Day 15” dose would be administered on the following Thursday to 
preserve a 7-day period between the Day 8 and Day 15 doses.
If the Day 8 or Day 15 doses of paclitaxel and alisertib (or paclitaxel alone, if 
applicable) have been delayed through additional days due to lack of adequate 
recovery (eg, dosing originally planned for Monday delayed through 
Thursday, and restart only possible on Friday or later), both the paclitaxel 
dose and the 3 associated alisertib doses (if applicable) should be omitted 
within that cycle.  If the doses started on Day 15 are omitted, the cycle should 
preserve a minimum 2-week treatment-free period between the last dose of 


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protocol treatment and the start of the new cycle.  When paclitaxel and 
alisertib (if applicable) are resumed, either on Day 15 or with the subsequent 
cycle, the doses of paclitaxel and/or alisertib should be modified with 
incremental reductions if appropriate (see Section 6.5.3).
Now 
reads

Grade 3 neutropenia (ANC 1,000 cells/mm3)

Febrile neutropenia

Grade 3 thrombocytopenia (platelet count < 50,000/mm3) 
…
Once the criteria for retreatment (Section 6.5) have been met
(ANC>1000/mm3, platelet count>50,000/mm3), the patient may resume 
therapy for completion of the cycle.  If the Day 8 or Day 15 doses of 
paclitaxel and alisertib (or paclitaxel alone if applicable) have been delayed 
through 2 additional days or less (eg, Monday delayed to Wednesday, but 
restart possible on Thursday), dosing should resume after the delay without 
omitting doses, and without dose reduction.  The subsequent dose of the cycle 
should preserve the same minimal days between doses within the cycle 
originally planned; thus, if the planned Day 8 dose is delayed but restarted on 
Thursday, then the next planned “Day 15” dose would be administered on the 
following Thursday to preserve a 7-day period between the Day 8 and Day 15 
doses.
If the Day 8 or Day 15 doses of paclitaxel and alisertib have been delayed 
through additional days due to lack of adequate recovery (eg, dosing 
originally planned for Monday delayed through Thursday, and restart only 
possible on Friday or later), both the paclitaxel dose and the 3 associated 
alisertib doses should be omitted within that cycle. If the doses started on 
Day 15 are omitted, the cycle should preserve a minimum 2-week treatment-
free period between the last dose of protocol treatment and the start of the 
new cycle.  When paclitaxel and alisertib are resumed, either on Day 15 or 
with the subsequent cycle, the doses of paclitaxel and/or alisertib should be 
modified with incremental reductions if appropriate (see Section 6.5.3).
Purpose:  Revise the dose modification instructions for dose-limiting hematologic 
toxicities.
The primary change occurs in Section 6.5.3, Dose Modifications:
Formerly 
read:
Patients who continue to experience any toxicity (hematologic or 
nonhematologic) of a severity that requires additional dose reductions after 1 
dose reduction of paclitaxel and 1 dose reduction of alisertib, given 
administration of appropriate supportive care, should discontinue protocol 
treatment.  However, if the patient has evidence of clinical benefit and would 
be considered to benefit from continued protocol treatment, the patient may 
continue protocol treatment with further dose reductions, upon review and 


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written approval by the project clinician.  These circumstances should be 
discussed on a case-by-case basis.  Similarly, if a patient requires elimination 
of alisertib on the last 3 days (Days 15, 16, and 17), alisertib will be dosed 
only on the earlier cycle days as planned for all subsequent cycles (see 
Table 6-1 ).
As a general rule, if a patient requires dose reduction due to a study drug-
related toxicity, the drug dose may not be re-escalated.  
…..
Paclitaxel or alisertib will be individually reduced for dose-limiting 
hematologic toxicities that are attributable to both agents, such as sustained 
Grade 4 neutropenia, thrombocytopenia, or febrile neutropenia according to 
Table 6-2.  As a general approach to manage these hematologic toxicities 
which are also attributable to the taxane, paclitaxel should be first delayed 
and/or reduced before initiation of myeloid growth factors or before 
modification of alisertib, if applicable.  To manage dose-limiting neutropenia 
attributable to paclitaxel alone or to the combination with alisertib, the 
general goals is to avoid reducing alisertib dosing below a range considered to 
be clinically relevant.  Given the consideration, the first intervention will be 
dose reduction of paclitaxel by 10 mg/m2.  The next recommended 
intervention would be to add myeloid growth factor without further paclitaxel 
dose reduction.  Only after intervention with myeloid growth factor would the 
alisertib be reduced by 5 mg/dose.
Prophylactic use of myeloid growth factors are not allowed for patients newly 
enrolled who receive the first cycle, but may be administered for supportive 
care to manage neutropenia events if clinically indicated, according to 
American Society of Clinical Oncology (ASCO) guidelines and/or 
institutional practices.  Thus, myeloid growth factors are not mandated, but if 
used per investigator discretion, they should be administered according to 
local guidelines, the product label, and Table 6-2.  During the first cycle of 
patients enrolled to the dose escalation part, the use of myeloid growth factors 
should be avoided unless DLT or dose interruption criteria have already been 
met.  Short acting myeloid growth factors are preferred, and they should be 
discontinued for an appropriate number of days before restart of protocol 
treatment.
Table 6-2  
Dose Modification Rules:  Hematological Toxicity 
(Greater Than Grade 3)
Alisertib + Paclitaxel
First occurrence 
Reduce paclitaxel 1 level 
(eg, 60 mg/m2 to 50 mg/m2)
Repeat occurrence
Add myeloid growth factor without further dose 
modification, if appropriatea


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Or
Repeat occurrence within 
dosing period (Days 1-17)
Reduce alisertib 1 level
(ie, a 5-mg reduction)a
Repeat occurrence after dosing 
complete, during treatment-free 
period (Days 18-28)
Omit alisertib in last 3 days of schedule (ie, Days 
15, 16, and 17) but maintain the same alisertib 
doses for Days 1-3 and 8-11 as administered on 
earlier cycles
Repeat occurrence 
Discontinueb 
Paclitaxel 40 mg/m2
AND/OR
Alisertib with 1 dose reduction level, omitting Days 
15-17
Abbreviations:  BID = twice daily.
a
The use of myeloid growth factors is not mandated but is strongly encouraged 
as an intervention step for neutropenia before dose reduction of alisertib or further 
dose reduction of paclitaxel if appropriate.
b
A patient may continue the protocol with further dose reductions 
(hematologic and nonhematologic toxicities) if he or she is deriving clinical benefit, 
upon review and written approval by the project clinician.  The actual doses to be 
administered in those situations are listed.  The decision to reduce only 1 of the agents 
or both should be based on similar considerations regarding the type of adverse event 
at this time.  Note:  If after the first occurrence, the myeloid growth factor was not an 
option, the patient may continue the protocol with myeloid growth factor, if 
appropriate, before discontinuation.
Regimen Modifications for Hematologic Toxicities according to Cycle 
Day Onset Time
1.
During dosing period (Days 1-17 with the combination of paclitaxel 
plus alisertib):

FIRST OCCURRENCE:  Reduce paclitaxel by 10 mg (eg, 60- to 50 
mg/m2) in future cycles

REPEAT OCCURRENCE:  Myeloid growth factors may be 
administered, maintaining the same doses of study drug(s), per investigator 
discretion

REPEAT OCCURRENCE:  Reduce alisertib by 1 level (ie, a 5-mg 
reduction).
2.
After dosing period (eg, during the treatment-free period upon 
recovery):

FIRST OCCURRENCE:  reduce paclitaxel by 10 mg (eg, 60 to 50 
mg/m2) in future cycles


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
REPEAT OCCURRENCE:  Myeloid growth factors may be 
administered, maintaining the same doses of study drug(s), per investigator 
discretion 

REPEAT OCCURRENCE:  omit the last 3 days (eg, Days 15, 16, and 
17) of alisertib in future cycles but maintain the same alisertib doses 
administered on earlier cycle days
No more than 1 dose reduction of paclitaxel will be allowed.  However, if the 
patient has clinical benefit and would benefit from continued protocol 
treatment, the patient may continue protocol treatment with further dose 
reductions, upon review by the project clinician. 
Now 
reads:
Patients who continue to experience any toxicity (hematologic or 
nonhematologic) of a severity that requires additional dose reductions after 1 
dose reduction of paclitaxel and 1 dose reduction of alisertib, given 
administration of appropriate supportive care, should discontinue protocol 
treatment.  However, if the patient has evidence of clinical benefit and would 
be considered to benefit from continued protocol treatment, the patient may 
continue protocol treatment with further dose reductions, upon review and 
written approval by the project clinician.  These circumstances should be 
discussed on a case-by-case basis.  
As a general rule, if a patient requires dose reduction due to a study drug-
related toxicity, the drug dose may not be re-escalated.  Similarly, if a 
patient requires elimination of alisertib on the last 3 days (Days 15, 16, 
and 17) (Table 6-2), as described previously, alisertib will only be dosed 
on the earlier cycle days as planned for all subsequent cycles.
…
Paclitaxel or alisertib will be individually reduced for dose-limiting 
hematologic toxicities that are attributable to both agents, such as sustained 
Grade 4 neutropenia, thrombocytopenia, or febrile neutropenia according to 
Table 6-2.  As a general approach to manage these hematologic toxicities 
which are also attributable to the taxane, paclitaxel should be first delayed 
and/or reduced before initiation of myeloid growth factors or before 
modification of alisertib, if applicable.  To manage dose-limiting neutropenia 
attributable to paclitaxel alone or to the combination with alisertib, the 
general goal is to avoid reducing alisertib dosing below a range considered to 
be clinically relevant.  Given these considerations, the first intervention will 
be dose reduction of paclitaxel by 10 mg/m2.  The next intervention would be 
to add myeloid growth factor if appropriate.  Only after intervention with 
myeloid growth factor, if appropriate, and in a situation of a repeat 
occurrence within dosing would the alisertib be reduced by 5 mg/dose. In 
the situation of a repeat occurrence of hematological toxicity after 
completion of dosing in a cycle, the last 3 days of alisertib or placebo 
would be omitted.  If the treating physician (or investigator) believes that 
at a particular occurrence and due to the nature of the event or patient 


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history, an intervention treatment that deviates from the described 
general guidelines is preferred, it should be discussed with and approved 
by the sponsor’s project clinician (or designee).
Prophylactic use of myeloid growth factors are not allowed for patients newly 
enrolled who receive the first cycle, but may be administered for supportive 
care to manage neutropenia events if clinically indicated, according to 
American Society of Clinical Oncology (ASCO) guidelines and/or 
institutional practices.  Thus, myeloid growth factors are not mandated, but if 
used per investigator discretion, they should be administered according to 
local guidelines, the product label, and Table 6-2.  During the first cycle of 
patients enrolled to the dose escalation part, the use of myeloid growth factors 
should be avoided unless DLT or dose interruption criteria have already been 
met.  Short acting myeloid growth factors are preferred, and they should be 
discontinued for an appropriate number of days before restart of protocol 
treatment.
Alternative dose modifications may be recommended after discussion 
with the investigator and project clinician/designee to maximize exposure 
of study treatment while protecting patient safety.
Table 6-2   
Dose Modification Rules:  Hematological Toxicity 
Alisertib + Paclitaxel
First occurrence 
Reduce paclitaxel 1 level 
(eg, 60 mg/m2 to 50 mg/m2)
Repeat occurrence
Add myeloid growth factor without further dose 
modification, if appropriatea
Repeat occurrence within dosing 
period (Days 1-17)
Reduce alisertib 1 level
(ie, a 5-mg reduction)a
Or
Repeat occurrence after dosing 
complete, during treatment-free 
period (Days 18-28)
Omit alisertib in last 3 days of schedule (ie, Days 15,
16, and 17) but maintain the same alisertib doses for 
Days 1-3 and 8-11 as administered on earlier cycles
Repeat occurrence 
Discontinueb 
Paclitaxel 40 mg/m2
AND/OR
Alisertib with 1 dose reduction level, omitting Days 
15-17
Abbreviations:  BID = twice daily.
a The use of myeloid growth factors is not mandated but is strongly encouraged as an 
intervention step for neutropenia before dose reduction of alisertib or further dose 
reduction of paclitaxel if appropriate.
b A patient may continue the protocol with further dose reductions (hematologic and 
nonhematologic toxicities) if he or she is deriving clinical benefit, upon review and written 
approval by the project clinician.  The actual doses to be administered in those situations 
are listed.  The decision to reduce only 1 of the agents or both should be based on similar 
considerations regarding the type of adverse event at this time.  Note:  If after the first 
occurrence, the myeloid growth factor was not an option, the patient may continue the 


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protocol with myeloid growth factor, if appropriate, before discontinuation.
No more than 1 dose reduction of paclitaxel will be allowed.  However, if the 
patient has clinical benefit and would benefit from continued protocol 
treatment, the patient may continue protocol treatment with further dose 
reductions, upon review and written approval by the project clinician. 
Purpose:  Add specific dose adjustment requirements due to occurrence of oral 
mucositis/stomatitis/mouth ulcers.
The change occurs in Section 6.5.3, Dose Modifications:
Formally 
read
Dose Modifications for Nonhematologic Toxicities

Dose modifications will be as described previously for hematologic 
toxicities; however, only the drug thought to be responsible for the 
toxicity should be reduced.  If both alisertib and paclitaxel may have 
contributed, or the investigator is uncertain which drug is responsible, 
then both alisertib and paclitaxel should be modified using the 
incremental reductions described previously. 

If a patient requires dose reduction due to a study drug-related 
toxicity, the drug dose may not be re-escalated.  Similarly, if a patient 
requires elimination of alisertib on the last 3 days (eg, Days 15, 16, 
and 17) due to DLT, as described previously, alisertib will only be 
dosed on the earlier cycle days as planned for all subsequent cycles.

REPEAT OCCURRENCES:  Patients who continue to experience
dose-limiting toxicity (hematologic or nonhematologic) after 1 dose 
reduction, given administration of appropriate supportive care, should 
discontinue protocol treatment.  However, if the patient has clinical 
benefit and would benefit from continued protocol treatment, the 
patient may continue protocol treatment with further dose reductions, 
upon review by the project clinician.
Now 
reads:
Dose Modifications for Nonhematologic Toxicities

Dose modifications with incremental reductions will be as described 
previously for hematologic toxicities; however, only the drug thought 
to be responsible for the toxicity should be reduced.  If both alisertib 
and paclitaxel may have contributed, or the investigator is uncertain 
which drug is responsible, then dose modification will be as 
described above for hematologic toxicities starting with paclitaxel 
(first occurrence).

For both the “within” and “after” dosing regimens at the next 
repeat occurrence with dose modified, drug will be discontinued 
but with the option to continue under the considerations detailed 


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in the last row of Table 6-2.  Specific dose adjustment is required 
for oral mucositis (Table 6-3).
Table 6-3   
Dose Adjustments for Oral Mucositis (Drug-related)
Toxicity
NCI 
CTCAE 
Grade
Finding
Action on Drug
Mucositis 
oral
Grade 1
Asymptomatic or mild 
symptoms; intervention not 
indicated
Medical management 
as appropriate, no 
action on study drug.
Grade 2
Moderate pain; not 
interfering with oral 
intake; modified diet 
indicated
•
Medical 
management as 
appropriate.
•
Hold alisertib until 
resolution to Grade 
≤ 1 or baseline but 
pursue paclitaxel as 
single agent at 
current dose level.
Upon recovery (at any 
time during the cycle), 
resume alisertib at 
current dose level.
Grade 3
Severe pain; interfering 
with oral intake
•
Hold paclitaxel and 
alisertib.
•
Upon recovery to 
Grade ≤ 2, resume 
paclitaxel only at 
current dose level. 
Upon recovery to 
Grade ≤ 1 or baseline 
(at any time during the 
cycle), resume alisertib
at the next lower dose 
level.
Grade 4
Life-threatening 
consequences; urgent 
intervention indicated
Discontinue study drug.
Lack of 
acceptable 
timely 
recovery
Delay > 21 days in the start 
of a subsequent cycle due to 
lack of recovery of oral 
mucositis to Grade 2 for 
initiation of paclitaxel 
and/or Grade 1 for 
initiation of alisertib
Discontinue study drug. 
The maximum delay 
before treatment should 
be discontinued is 
3 weeks (Section 6.3.1).
Abbreviation:  NCI CTCAE = National Cancer Institute Common Terminology 
Criteria for Adverse Event
Suggested Management of Stomatitis


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Stomatitis/oral mucositis/mouth ulcers should be treated using local 
supportive care.  In addition to standard oral and dental assessment and 
hygiene, please consider the paradigm below for treatment of 
stomatitis/oral mucositis/mouth ulcers:
1.
PROPHYLAXIS:

Consider prophylaxis with salt water (0.9%) mouthwash or 
baking soda (1 teaspoon per glass of warm water) 2 to 3 times 
per day to prevent mucositis starting the day of alisertib for up 
to 7 days thereafter.
2.
ESTABLISHED STOMATITIS:

For mild toxicity (Grade 1), use conservative measures such as 
nonalcoholic mouthwash, artificial saliva, or salt water (0.9%) 
mouthwash 4 to 6 times daily until resolution. Limit to foods that 
do not require significant chewing, and avoid acidic, salty, or 
dry foods.

For more severe toxicity (Grade 2 in which case patients have 
pain but are able to maintain adequate oral alimentation, or 
Grade 3 in which case patients cannot maintain adequate oral 
alimentation), use topical analgesic mouth treatments (eg, local 
anesthetics such as benzocaine, butyl aminobenzoate, tetracaine 
hydrochloride, menthol, or phenol) with or without topical 
corticosteroids, such as triamcinolone oral paste 0.1% (Kenalog 
in Orabase®).
3.
AGENTS THAT SHOULD BE AVOIDED: 

Agents containing hydrogen peroxide, iodine, and thyme 
derivatives may worsen mucositis and should be avoided.
Purpose:  Clarify that alternative therapy or medicine(s) are not allowed
The change occurs in Section 6.6, Excluded Concomitant Medications and Procedures:
Added 
text:
The following medications and procedures are prohibited during the study:
…

Alternative therapy or medicine(s) are not allowed.  Palliative 
radiation therapy for pain management on a lesion not established as 
progressive and located outside of the field of a target/nontarget lesion is 
allowed.  (Note that radiation therapy should occur during the rest period 
and not while dosing.)


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Purpose:  Prohibit the use of pancreatic enzyme during the study.
The change occurs in Section 6.6, Excluded Concomitant Medications and Procedures:
Added 
text:
The following medications and procedures are prohibited during the study:
…

Use of any PPI or pancreatic enzyme is prohibited during the conduct 
of the study.  Patients may be administered alternative agents to manage 
gastric acidity or reflux (eg, H2 receptor antagonists, antacids) with 
exceptions described in the following.
Purpose:  Permit premedication with corticosteroids, diphenhydramine, or histamine-2 
receptor antagonists before each treatment with paclitaxel.
The change occurs in Section 6.7, Permitted Concomitant Medications and Procedures:
Added 
text:
Premedication with corticosteroids, diphenhydramine, or histamine-2 
receptor antagonists is permitted before each treatment with paclitaxel.
Purpose:  Correct the definition of women of childbearing potential.
The primary change occurs in Section 7.4.7, Pregnancy Test:
Formerly 
read:
Women of childbearing potential will be defined as sexually mature females 
who meet the following criteria:
1. Those who have not undergone hysterectomy or bilateral oophorectomy, 
and
2. Those who have not had natural menopause for 24 consecutive months 
or longer (eg, FSH > 40 IU/L and no menopausal period for at least 24 
consecutive months) (loss of menopausal periods following 
chemotherapy may not rule out childbearing potential).
Now 
reads:
Women of childbearing potential will be defined as sexually mature females 
who meet the following criteria:
1. Those who have not undergone hysterectomy or bilateral oophorectomy, 
and
2. Those who have not had natural menopause (eg, FSH > 40 IU/L and no
menstrual period for at least 24 consecutive months) for 24 
consecutive months or longer (loss of menstrual periods following 
chemotherapy may not rule out childbearing potential).


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Purpose:  Clarify that radiographic images will be provided to the sponsor if necessary.
The change occurs in Section 7.4.15, Disease Assessment:
Formerly 
read
Repeat CT (with IV contrast) or MRI scans as appropriate, or both, are to be 
performed at the completion of Cycle 2 and every 2 cycles (approximately 
every 8 weeks, between Days 21 and 28 of every even cycle) thereafter for up 
to 12 months or until PD is documented.  The same imaging modality should 
be used throughout the study for each site of disease.  For responders, 
radiographic images will be read locally but will be collected and provided to 
the sponsor for subsequent review.  Scans are required at the EOT visit only if 
PD has not been documented previously and it has been 8 weeks or more 
since the previous evaluation.
Now
reads:
Repeat CT (with IV contrast) or MRI scans as appropriate, or both, are to be 
performed at the completion of Cycle 2 and every 2 cycles (approximately 
every 8 weeks, between Days 21 and 28 of every even cycle) thereafter until 
PD is documented.  The same imaging modality should be used throughout 
the study for each site of disease.  For responders, radiographic images will 
be read locally but will be collected and, if necessary, provided to the 
sponsor for subsequent review.  Scans are required at the EOT visit only if 
PD has not been documented previously and it has been 8 weeks or more 
since the previous evaluation.
Purpose:  Clarify when patients who are withdrawn in Cycle 1 should be replaced.
The change occurs in Section 7.7, Discontinuation of Treatment With Study Drug, and 
Patient Replacement:
Added
text:
Patients who are withdrawn from treatment during Cycle 1, either for reasons 
other than DLT, or because they do not meet DLT-evaluable criteria, will 
be replaced.
Purpose:  Add clarification to DLT evaluable population.
The change occurs in Section 8.1.3, Populations for Analysis:
Added 
text:

DLT-evaluable population:  the DLT-evaluable population, defined as 
all patients who either experience DLT during Cycle 1 or complete 
treatment with at least 15 of the planned 18 doses of alisertib and 2 of 
the planned 3 doses of paclitaxel in Cycle 1 unless AE/DLTs and 
have sufficient follow up data to allow the investigators and sponsor 
to determine whether DLT occurred, will be used for analysis of DLT.


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Purpose:  Update the TEAE definition to the current template.
The change occurs in Section 8.1.8, Safety Analysis.
Deleted 
text:
AEs will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary for the purpose of summarization.  All AEs 
occurring on study will be listed in data listings.  Treatment-emergent AEs 
will be tabulated, where treatment emergent is defined as any AE that occurs 
after administration of the first dose of any study drug through 30 days after 
the last dose of any study drug, any event that is considered by the 
investigator to be drug-related regardless of the start date of the event, or any 
event that is present at baseline but worsens in intensity or is subsequently 
considered by the investigator to be drug-related.  AEs are to be tabulated 
using MedDRA system organ class, high-level term, and preferred term, 
including the following treatment-emergent categories:  
Purpose:  Remove final study analysis description from interim analysis section.
The change occurs in Section 8.1.9, Interim Analysis:
Deleted 
text:
There is no formal interim analysis.  The final analyses for the CSR will be 
conducted after all patients enrolled in the study have completed study 
treatment and follow-up visits.  There will be an ongoing review of safety 
data with the medical monitor and study investigators.
Purpose:  Remove administrative language regarding study closure that was intended for 
a European regulatory system, and is not applicable to this study.
The change occurs in Section 10.12, Closure of the Study:
Deleted 
text:
Within 90 days of the end of the study, the sponsor will notify the competent 
authorities and the IECs in all member states where the study is being carried 
out that the study has ended.
Within 1 year of the end of the study, a summary of the clinical trial results 
will be submitted to the competent authorities and IECs in all member states 
involved in the study.
…
Within 15 days of premature closure, Millennium must notify the competent 
authorities and IECs of any member state where the study is being conducted, 
providing the reasons for study closure. 
Purpose:  Correct typographical errors, punctuation, grammar, and formatting
These changes are not listed individually.


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PPD

SAP_000.pdf: 
This may include, but is not limited to, redaction of the following: 

Named persons or organizations associated with the study.

•
Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content 
is masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
Proprietary information, such as scales or coding systems, which are considered confidential
information under prior agreements with license holder.
Title: A Phase 1b Study of Alisertib (MLN8237) in Combination With Weekly Paclitaxel in 
East Asian Patients With Advanced Solid Tumors
NCT Number: NCT02367352
SAP Approve Date: 25 January 2017


Alisertib (MLN8237)
Statistical Analysis Plan, Study C14022
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STATISTICAL ANALYSIS PLAN
A Phase 1/1b Study of Alisertib (MLN8237) in Combination with Weekly Paclitaxel in 
East Asian Patients with Advanced Solid Tumors
Protocol #:  C14022
SAP Version:
Date of Statistical Analysis Plan:
Final
25 January 2017
Approval Signatures
Date
Date
Date
Date
PPD
PPD
PPD
PPD


Alisertib (MLN8237)
Statistical Analysis Plan, Study C14022
Confidential
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TABLE OF CONTENTS
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.........................................4
1. INTRODUCTION............................................................................................................5
1.1 Study Design ..............................................................................................................5
1.2 Study Objectives.........................................................................................................6
2. POPULATIONS FOR ANALYSIS ..................................................................................6
2.1 Safety Population........................................................................................................6
2.2 Pharmacokinetics Population ......................................................................................7
2.3 DLT-evaluable Population ..........................................................................................7
3. HYPOTHESES AND DECISION RULES.......................................................................7
4. INTERIM ANALYSIS.....................................................................................................7
4.1 Interim Analysis..........................................................................................................7
4.2 Data Safety Monitoring Board (DSMB)......................................................................7
5. STATISTICAL METHODOLOGY .................................................................................8
5.1 Sample Size Justification.............................................................................................8
5.2 Randomization and Stratification ................................................................................8
5.3 Unblinding..................................................................................................................8
5.4 Data Handling.............................................................................................................8
5.4.1 Methods for Handling Missing Data .....................................................................8
5.4.2 Definition of Baseline Values..............................................................................11
5.4.3 Windowing of Visits...........................................................................................11
5.4.4 Justification of Pooling.......................................................................................11
5.4.5 Withdrawals, Dropouts, Lost to Follow-up ........................................................11
5.5 Patient Disposition....................................................................................................11
5.6 Demographics and Baseline Disease Characteristics ..................................................11
5.6.1 Demographics....................................................................................................11
5.6.2 Medical History..................................................................................................12
5.6.3 Baseline Disease Status......................................................................................12
5.7 Treatments and Medications .....................................................................................12
5.7.1 Concomitant Medications...................................................................................12
5.7.2 Study Treatments...............................................................................................13
5.8 Efficacy Analyses......................................................................................................14
5.9 Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis...................................14
5.9.1 Pharmacokinetic Analyses ..................................................................................14
5.9.2 Pharmacodynamic Analysis ................................................................................15
5.9.3 Biomarkers ........................................................................................................15
5.10 Safety Analyses.......................................................................................................15
5.10.1 Adverse Events ................................................................................................15
5.10.2 Laboratory Data...............................................................................................17
5.10.3 Electrocardiograms ..........................................................................................18
5.10.4 Vital Signs .......................................................................................................18
5.10.5 Other Safety Assessments.................................................................................18
6. SIGNIFICANT PROTOCOL DEVIATIONS.................................................................18
7. CHANGES TO PLANNED ANALYSES FROM PROTOCOL......................................19


Alisertib (MLN8237)
Statistical Analysis Plan, Study C14022
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8. PROGRAMMING CONSIDERATIONS .......................................................................19
8.1 Statistical Software...................................................................................................19
8.2 Rules and Definitions................................................................................................19
9. REFERENCES ..............................................................................................................19


Alisertib (MLN8237)
Statistical Analysis Plan, Study C14022
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4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ATC 
anatomical therapeutic chemical
AUC
area under the plasma concentration versus time curve
AUC0-τ
area under the plasma concentration versus time curve zero to next dose
BID
bis in die; twice a day
BSA
Body surface area
CLss/F
steady-state apparent oral clearance
Cmax
maximum plasma concentration
Ctrough
trough concentration
DLT
dose-limiting toxicity
DSMB
data safety monitoring board
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
ECT
enteric-coated tablet
G-CSF
granulocyte colony-stimulating factor
IWG
International Working Group
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NCI CTC
National Cancer Institute Common Terminology Criteria
NPO
nothing by mouth
PK
pharmacokinetic(s)
PO
per os; by mouth (orally)
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
recommended phase 2 dose
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
Tmax
first time to maximum plasma concentration
UGT
uridine diphosphate glucuronosyltransferase
WBC
white blood cell
WHO
World Health Organization


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Statistical Analysis Plan, Study C14022
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1. INTRODUCTION
In general, the purpose of the Statistical Analysis Plan (SAP) is to provide a framework that 
addresses the protocol objectives in a statistically rigorous fashion, with minimized bias or 
analytical deficiencies. Specifically, this plan has the following purpose:
To prospectively (a priori) outline the types of analyses and data presentations that will 
addresses the study objectives outlined in the protocol, and to explain in detail how the data 
will be handled and analyzed, adhering to commonly accepted standards and practices of 
biostatistical analysis in the pharmaceutical industry.
1.1
Study Design
This is an open-label, multicenter, phase 1b study to evaluate the safety, tolerability, and PK 
of alisertib in combination with weekly paclitaxel in East Asian patients. The study is in 2 
parts: the first part is a dose escalation to determine the MTD and define the RP2D of the 
alisertib plus paclitaxel combination in East Asian patients with advanced solid tumors; the 
second part is an expansion cohort at the RP2D of the alisertib plus paclitaxel combination in 
East Asian patients with either OC or SCLC. Alisertib will be administered orally 3 days on/4 
days off for 3 weeks on Days 1 through 3, 8 through 10, and 15 through 17 in 28-day cycles. 
Paclitaxel 60 mg/m2 IV will be administered on Days 1, 8, and 15 in 28-day cycles. The 
paclitaxel dose will remain constant throughout the dose escalation and expansion parts of 
this study. Enrolled patients may receive study drug until observed progression, need of 
discontinuation because of toxicity, lost to follow-up, study is terminated by the sponsor, 
protocol violation, unsatisfactory therapeutic response, or voluntary withdrawal by the 
patient from the study. Patients may discontinue therapy at any time. Patients will attend the 
End of Treatment visit 30 days after receiving their last dose of study drug.
Up to 3 dose cohorts are planned with 3 to 6 patients enrolled per cohort based on the 
standard 3+3 dose escalation scheme. Dosing will begin with 15 mg BID, followed by 25 mg 
as tolerated. 
If 2 of the first 6 patients experience a DLT at 15 mg BID, depending on the overall safety 
profile, the type of AEs/DLTs observed, and the available PK data, a decision will be made


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either to expand the 15 mg BID alisertib cohort with 6 additional patients, or to de-escalate 
the Alisertib dose to 10 mg BID (DL-1), or to terminate the study.
Once the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) levels are 
determined, at least 12 patients will be treated at the RP2D to more fully characterize the 
safety, tolerability, and pharmacokinetics (PK) of alisertib. 
1.2
Study Objectives
The primary objectives are:

To evaluate the safety and tolerability and determine the MTD to subsequently define 
an RP2D of alisertib in combination with weekly paclitaxel in East Asian patients with 
advanced solid tumors.

To characterize the PK of alisertib and paclitaxel in the combination setting in East 
Asian patients with advanced solid tumors.
The secondary objective is:

To identify initial signs of antitumor activity in patients with relapsed/refractory OC
or SCLC.
2. POPULATIONS FOR ANALYSIS
2.1
Safety Population
The safety population will include all patients who receive at least 1 dose of alisertib. The 
safety population will be used for all safety analyses.


Alisertib (MLN8237)
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2.2
Pharmacokinetics Population
The PK population, defined as all patients who have sufficient dosing data and plasma 
concentration-time data to permit calculations of PK parameters, will be used for PK 
analyses.
PK analyses will be performed using the PK population.
2.3
DLT-evaluable Population
The DLT-evaluable population, defined as all patients who either experience DLT during 
Cycle 1 or complete treatment with at least 15 of the planned 18 doses of alisertib and 2 of 
the planned 3 doses of paclitaxel in Cycle 1 unless AE/DLTs and have 28-day follow up data 
in Cycle 1 to allow the investigators and sponsor to determine whether DLT occurred, will be 
used for analysis of DLT.
The DLT-evaluable population will be used for the analysis of DLT and MTD.
3. HYPOTHESES AND DECISION RULES
No formal statistical hypothesis or decision rule is planned.
4. INTERIM ANALYSIS
4.1
Interim Analysis
No interim analysis is planned. Data will be reviewed on a continuous basis.
4.2
Data Safety Monitoring Board (DSMB)
There is no IDMC/DSMB in this study.


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5. STATISTICAL METHODOLOGY
Statistical analyses will be primarily descriptive and graphical in nature. No formal statistical 
hypothesis testing will be performed. In general, summary tabulations will be presented that 
display the number of observations, mean, standard deviation, median, minimum, and 
maximum for continuous variables, and the number and percent (of non-missing) per 
category for categorical data, unless specified otherwise. 
5.1
Sample Size Justification
Up to 3 dose cohorts are planned with 3 to 6 patients enrolled per cohort based on the 
standard 3+3 dose escalation scheme. Once the MTD and RP2D levels are determined, at 
least 12 patients additional patients will be treated at the RP2D to more fully characterize the 
safety, tolerability, and PK of alisertib. Assuming 10% of patients are not evaluable for DLT,
PK or both, it is anticipated that enrollment of approximately 30 patients is needed.
5.2
Randomization and Stratification
Randomization will not be used in this study.
5.3
Unblinding
This is an open-label study. No unblinding methodology is required.
5.4
Data Handling
5.4.1 Methods for Handling Missing Data
All available data will be presented. Data that are potentially spurious or erroneous will be 
examined under the auspices of standard data management operating procedures. Every 
effort will be made to avoid missing/partial date in on-study data.
In general, missing data will be treated as missing and no data imputation will be applied, 
unless otherwise specified. 


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5.4.1.1
Missing/Partial Dates in Adverse Events
Adverse events with start dates that are completely or partially missing will be analyzed as 
follows:

If the start date has month and year but day is missing, the event will be considered 
treatment emergent if the month and year of the start date of the event are: 
o
On or after the month and year of the date of the first dose of study drug,
and 
o
On or before the month and year of (the date of the last dose of study drug plus
30 days).

If the start date has year, but day and month are missing, the event will be considered 
treatment emergent if the year of the start date of the event is:
o
On or after the year of the date of the first dose of study,
and 
o
On or before the year of (the date of the last dose of study plus 30 days).

If the start date of an event is completely missing then the event is assumed to be 
treatment emergent. 
However, if the end date is complete or partially missing but it is clear that the end date is 
before the first dose of study drug, the event will not be considered treatment emergent.
5.4.1.2
Missing/Partial Dates in Concomitant Medications
Concomitant therapies with start dates that are completely or partially missing will be 
analyzed as follows:

If the start date has month and year but day is missing, the event will be considered 
concomitant if the month and year of the start date of the event are: 


Alisertib (MLN8237)
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o
On or after the month and year of the date of the first dose of study drug,
and 
o
On or before the month and year of (the date of the last dose of study drug plus 
30 days).

If the start date has year, but day and month are missing, the event will be considered 
concomitant if the year of the start date of the event is:
o
On or after the year of the date of the first dose of study,
and 
o
On or before the year of (the date of the last dose of study plus 30 days).

If the start date of an event is completely missing then the event is assumed to be 
concomitant. 
However, if the end date is complete or partially missing but it is clear that the end date is 
before the first dose of study drug, the event will not be considered concomitant. 
When the start date is complete and is before the first dose, and the concomitant medication
is not ongoing but the end date is missing completely or partially, similar algorithm should be 
used to assess whether end date is before last dose of study plus 30 days to be included.
5.4.1.3
Missing Data in PK Analyses
For AUC calculation in PK analyses, the pre-dose concentration in an individual following
multiple dose administration may be used in place of the concentration at the end of the 
dosing interval (or vice versa) if one of these data points is not available and scientific 
considerations based on PK characteristics of alisertib support conclusion of achievement of 
steady-state on the day of PK sampling.


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5.4.2 Definition of Baseline Values
Unless otherwise specified, the baseline value is defined as the value collected at the time 
closest to, but prior to, the start of study drug administration.   
5.4.3 Windowing of Visits
All data will be categorized based on the scheduled visit at which it was collected. These visit 
designators are predefined values that appear as part of the visit tab in the eCRF. 
5.4.4 Justification of Pooling
All data from all sites will be pooled. Study center or treatment-by-center interaction will not 
be included in any statistical analysis.
5.4.5 Withdrawals, Dropouts, Lost to Follow-up
Patients will be replaced if they are not evaluable for DLTs. These additional patients will 
receive the same allocation of treatment as those for whom they replaced. 
5.5
Patient Disposition
A disposition of patients includes the number and percentage of patients for the following 
categories by the dose level the patient is enrolled to and total: patients in the safety 
population, patients in the PK population, patients in the DLT-evaluable population, and 
patients discontinued from the study. The primary reason for study discontinuation will also 
be summarized in this table. All percentages will be based on the number of patients in the 
safety population. 
A listing will present data concerning patient disposition.
5.6
Demographics and Baseline Disease Characteristics
5.6.1 Demographics
Demographic and baseline characteristics will be summarized by the dose level the patient is 
enrolled to and total. Baseline demographic data to be evaluated will include age, gender, 


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race, ethnicity, country, height, weight, and body surface area (BSA). Demographic data will 
also be presented in a by-patient listing.
The formulation for BSA is:
BSA = sqrt(height(cm) x weight (kg) / 3600),
where weight is in kilograms and height in meters.
5.6.2 Medical History
Medical history will be presented in a by-patient listing, including the medical and surgical 
history, date of onset and the status (whether it is resolved or ongoing).
5.6.3 Baseline Disease Status
Baseline disease type will be summarized by the number and percentage of patients in the 
safety population, presented by the dose level the patient is enrolled to and total. Eastern 
Cooperative Oncology Group (ECOG) performance status will be summarized similarly in 
the same table. Separate by-patient listings will also be presented for baseline disease type
and ECOG performance status.
A separate by-patient listings may be presented for prior therapy, prior surgery, and prior 
radiation, pending data availability.
5.7
Treatments and Medications
5.7.1 Concomitant Medications
Concomitant medications will be coded by preferred term using the 2014 March version of 
the World Health Organization (WHO) Drug Dictionary. The number and percentage of
patients taking concomitant medications from 28 days before the first dose of study drug 
through 30 days after the last dose of study drug or until the start of subsequent 
antineoplastic therapy, whichever occurs first, will be tabulated by WHO drug generic term, 
presented by the dose level the patient is enrolled to and total. Patients are counted once for 


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each WHO drug generic term. Concomitant medications will also be presented in a by-patient 
listing.
Concomitant procedures will not be coded, but will be presented in a by-patient listing.
5.7.2 Study Treatments
Alisertib will be administered orally 3 days on/4 days off for 3 weeks on Days 1 through 3, 8 
through 10, and 15 through 17 in 28-day cycles. Alisertib dosing during Cycle 1 will begin at 
Cycle 1, Day 1, the same day as the first dose of paclitaxel; alisertib will be administered 1 
hour before the start of the paclitaxel infusion. In Cycle 2, alisertib doses will be held on Days 
1 through 3. During the dose escalation and expansion part, for Cycle 2 only, patients will 
receive 12 doses of alisertib, administered BID on Days 8 through 10 and 15 through 17 to 
permit PK assessment of paclitaxel alone up to 48 hours. Alisertib dosing in all subsequent 
cycles (Cycle 3 and beyond) will begin on Day 1. Paclitaxel 60 mg/m2 IV will be administered 
on Days 1, 8, and 15 in 28-day cycles. The paclitaxel dose will remain constant throughout 
the dose escalation and expansion parts of this study. 
5.7.2.1
Extent of Exposure
The exposure to alisertib will be characterized by total amount of dose taken in mg, total 
number of dose taken, number of treated cycles for alisertib, numbers and percentages of 
patients who had ≥1, ≥2, …, and ≥6 treated cycles for alisertib and relative dose intensity The 
exposure to paclitaxel will be characterized by total amount of dose taken in both mg and 
mg/m2, total number of dose taken, number of treated cycles for paclitaxel, numbers and 
percentages of patients who had ≥1, ≥2, …, and ≥6 treated cycles paclitaxel and relative dose 
intensity A treated cycle is defined as a cycle in which the patient received any amount of 
specified study drug. 
Relative dose intensity (%) for alisertib is defined as 100(total amount of dose taken (mg))/ 
(prescribed dose per day*planned treated days.
Relative dose intensity (%) for paclitaxel is defined as 100(total amount of dose taken 
(mg/m2))/(prescribed dose per day*planned treated days).


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Prescribed dose is determined by the dose level to which a patient is enrolled at the onset of 
the study.
Dosing data will also be presented in a by-patient listing.
5.7.2.2
Treatment Modifications
Action on study drug will be summarized for each of the Cycle 1 through 6, sum of the 
remainder Cycles, and total, by the dose level the patient is enrolled to and total. 
5.8
Efficacy Analyses
All efficacy evaluations will be conducted using the safety population. There is no primary 
efficacy endpoint in the study. The secondary efficacy endpoint in the expansion part of the 
study is the disease response based on the RECIST version 1.1 ORR (CR + PR), which will 
be presented in a listing.
Tumor measurements, if collected, will be presented in by-patient listings.
5.9
Pharmacokinetic, Pharmacodynamic, and Biomarker Analysis
5.9.1 Pharmacokinetic Analyses
Paclitaxel
Individual and mean plasma concentration data (grouped by alisertib dose level) will be 
plotted over time for paclitaxel alone (Cycle 2, Day 1) and for paclitaxel administered 
concomitantly with alisertib (Cycle 1, Day 1). Noncompartmental PK analysis will be 
performed on individual concentration-time data to calculate plasma PK parameters, 
including, but not limited to, Cmax, AUC0-tlast, AUC0-inf, and t½, for paclitaxel administered 
alone (Cycle 2, Day 1) and during concomitant administration of alisertib (Cycle 1, Day 1).
Descriptive statistics will be presented for plasma PK parameters grouped by alisertib dose
level. Additionally, the ratio of geometric means of paclitaxel Cmax, AUC0-tlast, and AUC0-inf
(when administered with the MTD/RP2D of alisertib in reference to when administered
alone) and the associated 90% CI will be calculated.. 


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Alisertib
Individual and mean plasma concentration-time data will be plotted for alisertib on Days 1 
and 3 by dose level. Noncompartmental PK analysis will be performed on individual 
concentration-time data to calculate plasma PK parameters of alisertib, including but not 
limited to, Day 1 and Day 3 Cmax, Tmax, and AUC0-. Alisertib plasma concentration-time data 
and PK parameters will be summarized descriptively by dose level using the PK-evaluable 
population.
5.9.2 Pharmacodynamic Analysis
This is not applicable to this study.
5.9.3 Biomarkers
This is not applicable to this study.
5.10 Safety Analyses
Safety evaluations will be based on the incidence, severity, type of AEs, clinically significant 
changes, vital signs, weight, and clinical laboratory results. 
These analyses will be performed using the safety population.
5.10.1 Adverse Events
5.10.1.1 Adverse Events
Adverse events will be coded using MedDRA version 18.0 or higher. All AEs will be 
presented in a by-patient listing. Treatment-emergent AEs will be tabulated where treatment-
emergent is defined as any AE that occurs after administration of the first dose of study drug
and up through 30 days after the last dose of any study drug, or until the start of subsequent 
antineoplastic therapy, whichever occurs first. Treatment-emergent AEs will be tabulated 
according to the MedDRA by system organ class, high level terms and preferred terms and 
will include the following categories. Patients with the same AE more than once will have 


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that event counted only once within each body system, once within each high level term, and 
once within each preferred term. 

Treatment-emergent AEs.

Drug-related treatment-emergent AEs.

Grade 3 or higher treatment-emergent AEs.

Grade 3 or higher drug-related treatment-emergent AEs.
Drug-related treatment-emergent AEs will also be summarized by the National Cancer 
Institute Common Toxicity Criteria (NCI CTC) version 4.03 AE intensity. Patients with the 
same AE more than once will have the maximum intensity of that event counted within each 
body system, once within each high level term, and once within each preferred term. 
The most commonly reported treatment-emergent AEs (ie, those events reported by 10% of 
all patients in the safety population) will be tabulated by system organ class and preferred 
term. Patients with the same AE more than once will have that event counted only once 
within each system organ class and once within each preferred term.
The overall treatment-emergent AE summary, Grade 3 or higher treatment-emergent AE, 
drug-related treatment-emergent AE, and most common treatment-emergent AE will be 
summarized by the dose level the patient is enrolled to and total.   
5.10.1.2 Serious Adverse Events
The number and percentage of patients experiencing at least one treatment-emergent serious 
AE (SAE) will be summarized by MedDRA primary system organ class, high level term, and 
preferred term. Drug-related SAE will be summarized similarly.
In addition, a by-patient listing of the SAEs will be presented (the patient listing will contain 
all SAEs regardless of treatment-emergent AE status).


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5.10.1.3 Deaths
A by-patient listing of the deaths will be presented. All deaths occurring on-study will be 
displayed (regardless of treatment-emergent AE status). On-study death is defined as the 
death that occurs between the first dose of study drug and 30 days of the last dose of study 
drug, or until the start of subsequent antineoplastic therapy, whichever occurs first.
5.10.1.4 Adverse Events Resulting in Discontinuation of Study Drug
A by-subject listing of AEs resulting in discontinuation of study drug will be presented. All 
AEs resulting in discontinuation of study drug occurring on-study will be displayed 
(regardless of treatment emergent AE status).
5.10.1.5 Dose-limiting Toxicities
A by-subject listing of DLTs will be presented. 
5.10.2 Laboratory Data
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. If a lab value is reported using a non-numeric qualifier (eg, 
less than (<) a certain value, or greater than (>) a certain value), the given numeric value will 
be used in the summary statistics, ignoring the non-numeric qualifier. 
If a patient has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results (and/or change from baseline in clinical laboratory parameters) will be 
summarized according to the scheduled sample collection time point. Unscheduled laboratory 
test results will only be listed and included in laboratory shift tables.
Shift tables will be constructed for laboratory parameters to tabulate changes in NCI CTC for 
toxicity (version 4.0) from baseline to post baseline worst CTC grade. Parameters to be 
tabulated will include:

Hematology: hemoglobin, platelets, neutrophils, lymphocytes, leukocytes.


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
Clinical chemistry: ALT, AST, alkaline phosphatase, creatinine, total bilirubin, 
calcium, magnesium, potassium, albumin, and sodium.
Laboratory-related tables will be presented by the dose level the patient is enrolled to and 
total.
By-patient listings to be presented include hematology and clinical chemistry.
5.10.3 Electrocardiograms
ECG will be presented in a by-patient listing.
5.10.4 Vital Signs
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs 
and weight over time will be tabulated by scheduled time point through Cycle 6. Vital sign
tables will be presented by the dose level the patient is enrolled to and total.
5.10.5 Other Safety Assessments
Pregnancy testing results will be presented in a by-patient listing.
Additional safety analyses may be determined at any time without prejudice to enumerate 
rates of toxicities and to further define the safety profile of study drugs.
6. SIGNIFICANT PROTOCOL DEVIATIONS
A listing will be generated for major protocol deviations, which will include, but not limited
to, at least one of the following:

Violation of inclusion/exclusion criteria.

Use of the following prohibited medications while on study: G-CSF use in Cycle 1, 
proton pump inhibitors, and H2-receptor antagonists.


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
Took less than 75% of expected study drug in a cycle and the cycle length was 
greater than 35 days; any overdose.
7. CHANGES TO PLANNED ANALYSES FROM PROTOCOL
There is no change made to the planned analyses from the protocol.
8. PROGRAMMING CONSIDERATIONS
8.1
Statistical Software 
SAS version 9.2 (or higher) will be used for all analyses. 
8.2
Rules and Definitions
Subject populations are defined in Section 2.
Baseline values are defined in Section 5.4.2.
Treatment-emergent AEs are defined in Section 5.10.1.1.
9. REFERENCES
Not applicable.