Conditions: Metastatic Breast Cancer Solid Tumors
Keywords: MLN0128 Dual TORC1/2 Inhibitor MLN8237 Aurora A inhibitor Alisertib Triple-Negative Breast Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: no

Brief summary:
This is a phase Ib study designed to evaluate the safety and toxicity of the combination of Alisertib and MLN0128 in patients with advanced solid tumors with an expansion cohort in patients with previously treated metastatic TNBC.

Detailed description:
The purpose of this study is to evaluate the combination of Alisertib and MLN0128 in patients with advanced solid tumors refractory to standard treatment followed by an expansion cohort of patients with metastatic TNBC with exploratory correlative studies.

Arms:
arm 1: This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 30 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 1 mg given by mouth (PO) once daily with continuous dosing.

Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study.

MLN0128: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study. arm 2: This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 30 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 2 mg given by mouth (PO) once daily with continuous dosing.

Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study. arm 3: This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 40 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 1 mg given by mouth (PO) once daily with continuous dosing.

Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study. arm 4: This group will receive a Dose-Escalation: Combination of MLN0128 and Alisertib using a standard 3 + 3 design. The starting dose of Alisertib is 40 mg given PO twice daily (BID) Days 1-7 repeat every 21 days. The starting dose for MLN0128 is 3 mg given by mouth (PO) once daily with continuous dosing.

Alisertib: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study. arm 5: This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. In cycle 1, single agent Alisertib will be administered at the MTD on days 1-7 and MLN0128 will be administered on days 8-21. In cycle 2 and beyond, dosing with both agents will begin on day 1, with Alisertib administered days 1-7 and MLN0128 administered days 1-21.

Pancreatic Cancer Cohort:

This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. On each cycle, Alisertib will be administered on days 1-7, while MLN0128 will be administered continuously on days 1-21. arm 6: This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. In cycle 1, MLN0128 will be administered at the MTD days 1-28 and Alisertib will be administered at the MTD on days 8-15. In cycle 2 and beyond, dosing with both agents will begin on day 1, with Alisertib administered days 1-7 and MLN0128 administered days 1-21. arm 7: This group will receive a Dose-Expansion of Alisertib and Dose-Expansion of MLN0128. On each cycle, Alisertib will be administered on days 1-7, while MLN0128 will be administered continuously on days 1-21.

Interventions: intervention 1: Alisertib intervention 2: MLN0128
Intervention descriptions: intervention 1: Participants will receive Alisertib in the dose-escalation and the dose-expansion part of the study. intervention 2: Participants will receive MLN0128 in the dose-escalation and the dose-expansion part of the study.

Protocol document:
Prot_SAP_000.pdf: 
Phase I Study of MLN0128 and MLN8237 in Patients With Advanced Solid Tumors and Metastatic Triple-
negative Breast Cancer 
 
NCT02719691 
 
July, 25, 2018 


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CLINICAL STUDY PROTOCOL 
COMIRB 15-1135 
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A phase Ib study of the combination of MLN0128 (Dual TORC1/2 Inhibitor) and MLN8237 
(Aurora A inhibitor, alisertib) in patients with advanced solid tumors with an expansion cohort 
in metastatic triple-negative breast cancer (TNBC) 
 
 
 
 
Indication: 
Advanced solid tumors, triple-negative breast cancer 
Phase: 
Ib 
 
 
 
Protocol History 
Version 1 
Version 1.1 
Version  2 
Version 3 
Version 4 
 
13 Oct 2015  
01 Dec 2015 
23 Mar 2017 
09 May 2018 
25 July 2018 
 
 
Investigator and Study Center: 
Jennifer R. Diamond, MD 
University of Colorado Cancer Center 
Mail Stop 8117 
12801 East 17th Ave, L18-8112 
Aurora, CO 80045 
Telephone:  303-724-5499 
 
 
 
 
 
 
 
This is an investigator-initiated study.  The principal investigator Jennifer R. Diamond, (who may 
also be referred to as the sponsor-investigator), is conducting the study and acting as the sponsor.  
Therefore, the legal/ethical obligations of the principal investigator include both those of a sponsor 
and those of an investigator. 
 
 
 
 


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PROTOCOL SUMMARY 
Study Title:  A phase Ib study of the combination of MLN0128 (Dual TORC1/2 Inhibitor) 
and MLN8237 (Aurora A inhibitor, alisertib) in patients with advanced solid tumors with 
an expansion cohort in metastatic triple-negative breast cancer (TNBC) 
Phase:  Ib 
Number of Patients:  A maximum of 6 patients can be enrolled at each dose level.  With 5 
potential dose levels and an expansion cohort of 30 patients, including TNBC, the 
maximum number of patients that can be enrolled is 56 and the minimum number is 6. 
Study Objectives 
Primary 
• To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) 
of the combination of MLN0128 and alisertib in adult patients with advanced solid 
tumors. 
Secondary 
• To determine the safety profile and tolerability of the combination of MLN0128 and 
alisertib in adult patients with advanced solid tumors. 
• To determine the pharmacokinetics of MLN0128 and alisertib in the combination. 
• To evaluate the pharmacodynamic effects of MLN0128 and alisertib in serial tumor 
biopsies and blood samples in patients with metastatic TNBC and other solid tumors 
enrolled in the expansion cohort at the MTD. 
• To estimate the objective response rate using RECIST 1.1 and time to progression in 
patients with advanced solid tumors treated with MLN0128 and alisertib. 
Tertiary/Exploratory 
• To explore biomarkers predictive of response to MLN0128 and alisertib including 
the investigation of mechanisms of acquired resistance to treatment in patients with 
metastatic TNBC and other solid tumors treated in the expansion cohort at the MTD. 
• To evaluate the pharmacodynamic effect of the combination of MLN0128 and 
alisertib on cellular metabolism using functional imaging with FDG-PET (5-fluoro-
deoxy-glucose-PET) and diffusion weighted magnetic resonance imaging (DWI-
MRI). 
Overview of Study Design:   
This is a single institution, Phase Ib study designed to evaluate the safety and toxicity of 
the combination of MLN0128 and alisertib in patients with advanced solid tumors with an 
expansion cohort in patients with previously treated metastatic TNBC and other solid 
tumors. 
 
The dose escalation portion of the trial with be conducted using a standard 3 + 3 dose-
escalation design in patients with advanced solid tumors refractory to standard 
therapies or where no standard therapy exists (see Figure 1 for dose escalation 


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schema and Table 1 for planned dose levels).  Once the maximum tolerated 
dose (MTD) / recommended phase II dose (RP2D) is identified, the dose 
expansion portion will be conducted in patients with previously treated 
metastatic TNBC and other solid tumors.  Exploratory correlative studies will 
be conducted in the expansion cohort including:  evaluation of 
pharmacodynamics markers in serial tumor biopsies and blood samples, 
exploration of predictive biomarkers using fresh and archival tissue samples, 
and evaluation of cellular metabolism using functional imaging.  
A total of 20 patients will be treated in the dose-expansion cohort at the MTD/RP2D (see 
Figure 2 for dose expansion cohort schema).  All patients in the expansion cohort group 1 
and 2, will be required to undergo a fresh tumor biopsy prior to initiating treatment, Cycle 
1 Day 7, and Cycle 2 Day 7.  In expansion cohort Group 1, single agent alisertib will be 
administered at the MTD on Days 1-7 and MLN0128 will be administered on Days 8-21.  
In Cycle 2 and beyond, dosing with both agents will begin on Day 1.  In expansion cohort 
Group 2, MLN0128 will be administered at the MTD in Cycle 1 Days 1-28 and alisertib 
will be administered at the MTD on Days 8-15.  An attempt will be made to obtain a repeat 
tumor biopsy at the time of progression in patients with an initial response to treatment in 
group 1 and 2. Objective tumor response using RECIST 1.1 will be evaluated every three 
cycles (approximately 9 weeks in the dose escalation cohort and 10 weeks in the dose 
expansion cohort Group 2). 
 
An additional 10 patients with previously treated locally advanced or metastatic pancreatic 
cancer will be treated at the MTD/RP2D to further evaluate tolerability and explore 
efficacy in this population. 
Study Population:   
Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female patients 18 years or older.  
2. Dose Escalation Cohort:  Patients must have a diagnosis of a histologically 
confirmed solid tumor that is incurable and refractory to standard therapy or for 
which no standard therapy exists. 
 
3. Dose Expansion Cohort Group 1 and 2: Patients must have a diagnosis of 
histologically confirmed metastatic TNBC defined as negative for estrogen receptor, 
progesterone receptor and HER2. Patients must have received either adjuvant or first 
line chemotherapy for metastatic disease. Negative for Estrogen and Progesterone 
Receptor includes the following: 
• Local Pathology report classifies them as negative 
• Allred Score of 2 or below 
• <1% positive staining 
Subjects with solid tumor types other than TNBC may also be enrolled after 


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discussion with the Sponsor.  These subjects must have a diagnosis of a 
histologically confimed solid tumor that is incurable and refractory to 
standard therapy or for which no standard therapy exists. 
 
4. Pancreatic Cancer Cohort: Patients must have a diagnosis of locally advanced or 
metastatic pancreatic adenocarcinoma previously treated with or not a candidate for 
standard of care systemic therapy.  
5. Dose Expansion Cohort Group 1 and 2:  At least one tumor lesion amenable to 
repeat core needle biopsy or punch biopsy without unacceptable risk of a major 
procedural complication.  
6. Eastern Cooperative Oncology Group (ECOG) performance status < 1 (See 
Appendix 1) 
7. Three weeks or 5 half-lives (whichever is shorter) from previous systemic anticancer 
therapy; at least 4 weeks from major surgery and recovered; at least 2 weeks from 
palliative radiation and recovered. No more than 450 mg/m2 cumulative dose of 
doxorubicin or equivalent anthracycline dose is allowed.   
8. All acute treatment-related toxicities from prior therapy must have resolved to 
Grade < 1 prior to study entry excluding alopecia. 
9. For women: 
• 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, at the same time, from the time of signing the informed consent  
through 90 days after the last dose of study drug OR agree to practice true 
abstinence, when this is in line with the preferred and usual lifestyle of the 
patient (Periodic abstinence [e.g, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of 
contraception 
            For men, even if surgically sterilized (ie, status post-vasectomy), they must: 
• Agree to practice effective barrier contraception during the entire study 
treatment  period and through 120 days after the last dose of study drug, OR 
agree to practice true abstinence, when this is in line with the preferred and 
usual lifestyle of the patient (Periodic abstinence [e.g, calendar, ovulation, 
symptothermal, postovulation methods for the female partner] and withdrawal 
are not acceptable methods of contraception 
• Agree not to donate sperm during the course of this study or 120 days after 
receiving their last dose of study drug 
10. Screening clinical laboratory values as specified below:  


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a) Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 
1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL. Values 
must be obtained without the need for myeloid growth factor support, 
platelet or PRBC transfusion support within 14 days. 
b) Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN), transaminases 
(aspartate aminotransferase/serum glutamic oxaloacetic transaminase-
AST/SGOT and alanine aminotransferase/serum glutamic pyruvic 
transaminase-ALT/SGPT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are 
present); 
c) Renal: Creatinine < 1.5 X ULN or creatinine clearance ≥ 50 mL/min based 
either on Cockroft-Gault estimate or based on urine collection (12 or 24 
hour)(Appendix 2); 
d) Metabolic: Glycosylated hemoglobin (HbA1c)<7.0%, fasting serum glucose 
(≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL;  
e) For patients undergoing serial tumor biopsies, INR and activated partial 
thromboplastin time (PTT) must be within 1.5 X the upper limit of normal.    
11. Left ventricular ejection fraction (LVEF) > LLN of the institutional standard of 
normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan 
(MUGA) within 4 weeks prior to first study drug administration. 
12. Ability to swallow oral medications.  
13. 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. 
14. Patients who have a history of brain metastasis are eligible for the study provided 
that all the following criteria are met: 
a) Brain metastases which have been treated 
b) No evidence of disease progression for ≥ 4 weeks or hemorrhage after 
treatment 


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c) Off-treatment with dexamethasone for 2 weeks before administration of the 
first dose of MLN0128 
d) No ongoing requirement for dexamathasone or anti-epileptic drugs 
Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active central nervous system disease, active infection, or any other condition that 
could compromise the patient’s participation in the study. 
2. Known human immunodeficiency virus infection. 
3. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is 
considered to be over 25%. 
4. Known history of uncontrolled sleep apnea syndrome and other conditions that 
could result in excessive daytime sleepiness, such as severe chronic obstructive 
pulmonary disease; requirement for supplemental oxygen. 
5. Systemic infection requiring IV antibiotic therapy within 14 days preceding the 
first dose of study drug, or other severe infection. 
6. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis 
C infection. 
7. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
8. Diagnosed or treated for another malignancy within 2 years before administration 
of the first dose of study drug, or previously diagnosed with another malignancy 
and have any evidence of residual disease. Patients with nonmelanoma skin cancer 
or carcinoma in situ of any type are not excluded if they have undergone complete 
resection. 
9. Breast feeding or pregnant. 
10. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI 
disease, or for an unknown reason that may alter the absorption of MLN0128. In 
addition, patients with enteric stomata are also excluded. 


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11. Treatment with any investigational products within 3 weeks before the first dose of 
study drug. 
12. History of any of the following within the last 6 months before administration of 
the first dose of the drug: 
a) Ischemic myocardial event, including  angina requiring therapy  and artery 
revascularization procedures   
b) Ischemic cerebrovascular event, including transient ischemic attack and 
artery revascularization procedures 
c) Requirement for inotropic support (excluding digoxin) or serious 
(uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, 
ventricular fibrillation or ventricular tachycardia)  
d) Placement of a pacemaker for control of rhythm 
e) New York Heart Association (NYHA) Class III or IV heart failure (See 
Appendix 3)   
f) Pulmonary embolism  
13. Significant active cardiovascular or pulmonary disease including: 
a) Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, 
diastolic blood pressure > 95 mm Hg). Use of anti-hypertensive agents to 
control hypertension before Cycle1 Day 1 is allowed. 
b) Pulmonary hypertension   
c) Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis 
or pulse oximetry on room air    
d) Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention, or history of 
valve replacement   
e) Medically significant (symptomatic) bradycardia    
f) History of arrhythmia requiring an implantable cardiac defibrillator   


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g) Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., 
repeated demonstration of QTc interval > 480 milliseconds, or history of 
congenital long QT syndrome, or torsades de pointes)  
14. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, 
CYP2C19 or CYP2C19 within 1 week preceding the first dose of study drug. 
15. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding 
inhalers or low-dose hormone replacement therapy) within 1 week before 
administration of the first dose of study drug. 
16. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI 
within 7 days before receiving the first dose of study drug. 
17. For patients undergoing serial tumor biopsies, known bleeding diathesis or history 
of abnormal bleeding or require anti-coagulation therapy which cannot be interrupted 
for biopsy. 
 
Duration of Study:  Patients will continue to receive treatment with MLN0128 and 
alisertib until they experience disease progression or have an unacceptable drug-related 
toxicity.  There is no maximum duration of treatment.  The study will be terminated 6 
months after the last patient completes the End-of-Treatment (EOT) study visit. 


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STUDY OVERVIEW DIAGRAM  
Figure 1. 
Dose Escalation Study Schema 
 
 
 


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Figure 2.  Dose Expansion Cohort Schema 
 
 
 
a. Up to 28 days prior to initiation of treatment. 
b. Up to 2 days prior to initiating MLN0128 dosing on Cycle 1 Day 7.  Biopsy should be timed to occur within 5 
hours after alisertib dosing, if possible. 
c. Up to 2 days prior to Cycle 2 Day 7.  Biopsy should be timed to occur within 5 hours after alisertib and MLN0128 
dosing, if possible. 
d. Up to 2 days prior to initiating alisertib dosing on Cycle 1 Day 8.  Biopsy should be timed to occur within 5 hours 
after MLN0128 dosing, if possible. 
e.  DWI-MRI will be performed at Baseline, Cycle 1 Day 7 and Cycle 2 Day 7 in Group 1 and Group 2.  For patients 
who undergo baseline FDG-PET/CT for evaluation of their disease, an additional FDG-PET may be performed for 
exploratory correlatives only at Cycle 2 Day 7.  This scan will not be used to determine response to treatment.  
Functional imaging should be performed before the biopsy if the specific tumor biopsied is being followed on 
imaging.  See Study Procedure Manual for additional details. 
 
 


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SCHEDULE OF EVENTS – Dose Escalation 
  
  
Cycle 1 
  
  
  
Cycles 2-3 
Cycle 4+  
  
Assessments1 
Screening 
Day -28 to 
Day -1 
C1 Day 
-7 to -3 
C1D1 
C1D7 
C1D15 
C2D1 
C2D8 
C2D15 
D1 
Termination 
Inclusion/Exclusion 
X 
X 
  
  
  
  
  
  
  
  
Informed Consent and 
HIPAA Authorization 
X 
  
  
  
  
  
  
  
  
  
Demographics, 
Medical/Cancer History 
including ER, PR and HER2 
status (Breast Cancer 
Patients Only), tumor grade, 
stage, and prior 
therapy/dates/response 
X 
  
  
  
  
  
  
  
  
  
ECHO/MUGA 
X 
  
  
  
  
  
  
  
  
  
Physical Exam 
X 
  
X 
X 
X 
X 
X 
X 
X 
X 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry3 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation (PT/INR, 
aPTT)(Expansion Only)4 
X 
  
  
X 
  
  
X5 
  
  
  
HbA1c 
X 
  
  
  
  
  
  
  
C3D16 
  
Fasting serum glucose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile7 
X 
  
  
  
  
X 
  
  
X 
X 
Urinalysis  
X 
X 
X 
  
  
X 
  
  
X 
X 
Pregnancy Test8 
X 
X2 
  
  
  
X 
  
  
X 
  
In home daily fasting 
glucose monitoring9 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Retained plasma and serum 
samples for 
Pharmacodynamics and 
Pharmacogenomics 
  
X 
X 
X 
  
X 
  
  
  
  
Plasma Sample 
Pharmacokinetics10 
  
X 
X 
X 
  
X 
X 
  
X 
  
MLN0128 Admin (oral 
daily Day 1-21, start Day 2 
Cycle 1 only, single lead-in 
dose on Cycle 1 Day -7 to -
3)11 
  
X 
  
X 
X 
X 
X 
X 
X 
  
Alisertib Admin (oral BID 
Day 1-7, single dose on 
Cycle 1 Day 1 only)11 
  
  
X 
X 
  
X 
  
  
X 
  
DWI-MRI (Expansion 
Only)12, 
X 
  
  
X 
  
  
X 
  
  
  
FDG-PET (Expansion 
Only)13 
X 
  
  
  
  
  
X 
  
  
  
Tumor Biopsy (Expansion 
Only) 
X 
  
  
X 
  
  
X5 
  
  
  


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        1 With the exception of EKGs, assessments may be done within 24-48 hours of MLN0128 or alisertib administration 
        2 Repeated only if more than 96 hours since screening assessments. Assessments must continue to be acceptable if repeated at baseline. 
        3 CBC with differential, electrolyte panel, LFTs and kidney function tests, total protein, calcium, phosphate, magnesium 
        4 Coagulation tests must be within 1.5 X ULN and platelets > 75,000 within 24 hours of biopsy 
        5 Tumor biopsy should be performed C2 Day 6-7 in the Expansion Cohort. Functional imaging should be performed before the biopsy if 
        specific tumor biopsied is being followed on imaging. See Study Procedure Manual for additional details.  
        6 Should be repeated every 3 cycles for patients continuing on treatment. 
        7 Total cholesterol, HDL, LDL and triglycerides 
        8 Women of child bearing potential only 
        9 Fasting serum glucose will be measured in the clinic. Patients are required to fast overnight (nothing except water and/or medications 
       after midnight of for a minimum of 8 hours before the assessment) for each of these measurements. In-home glucose monitoring is not 
       required on days when fasting glucose is measured in the clinic.  
     10 Blood samples for pharmacokinetic analysis will be drawn and processed Cycle 1 Day -7 to -3, Cycle 1 Day 1, and Cycle 1 Day 7. 
       Samples will be obtained for MLN0128 PK on Cycle 1 Day -7 to -3 pre-dose and 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours. Samples will be 
       obtained for alisertib PK on Cycle 1 Day 1 pre-dose and at 1, 2, 4, 6, 8, and 24 hours.  Samples will be obtained for MLN0128 and 
       alisertib PK on Cycle 1 Day 7 pre-dose and at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours.  Samples will also be obtained pre-dose on Day 1 of 
       Cycles 2+ and on the days of on treatment biopsies.  There is a 5 minute window for the 0.25, 0.5 and 1.0 hour timepoints, a 30 minute 
       window for the 2 - 6 hour timepoints and a 1 hour window for the 8 hour and 24 hour timepoints.  Add additional PK sample will be 
       obtained on the day of the on treatment tumor biopsies.  
     11 For Expansion Cohort, see Figure 2 Dose Expansion Cohort Schema for dosing instructions. 
     12 DWI-MRI will be performed at baseline, Cycle 1 Day 7 and Cycle 2 Day 7 in Expansion Cohort Group 1 and Group 2.  See Figure 2 
       Dose Expansion Cohort Schema for more details.  Functional imaging should be performed before the biopsy if specific tumor biopsied  
       is being followed on imaging.  See Study Procedure Manual for additional details. 
     13 For patients who undergo baseline FDG-PET/CT for evaluation of their disease, an additional optional FDG-PET/CT may be performed 
       for exploratory correlatives only at Cycle 2 Day 7.  This scan will not be used to determine response to treatment.  Functional imaging 
       should be performed before the biopsy if specific tumor biopsied is being followed on imaging.  See Study Procedure Manual for 
       additional details. 
    14 CT of the chest and abdomen is recommended in all patients; additional scans should be obtained depending on where baseline disease 
       was known.  MRI brain should be considered if clinical symptoms concerning for brain mets and is required in patients with previously 
       treated brain mets.  Scans must be performed within 28 days of starting study treatment.  Imaging at Cycle 4 Day 1 and beyond may be 
       performed within 7 days of Day 1.  Imaging should be repeated every 3 cycles beyond Cycle 4. 
     15 Single, 12-lead ECGs will be collected predose and 2 hours (± 30 min) postdose on Cycle 1, Day -7 to -3 and Cycle 2 Day 1.  Further 
       ECGs should be performed at the investigator's discretion if there are cardiac concerns or the patient experiences QTc prolongation in 
       the scheduled ECGs. 
 
 
 
Radiographic Tumor 
Response Evaluation 14 
X 
  
  
  
  
  
  
  
X Cycle 4 
Day 1 
  
ECG (locally read)15 
X 
X 
  
  
  
X 
  
  
  
X 
Con Med Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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SCHEDULE OF EVENTS – Expansion Group 1 and 2   
  
  
 Cycle1 
  
  
Cycles 2-3 
Cycle 4+  
  
Assessments1 
Screening 
Day -28 to 
Day -1 
C1D1 
C1D7 
C1D15 
C2D1 
C2D8 
C2D15 
D1 
Termination 
Inclusion/Exclusion 
X 
  
  
  
  
  
  
  
  
Informed Consent and 
HIPAA Authorization 
X 
  
  
  
  
  
  
  
  
Demographics, 
Medical/Cancer History 
including ER, PR and HER2 
status (Breast Cancer 
Patients Only), tumor grade, 
stage, and prior 
therapy/dates/response 
X 
  
  
  
  
  
  
  
  
ECHO/MUGA 
X 
  
  
  
  
  
  
  
  
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry3 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
Coagulation (PT/INR, 
aPTT)(Expansion Only)4 
X 
  
X 
  
  
X5 
  
  
  
HbA1c 
X 
  
  
  
  
  
  
C3D16 
  
Fasting serum glucose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile7 
X 
  
  
  
X 
  
  
X 
X 
Urinalysis  
X 
X 
  
  
X 
  
  
X 
X 
Pregnancy Test8 
X 
  
  
  
X 
  
  
X 
  
In home daily fasting 
glucose monitoring9 
  
X 
X 
X 
X 
X 
X 
X 
X 
Retained plasma and serum 
samples for 
Pharmacodynamics and 
Pharmacogenomics 
  
X 
  
X 
  
  
X  
 X 
Plasma Sample 
Pharmacokinetics10 
  
X 
X 
  
X 
X 
  
X 
  
MLN0128 Admin (oral 
daily Day 1-21, start Day 2 
Cycle 1 only, single lead-in 
dose on Cycle 1 Day -7 to -
3)11 
  
  
X 
X 
X 
X 
X 
X 
  
Alisertib Admin (oral BID 
Day 1-7, single dose on 
Cycle 1 Day 1 only)11 
  
X 
X 
  
X 
  
  
X 
  
DWI-MRI (Expansion 
Only)12, 16 
X 
  
X 
  
  
X 
  
  
  
FDG-PET (Expansion 
Only)13 
X 
  
  
  
  
X 
  
  
  
Tumor Biopsy (Expansion 
Only)16 
X 
  
X 
  
  
X5 
  
  
  


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        1 With the exception of EKGs, assessments may be done within 24-48 hours of MLN0128 or alisertib administration 
        2 Repeated only if more than 96 hours since screening assessments. Assessments must continue to be acceptable if repeated at baseline. 
        3 CBC with differential, electrolyte panel, LFTs and kidney function tests, total protein, calcium, phosphate, magnesium 
        4 Coagulation tests must be within 1.5 X ULN and platelets > 75,000 within 24 hours of biopsy 
        5 Tumor biopsy should be performed C2 Day 6-7 in the Expansion Cohort. Functional imaging should be performed before the biopsy if 
        specific tumor biopsied is being followed on imaging. See Study Procedure Manual for additional details.  
        6 Should be repeated every 3 cycles for patients continuing on treatment. 
        7 Total cholesterol, HDL, LDL and triglycerides 
        8 Women of child bearing potential only 
        9 Fasting serum glucose will be measured in the clinic. Patients are required to fast overnight (nothing except water and/or medications 
       after midnight of for a minimum of 8 hours before the assessment) for each of these measurements. In-home glucose monitoring is not 
       required on days when fasting glucose is measured in the clinic.  
     10 Blood samples for pharmacokinetic analysis will be drawn and processed Cycle 1 Day 1, Cycle 1 Day 7. 
       Cycle 2 Day 1, Cycle 2 Day 8 and Cycles 3+ Day 1 predose. 
   11 For Expansion Cohort, see Figure 2 Dose Expansion Cohort Schema for dosing instructions. 
     12 DWI-MRI will be performed at baseline, Cycle 1 Day 7 and Cycle 2 Day 7 in Expansion Cohort Group 1 and Group 2.  See Figure 2 
       Dose Expansion Cohort Schema for more details.  Functional imaging should be performed before the biopsy if specific tumor biopsied  
       is being followed on imaging.  See Study Procedure Manual for additional details. 
     13 For patients who undergo baseline FDG-PET/CT for evaluation of their disease, an additional optional FDG-PET/CT may be performed 
       for exploratory correlatives only at Cycle 2 Day 7.  This scan will not be used to determine response to treatment.  Functional imaging 
       should be performed before the biopsy if specific tumor biopsied is being followed on imaging.  See Study Procedure Manual for 
       additional details. 
    14 CT of the chest and abdomen is recommended in all patients; additional scans should be obtained depending on where baseline disease 
       was known.  MRI brain should be considered if clinical symptoms concerning for brain mets and is required in patients with previously 
       treated brain mets.  Scans must be performed within 28 days of starting study treatment.  Imaging at Cycle 4 Day 1 and beyond may be 
       performed within 7 days of Day 1.  Imaging should be repeated every 3 cycles beyond Cycle 4. 
     15 Single, 12-lead ECGs will be collected predose and 2 hours (± 30 min) postdose on Cycle 1 Day 1 and Cycle 2 Day 1.  Further 
       ECGs should be performed at the investigator's discretion if there are cardiac concerns or the patient experiences QTc prolongation in 
       the scheduled ECGs. 
    
 
 
Radiographic Tumor 
Response Evaluation 14 
X 
  
  
  
  
  
  
X Cycle 4 
Day 1 
  
ECG (locally read)15 
X 
  
  
  
X 
  
  
  
X 
Con Med Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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SCHEDULE OF EVENTS – Pancreatic Cancer Cohort    
        1 With the exception of EKGs, assessments may be done within 24-48 hours of MLN0128 or alisertib administration 
        2 Repeated only if more than 96 hours since screening assessments. Assessments must continue to be acceptable if repeated at baseline. 
        3 CBC with differential, electrolyte panel, LFTs and kidney function tests, total protein, calcium, phosphate, magnesium 
        4 Should be repeated every 3 cycles for patients continuing on treatment. 
        5 Total cholesterol, HDL, LDL and triglycerides 
        6 Women of child bearing potential only 
        7 Fasting serum glucose will be measured in the clinic. Patients are required to fast overnight (nothing except water and/or medications 
       after midnight of for a minimum of 8 hours before the assessment) for each of these measurements. In-home glucose monitoring is not 
  
  
Cycle 1  
  
  
Cycles 2-3 
Cycle 4+  
  
Assessments1 
Screening 
Day -28 to 
Day -1 
C1D1 
C1D8 
C1D15 
C2D1 
C2D8 
C2D15 
D1 
Termination 
Inclusion/Exclusion 
X 
  
  
  
  
  
  
  
  
Informed Consent and 
HIPAA Authorization 
X 
  
  
  
  
  
  
  
  
Demographics, 
Medical/Cancer History 
including ER, PR and HER2 
status (Breast Cancer 
Patients Only), tumor grade, 
stage, and prior 
therapy/dates/response 
X 
  
  
  
  
  
  
  
  
ECHO/MUGA 
X 
  
  
  
  
  
  
  
  
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vitals 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry3 
X 
X2 
X 
X 
X 
X 
X 
X 
X 
HbA1c 
X 
  
  
  
  
  
  
C3D14 
  
Fasting serum glucose 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fasting lipid profile5 
X 
  
  
  
X 
  
  
X 
X 
Urinalysis  
X 
X 
  
  
X 
  
  
X 
X 
Pregnancy Test6 
X 
  
  
  
X 
  
  
X 
  
In home daily fasting 
glucose monitoring7 
  
X 
X 
X 
X 
X 
X 
X 
X 
Retained plasma and serum 
samples for 
Pharmacodynamics and 
Pharmacogenomics 
  
X 
  
X 
  
  
  
 X 
Plasma Sample 
Pharmacokinetics8 
  
X 
  
X 
  
X 
  
MLN0128 Admin 9 
  
X  
X 
X 
  
Alisertib Admin  9 
  
X 
  
  
X 
  
  
X 
  
Radiographic Tumor 
Response Evaluation 10 
X 
  
  
  
  
  
  
X Cycle 4 
Day 1 
  
ECG (locally read)11 
X 
  
  
  
  
  
  
Con Med Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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       required on days when fasting glucose is measured in the clinic.  
     8 Blood samples for pharmacokinetic analysis will be drawn and processed Cycle 1 Day 1, Cycle 2 Day 1 
       and Cycles 3+ Day 1 predose. 
     9 For Expansion Cohort, see Figure 2 Dose Expansion Cohort Schema for dosing instructions. 
    10 CT of the chest and abdomen is recommended in all patients; additional scans should be obtained depending on where baseline disease 
       was known.  MRI brain should be considered if clinical symptoms concerning for brain mets and is required in patients with previously 
       treated brain mets.  Scans must be performed within 28 days of starting study treatment.  Imaging at Cycle 4 Day 1 and beyond may be 
       performed within 7 days of Day 1.  Imaging should be repeated every 3 cycles beyond Cycle 4. 
     11 Single, 12-lead ECGs will be collected at screening.  Further 
       ECGs should be performed at the investigator's discretion if there are cardiac concerns or the patient experiences QTc prolongation in 
       the scheduled ECGs. 
 
 
 


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TABLE OF CONTENTS 
STUDY OVERVIEW DIAGRAM .........................................................................................10 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................................21 
1. BACKGROUND AND STUDY RATIONALE ................................................................24 
1.1 Scientific Background ..................................................................................................24 
1.1.1 Metastatic Triple-Negative Breast Cancer .............................................................24 
1.1.2 MLN0128...............................................................................................................24 
2. NONCLINICAL SUMMARY ...........................................................................................25 
2.1 Pharmacology ...............................................................................................................25 
2.2 Safety Pharmacology ....................................................................................................25 
2.3 Drug Metabolism and Pharmacokinetics ......................................................................25 
2.4 Toxicology ....................................................................................................................26 
3. SUMMARY OF EFFECTS IN HUMANS ........................................................................27 
3.1 Pharmacokinetics ..........................................................................................................28 
3.2 Safety ............................................................................................................................28 
3.2.1 Study INK128-001 .................................................................................................28 
3.2.2 Study INK128-002 .................................................................................................30 
3.2.3 Study INK128-003 .................................................................................................31 
3.2.4 Study C31001 ........................................................................................................32 
3.2.5 Study C31002 ........................................................................................................33 
4. UPDATED MANUFACTURING PROCESS ...................................................................34 
5. CLINICAL SUMMARY OF SAFETY ..............................................................................34 
5.1 Special Warnings and Precautions for Use ...................................................................34 
5.1.1 Insulin and Glucose Levels ....................................................................................34 
5.1.2 Cardiac Effects .......................................................................................................35 
5.1.3 Renal Function .......................................................................................................35 
5.1.4 Rash .......................................................................................................................35 
5.1.5 Pneumonitis ...........................................................................................................36 
5.2 Interactions With Other Medicaments and Other Forms of Interaction .......................36 
6. ALISERTIB (MLN8237) ...................................................................................................36 
6.1 Aurora A Kinases and the Aurora A Kinase Inhibitor Alisertib (MLN8237) ..............36 
6.1.1 Alisertib In Vitro Studies .......................................................................................37 
6.1.2 Alisertib In Vivo Studies ........................................................................................37 
6.1.3 Alisertib Safety Pharmacology, Toxicology, and Drug Metabolism.....................38 
6.1.4 Alisertib Clinical Experience .................................................................................38 
6.1.5 Alisertib Pharmacokinetics ....................................................................................39 
6.1.6 Alisertib Potential Risks and Benefits ...................................................................40 
6.2 Risk of MLN0128 and Alisertib Combination Therapy ...............................................41 
7. STUDY RATIONALE .......................................................................................................41 
7.1 Alisertib and MLN0128 in TNBC ................................................................................41 
7.2 Correlative Studies .......................................................................................................43 
8. STUDY OBJECTIVES ......................................................................................................44 
8.1 Primary Objectives .......................................................................................................44 
8.2 Secondary Objectives ...................................................................................................44 
8.3 Tertiary/Exploratory Objectives ...................................................................................44 


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9. STUDY ENDPOINTS ........................................................................................................44 
9.1 Primary Endpoints ........................................................................................................44 
9.2 Secondary Endpoints ....................................................................................................44 
9.3 Tertiary/Exploratory Endpoints ....................................................................................45 
10. STUDY DESIGN .............................................................................................................45 
10.1 Overview of Study Design .........................................................................................45 
10.2 Dose Escalation Cohort ..............................................................................................47 
10.3 Study Procedures ........................................................................................................48 
10.3.1 Informed Consent ................................................................................................48 
10.3.2 Patient Demographics ..........................................................................................48 
10.3.3 Medical History ...................................................................................................48 
10.3.4 Physical Examination ..........................................................................................49 
10.3.5 Vital Signs............................................................................................................49 
10.3.6 ECOG Performance Status ..................................................................................49 
10.3.7 Concomitant Medications and Procedures ..........................................................49 
10.3.8 In-home fasting glucose monitoring ....................................................................50 
10.3.9 Pharmacokinetic measurements ...........................................................................50 
10.3.10 Tumor Biopsies ..................................................................................................50 
10.3.11 Functional Imaging ............................................................................................51 
10.4 Number of Patients .....................................................................................................51 
10.5 Duration of Study .......................................................................................................51 
11. STUDY POPULATION ...................................................................................................51 
11.1 Inclusion Criteria ........................................................................................................51 
11.2 Exclusion Criteria .......................................................................................................54 
12. STUDY DRUG .................................................................................................................56 
12.1 Study Drug Administration ........................................................................................56 
12.2 Definitions of Dose-Limiting Toxicity .......................................................................57 
12.3 MLN0128 Dose modification Guidelines ..................................................................58 
Criteria for Dose Interruption and Dose Modification During a Cycle ..........................58 
12.4 Alisertib Dose Modifications Guidelines ...................................................................59 
12.4.1 Dose Modifications for Hematological Toxicity .................................................59 
12.4.2 Dose Modifications for Non-Hematological Toxicities ......................................60 
12.5 Excluded Concomitant Medications and Procedures and potential Drug-Drug 
interactions ............................................................................................................61 
12.6 Permitted Concomitant Medications and Procedures .................................................61 
12.7 Precautions and Restrictions .......................................................................................62 
12.8 Management of Clinical Events Related to MLN0128 and Alisertib ........................63 
12.8.1 Management of Hyperglycemia...........................................................................63 
12.8.2 Management of Hyperlipidemia ..........................................................................65 
12.8.3 Management of Oral Mucositis ...........................................................................66 
12.8.4 Management of Rash ...........................................................................................66 
12.8.5 Management of Nausea/Vomiting .......................................................................67 
12.8.6 Management of Cardiac Abnormalities ...............................................................68 
12.8.7 Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness and Fatigue) ...................................................................................69 


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12.8.8 Management of Aspartate Aminotransferase/Alanine Aminotransferase 
Elevations .......................................................................................................70 
12.8.9 Management of Non-infectious Pneumonitis ......................................................70 
12.9 Management of Clinical Events Related to alisertib ..................................................71 
12.9.1 Management of Central Nervous System Effects ................................................71 
12.10 Description of Investigational Agents ......................................................................72 
12.10.1 MLN0128...........................................................................................................72 
12.10.2 Alisertib .............................................................................................................72 
12.11 Preparation, Reconstitution, and Dispensation .........................................................72 
12.11.1 MLN0128...........................................................................................................72 
12.11.2 Alisertib .............................................................................................................72 
12.12 Packaging and Labeling ............................................................................................73 
12.12.1 MLN0128...........................................................................................................73 
12.12.2 Alisertib .............................................................................................................73 
12.13 Storage, Handling, and Accountability .....................................................................73 
12.13.1 MLN0128...........................................................................................................73 
12.13.2 Alisertib .............................................................................................................74 
12.14 Study Compliance .....................................................................................................74 
12.15 Treatment Assignment ..............................................................................................74 
12.16 Termination of Treatment and/or Study Participation ..............................................74 
13. STATISTICAL AND QUANTITATIVE ANALYSES ...................................................75 
13.1 Statistical Methods .....................................................................................................75 
13.1.1 Determination of Sample Size .............................................................................76 
13.1.2 Randomization and Stratification ........................................................................76 
13.1.3 Populations for Analysis ......................................................................................76 
13.1.4 Procedures for Handling Missing, Unused, and Spurious Data ..........................77 
13.1.5 Demographic and Baseline Characteristics .........................................................77 
13.1.6 Efficacy Analysis .................................................................................................77 
13.1.7 Pharmacokinetics .................................................................................................77 
13.1.8 Safety Analysis ....................................................................................................77 
14. ADVERSE EVENTS........................................................................................................78 
14.1 Definitions ..................................................................................................................78 
14.1.1 Adverse Event Definition ....................................................................................78 
14.1.2 Serious Adverse Event Definition .......................................................................78 
14.2 Procedures for Reporting Serious Adverse Events .....................................................79 
14.3 Procedures for Reporting Drug Exposure During Pregnancy and Birth Events ........80 
15. ADMINISTRATIVE REQUIREMENTS ........................................................................81 
15.1 Product Complaints ....................................................................................................81 
16. DATA AND SAFETY MONITORING ...........................................................................81 
17. REFERENCES .................................................................................................................83 
18. APPENDICES ..................................................................................................................86 
Appendix 1: Eastern Cooperative Oncology Group (ECOG) Scale for Performance 
Status.....................................................................................................................86 
Appendix 2: Cockcroft-Gault Equation ..............................................................................87 
Appendix 3: New York Heart Association Classification of Cardiac Disease ...................88 
Appendix 4: List of Relevant Cytochrome P450 Inhibitors and Inducers..........................89 


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LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
Abbreviation 
Term 
5-HT3 
AE 
AKI 
5-hydroxytryptamine 3 
adverse event 
aurora kinase inhibitor 
AKT 
 protein kinase B 
ALP/ SGPT 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
API 
active pharmaceutical ingredient 
AST/ SGOT 
aspartate aminotransferase 
ATP 
AUC 
AurA 
adenosine 5’triphosphate 
area under curve 
Aurora kinase A 
BCRP 
 breast cancer resistance protein 
BID 
BRCA1 
   bis in die; twice a day 
breast cancer susceptibility gene 
Cmax 
 maximum observed plasma concentration 
CNS 
       central nervous system 
CV 
cardiovascular; coefficient of variation 
CYP 
cytochrome P450 
DDI 
drug-drug interaction 
DLT 
DSMC 
DWI-MRI 
  dose-limiting toxicity 
Data and Safety Monitoring Committee 
Diffusion-weighted MRI 
EC 
ethics committee 
ECG 
ECT 
electrocardiogram; electrocardiography 
enteric coated tablet 
ECHO 
echocardiogram 
ECOG 
       Eastern Cooperative Oncology Group 
eCRF 
ER 
electronic case report form 
estrogen receptor 
4EBP1 
FDG-PET 
eukaryotic translation Initiation Factor 4E-binding Protein 1 
5-fluoro-deoxy-glucose-PET 
FSG 
 fasting serum glucose 
Hb 
 hemoglobin 
HbA1c 
glycosylated hemoglobin 


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Abbreviation 
Term 
HEENT 
head, eyes, ears, nose and throat 
hERG 
human ether-à-go-go related gene 
IRB 
Intitutional review board 
GI 
gastrointestinal  
GLP 
H2 
HER2 
HDL 
 good laboratory practice 
 histamine-2 
 human epidermal growth factor 2 
 high-density lipoprotein cholesterol 
HDPE 
 high-density polyetylene 
ICF 
informed consent form 
IC50 
INR 
concentration producing 50% inhibition 
international normalized ratio 
IV 
 intravenous(ly) 
IVF 
KD 
LDL 
 intravenous fluids 
 knock-down 
 low-density lipoprotein cholesterol 
LFT 
liver function test(s) 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
MM 
multiple myeloma 
MOA 
 mechanism of action 
MTD 
maximum tolerated dose 
mTOR 
mechanistic target of rapamycin 
mTORC[1] or [2] 
 target of rapamycin complex [1 or 2] 
MUGA 
Multigated acquisition scan 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
NHL 
NYHA 
Non- Hodgkin Lymphoma 
New York Heart Association 
OCT 
organic cation transporter [1 or 2] 
PBL 
 peripheral blood lymphocytes 
PK 
pharmacokinetic(s) 
PD 
PDX 
pharmacodynamic(s) 
patient-derived tumor xenograft 
PGx 
pharmacogenomic(s) 
PO 
per os; by mouth (orally) 
PPI 
Protein pump inhibitor 


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Abbreviation 
Term 
PR 
PRBC 
PT 
PTT 
Progesterone receptor 
Packed red blood cells 
Prothrombin time 
Partial thromboplastin time 
QD 
once daily 
QD×3days per week 
once daily for 3 consecutive days followed by a 4-day dosing holiday every week 
QD×5days per week 
once daily for 5 consecutive days followed by a 2-day dosing holiday every week 
QT 
interval on ECG between the start of the Q wave and end of the T wave 
QTc 
rate-corrected QT interval (millisec) of electrocardiograph 
 QW 
once weekly 
RBC 
RECIST 
red blood cell 
response evaluation criteria in solid tumors 
RP2D 
SA-β-gal 
recommended phase 2 dose 
senescence associated-β-galactosidase 
SAE 
serious adverse event 
SD 
standard deviation 
TGI                                
tumor growth inhibition 
tmax 
time to reach Cmax 
TIA 
TNBC 
 Transient ischemic attack 
triple-negative breast cancer 
TPN 
 total parental nutrition 
ULN 
upper limit of normal 
WM 
Waldenström macroglobulinemia 
 
 
 
 
 


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1.    
BACKGROUND AND STUDY RATIONALE 
1.1    Scientific Background 
1.1.1    
Metastatic Triple-Negative Breast Cancer 
Breast cancer is the most prevalent malignancy in women worldwide and accounts for more 
than 400,000 cancer deaths annually (1).  Triple-negative breast cancer (TNBC) is defined 
as breast cancer which is negative for the estrogen receptor (ER), progesterone receptor 
(PR), and human epidermal growth factor receptor 2 (HER2).  TNBC accounts for 10-15% 
of all newly diagnosed breast cancer (2,3), although there is a higher incidence in breast 
cancer susceptibility gene (BRCA1) mutation carriers (4) in African-American women (5).  
The molecular profiling of breast cancers has revealed that a basal-like gene expression 
signature most commonly characterizes TNBC; however, the overlap is not complete (6,7).  
Patients with TNBC are more likely to develop distant metastasis and have an increased risk 
of death from breast cancer compared to other breast cancer subtypes (2,8). 
 
Systemic chemotherapy is the mainstay of treatment for advanced or metastatic TNBC (9).  
The principle goal of chemotherapy in metastatic breast cancer is the palliation of symptoms 
related to sites of disease; however, prolongation of survival is also a goal where feasible.  
Combination chemotherapy generally has higher response rates compared to the sequential 
administration of single agents.   Combination chemotherapy, however, does not always 
confer a survival benefit and can produce significantly more toxicity (10).  First line 
chemotherapy for TNBC generally involves an anthracycline or taxane-based regimen.  A 
number of other chemotherapeutic agents have some degree of activity (11) and there are 
currently no targeted agents FDA-approved for the treatment of TNBC.  Patients with 
metastatic TNBC have a median overall survival of around 13 months and a median 
duration of first line therapy of just 12 weeks (12). 
1.1.2         MLN0128  
Millennium has developed MLN0128, which is a novel, highly selective, orally bioavailable 
adenosine 5’ triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase 
referred to as the mechanistic target of rapamycin (mTOR). MLN0128 (formerly INK128) 
targets 2 distinct mTOR complexes, mTORC1 and mTORC2. 
 
MLN0128 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits 
mTORC1/2 signaling, and prevents cellular proliferation. The mTOR is a kinase that 
regulates cell growth, translational control, angiogenesis, and cell survival by integrating 
nutrient and hormonal signals. mTOR kinase plays a key role in several pathways that are 
requently dysregulated in human cancer (13).  mTORC1 is best known as a key regulator of 
protein translation through phosphorylation of 4EBP1 (the eukaryotic translation Initiation 
Factor 4E-binding Protein 1) and ribosomal protein S6 (known as S6) kinase. mTORC2 is 
best known for its ability to fully activate protein kinase B (AKT) by phosphorylation on the 
S473 site, which regulates proliferation and survival pathways (14). 
 
The mTORC is an important therapeutic target that is a key intracellular point of 
convergence for a number of cellular signaling pathways. Inhibiting mTOR may inhibit 


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abnormal cell proliferation,tumor angiogenesis, and abnormal cellular metabolism, thus 
providing the rationale for mTOR inhibitors as potential agents in the treatment of a number 
of indications including solid tumor and hematological malignancies, as either monotherapy 
or in combination with other chemotherapeutic agents. Like rapamycin, several newly 
approved rapalogs (temsirolimus and everolimus) are specific and allosteric inhibitors of 
mTORC1, and only partially inhibit mTORC1 signaling pathways. They do not directly 
inhibit mTORC2, which has shown to be an emerging target in cancer research. MLN0128 
was developed to address the incomplete inhibition of the mTOR pathway by rapalogs by 
targeting both mTORC1 and mTORC2. 
 
MLN0128 is being developed for both oncology and non-oncology indications. In 
oncology, MLN0128 is being investigated as a treatment for advanced solid tumors and 
hematologic malignancies, either as monotherapy or in combination with chemotherapy, 
other molecularly targeted therapies, or antihormonal agents. Non-oncology indications 
being investigated include fibrotic and inflammatory diseases.  
 
2.    
NONCLINICAL SUMMARY 
2.1 Pharmacology 
MLN0128 selectively and potently inhibits mTOR kinase (the concentration inhibiting 50% 
of enzyme activity [IC50] is 1.1 nM), inhibits mTORC1/2 signaling, and prevents cellular 
proliferation. 
 
MLN0128 inhibited phosphorylation of downstream modulators of mTORC1and mTORC2 
in human U87 glioblastoma tumor xenograft models in mice and showed strong tumor 
growth inhibition (TGI) at tolerable oral (PO) doses in all 8 xenograft models tested (see IB 
Ed8 for details). 
 
2.2  Safety Pharmacology 
MLN0128 has a low potential to affect the human ether-à-go-go related gene (hERG) 
potassium ion channel and did not affect cardiovascular (CV) parameters in vivo in 
telemeterized monkeys. 
 
2.3 Drug Metabolism and Pharmacokinetics 
MLN0128 was rapidly absorbed after PO administration to mice, rats, dogs, and monkeys, 
with high oral bioavailability. [14C]MLN0128 was rapidly and widely distributed 
throughout the body in Long-Evans rats; radioactivity was eliminated from most tissues at 
48 hours postdose. MLN0128 displayed dose-proportional plasma exposures, a moderate 
propensity to cross the blood-brain barrier, and was modestly bound (70.5%) to human 
plasma proteins. MLN0128 distributed mainly to the plasma of human blood. There was no 
obvious concentration-dependent red blood cell (RBC) distribution of MLN0128 in human 


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blood. 
 
MLN0128 did not inhibit P-glycoprotein, but did inhibit breast cancer-resistance protein 
(BCRP), organic cation transporter (OCT)1 and OCT2. 
 
M1, the single metabolite (monohydroxylation product) observed in human microsomal 
incubations, was also observed in rats and monkeys. The main isozymes responsible for 
phase 1 metabolism appear to be cytochrome P450 (CYP) 2C9, 2C19, and 3A4. MLN0128 
did not induce CYP1A2, 2B6, and 3A4 activity and expression at concentrations up to 
10 µM. MLN0128 displayed low potential for inhibition and is not a time-dependent 
inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. 
 
Oral administration of MLN0128 in humans has a low potential for metabolic and 
transporter-based drug-drug interactions (DDIs), especially given clinical exposures 
observed to date after administration of the highest anticipated therapeutic dose to be used in 
the clinic in oncology indications (total maximum plasma concentration [Cmax] of 0.48 µM 
[free Cmax of 0.14 µM] at 30 mg once weekly [QW]). 
2.4 Toxicology 
The toxicologic profiles obtained in the Good Laboratory Practice (GLP)-compliant and 
non-GLP-compliant studies in rats and monkeys were generally consistent with 
pharmacologic inhibition of mTORC1/2 activity. Observed toxicities were mostly consistent 
between sexes. MLN0128 repeat-dose GLP studies include completed 28-day and 
preliminary 3-month toxicology studies in rat and monkeys, and embryo-fetal studies in rats 
and rabbits. 
 
The primary dose-limiting toxicities (DLTs) of MLN0128 in rats and monkeys were 
secondary to an exaggerated pharmacologic response and consisted of body weight loss and 
associated clinical observations that included hunched posture, dehydration, gastrointestinal 
(GI) distress and decreased activity, appetite, and body temperature. In addition to the 
previously mentioned effects, a single monkey in the 3-month toxicology study 
demonstrated a DLT of skin toxicity characterized as progressive acanthosis. The highest 
exposures tolerated in the preliminary 3-month rat and monkey toxicology studies were 
1233 and 194 ng⋅hr/mL, respectively. 
 
Adverse effects in rats included body weight loss, decreased activity, increased glucose and 
insulin levels, alterations in white blood cells, bone marrow and lymphoid depletion, thymic 
necrosis, oligospermia, testes degeneration/atrophy, nonglandular stomach epithelial 
degeneration/ulceration/hyperplasia, pancreatic islet degeneration and fibrosis, lens fiber 
degeneration with cataract correlate, adrenal cortex hypertrophy, pituitary atrophy secondary 
to body weight loss, liver hepatocellular vacuolation, retinal dysplasia with or without optic 
nerve atrophy, and alveolar histiocytosis. The alveolar histiocytosis was only present in the 
28-day rat study and was absent in the 3-month rat study. Both retinal dysplasia and alveolar 
histiocytosis are thought to be potential background findings. The pancreatic islet 
degeneration and fibrosis, as well as the other findings of lens fiber degeneration, pituitary 
atrophy, and liver vacuolation, were consistent with the mechanism of action (MOA) and 


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effects observed with other rapalogs. The microscopic findings observed in the testes, 
epididymides, and eyes in the 28-day and/or 3-month rat studies were not resolved after a 
14-day recovery period, while partial to complete resolution was seen in the pancreas, 
adrenal gland, pituitary, liver, lungs, thymus, nonglandular stomach, and bone marrow.  
 
The adverse effects in monkeys included hunched posture, dehydration, GI distress, and 
decreased activity, appetite, and body weight; increased glucose and insulin; lymphoid and 
bone marrow depletion; adrenal hypertrophy/hyperplasia; pancreatic and salivary gland 
acinar cell secretory depletion; neutrophilic inflammation of GI tract with occasional erosion 
and ulceration, skin effects including ulceration, epidermal hyperplasia, acanthosis and 
hyperkeratosis; and adipose tissue depletion. Additionally, there were sporadic inflammatory 
findings among some animals that were of uncertain association to the test article. The 
findings in the pancreas, adrenal glands, and salivary glands may have been related to a 
stress response or reduced food consumption. The findings observed in repeat-dose monkey 
studies were generally reversible after a 14-day recovery period. 
 
The findings in rat and monkey repeat-dose toxicology studies with MLN0128, including 
bone marrow and lymphoid depletion; GI, liver, pancreas, and skin effects; and effects on 
glucose and insulin levels, can be monitored in clinical trials. The toxicities seen in the 
repeat-dose toxicology studies, such as GI effects and glucose and insulin increases, are 
consistent with the treatment-emergent adverse events (TEAEs), including mucositis and 
hyperglycemia, observed to date in patients receiving MLN0128. 
 
Rat and rabbit range-finding embryo-fetal studies demonstrated teratogenic, fetotoxic, and 
abortive effects with MLN0128. Embryo-fetal lethality and/or teratogenic effects have been 
reported with the mTORC1 inhibitors rapamycin and the rapalogs. 
 
MLN0128 was negative for genotoxicity in an in vitro bacterial mutagenesis (Ames) assay, 
an in vivo rat micronucleus assay, and an in vivo rat comet assay. An in vitro chromosomal 
aberration assay with MLN0128 in human peripheral blood lymphocytes (PBLs) was 
positive for chromosomal aberrations in the presence and absence of metabolic activation. 
However, the weight of evidence from the combined results of a negative mutagenicity 
assay and negative genotoxicity assessments in 2 in vivo assays in 3 tissues (bone marrow, 
liver, and duodenum) demonstrate that MLN0128 does not present a genotoxic risk. 
MLN0128 was negative for phototoxicity in the 3T3 fibroblast assay. 
 
3.    
SUMMARY OF EFFECTS IN HUMANS  
MLN0128 is in clinical development as a single agent in 3 phase 1 studies including study 
INK128-01 in patients with advanced solid malignancies, study INK128-002 in patients 
with multiple myeloma [MM], non-Hodgkin lymphoma [NHL] and Waldenström 
macroglobulinemia [WM]) and study C31002 to measure the effect of MLN0128 on QTc 
interval in patients with advanced solid malignancies.  It is also being investigated in 
combination with paclitaxel (with or without trastuzumab) in patients with advanced solid 
tumors (Ph1 study INK128-003), and in combination with exemestane or fulvestrant in 


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women with ER+/HER2− (estrogen receptor-positive /human epidermal growth factor 
receptor 2 protein-negative) advanced or metastatic breast cancer (Ph1b/2 study C31001) 
 
MLN0128 dosing regimens tested thus far include QD, QW, QD×3days per week (once 
daily for 3 consecutive days followed by a 4-day dosing holiday every week), and 
QD×5days per week (once daily for 5 consecutive days followed by a 2-day dosing holiday 
every week). 
 
Please note that the data described in this section (sections 3.1 and 3.2) was obtained with 
the original unmilled MLN0128 active pharmaceutical ingredient (API); current 
manufacturing process produces milled MLN0128 API (see section 4). 
 
3.1  Pharmacokinetics 
Overall, pharmacokinetic (PK) data from Studies INK128-001, INK128-002, and 
INK128-003 indicate that MLN0128 exhibits fast oral absorption (time to reach Cmax [tmax], 
generally between 1-4 hours after dosing); has dose-linear PK, with a mean plasma half-life 
of approximately 8 hours; and does not accumulate meaningfully in plasma when dosed as 
frequently as once daily (QD) and under any of 4 tested dosing regimens. The PK of 
MLN0128 was generally consistent, with no appreciable differences across the clinical 
studies that measured PK. Neither paclitaxel nor MLN0128 appeared to alter the PK of the 
other agent when co-administered.  
 
3.2  Safety 
As of the clinical data cutoff (09 December 2014), a total of 335 patients had received 
≥ 1 dose of study drug across studies. A total of 18 deaths that occurred within 30 days of 
the last study drug dose had been reported to the clinical database as of the data cutoff; of 
these events, 1 (cardiac arrest; Study INK128-001) was considered related to MLN0128 (see 
section 5.3.1.1 of the IB Ed 8) 
 
At least 1 treatment-emergent SAE, regardless of causality, had been reported in 
125/335 patients (37%). Across the studies and regardless of causality or dosing regimen, 
the most common TEAEs included nausea, fatigue, hyperglycemia, vomiting, diarrhea, 
stomatitis, and decreased appetite. 
 
 
3.2.1Study INK128-001 
Study INK128-001 is a phase 1, first-in-human, dose-escalation study of single-agent 
MLN0128 administered to patients diagnosed with advanced solid malignancies, including, 
but not limited to, colorectal, renal, endometrial, and urothelial tumors. Four dosing 
schedules are being evaluated (QD, QW, QD×3days per week, and QD×5days per week). 
Each schedule is administered in 28-day cycles. 
 


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As of 09 December 2014, a total of 194 patients had been enrolled. Median age at baseline 
was 60 years (range, 24-89 years), most (95%) patients are white, and 54% are women. As 
of data cutoff, 42% had received ≥1 dose of MLN0128 in 2 treatment cycles, while 8% had 
entered 3 cycles, and 10% had entered 4 cycles. The highest number of cycles that had been 
initiated as of data cutoff was 46.  
 
The maximum tolerated doses (MTDs) for the 4 schedules investigated in INK128-001 were 
determined to be 6 mg for QD dosing, 16 mg for QD×3days per week dosing, 10 mg for 
QD×5days per week dosing, and 40 mg for QW dosing. 
 
Deaths 
As of 09 December 2014, a total of 7 patients in this study had died within 30 days of their 
last dose of study drug as reported to the clinical database. One death was due to ventricular 
fibrillation and cardiac arrest, 1 was due to pleural effusion, 1 was due to sepsis, 1 was due 
to respiratory failure, and the remainder was due to disease progression. The event of 
ventricular fibrillation and cardiac arrest was the only case considered study drug-related; 
details are provided in section 5.3.1.1. of the IB Ed8. 
 
Serious Adverse Events 
As of the clinical database cutoff date, treatment-emergent SAEs had been reported for 
82 patients (42%) in this study. The most commonly reported (≥4 patients, overall) preferred 
terms were stomatitis in 7 patients (4%), pneumonia in 6 patients (3%), abdominal pain or 
anemia in 5, each (3%), and vomiting, asthenia, or renal failure acute in 4, each (2%).  
 
Treatment-Emergent Adverse Events 
Overall, ≥1 TEAE was reported for 194 (100%) of the patients. Across the dosing groups, 
the most commonly reported TEAEs were nausea or hyperglycemia, which were each 
reported in 125 patients (64%). The second most common TEAE was vomiting (54% of 
patients), followed by fatigue (51%).  
 
Across all dosing groups, ≥1 TEAE of severity ≥Grade 3 had been reported for 68% of 
treated patients as of the clinical data cutoff date. Severity ≥Grade 3 TEAEs, regardless of 
causality, that were reported in ≥5% of patients as of the data cutoff were hyperglycemia 
(14% of patients), fatigue or hypophosphatemia (8% each), asthenia (7%), anemia or 
stomatitis (6% each), and lymphopenia or nausea (5% of patients each). 
 
Events leading to study discontinuation 
Of the 194 patients treated in Study INK128-001 as of the clinical data cutoff, 110 (57%) 
discontinued because of disease progression, 20 (10%) withdrew consent, and 15 (8%) were 
lost to follow-up or discontinued for other reasons.  
 
A total of 68 AEs led to study discontinuation among 35 patients (18%). Of these events, 
32 (47%), including 16 nonserious AEs, were reported as severity Grade 3, and 6 SAEs 
were Grade 5. No Grade 4 events were reported as resulting in study discontinuation. Most 
(71%) events were considered study drug-related and had resolved as of the data cutoff date. 
 


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A total of 12 preferred terms were reported as leading to discontinuation for >1 patient, 
including rash (9 patients, including the terms maculopapular [5 patients], rash [2], and rash 
erythematous or rash pruritic [1 each]), nausea or stomatitis (7 patients each), pruritus or 
pruritus generalized (4 patients total), and asthenia, fatigue, renal failure/renal failure acute 
(3 patients, each). Events reported in 2 patients included hyperglycemia, pain or pain in 
extremity, performance status decreased, and vomiting.  
 
3.2.2 Study INK128-002 
Study INK-002 is a completed phase 1, open-label, dose-escalation study of oral MLN0128 
administered as a single agent in patients with relapsed or refractory hematologic 
malignancies (MM or non-Hodgkin lymphoma, including WM). A total of 39 patients 
received MLN0128 in 1 of 2 regimens: 26 patients received QD doses (range, 2-7 mg) and 
13 patients were dosed on a QD×3days per week schedule (range, 9-12 mg). The MTD for 
the QD schedule was 4 mg. The MTD for the QD×3days per week schedule was 9 mg. 
 
A total of 21 of the patients (54%) in this study were male and 87% were white. The 
median age at baseline was 61 years (range, 46-85 years). 
 
Deaths 
Two patients died during Study INK128-002. One death was due to a subdural hemorrhage, 
and the other was due to disease progression. Both events were considered by the 
investigator to be unrelated to MLN0128. 
 
Serious Adverse Events 
Treatment-emergent SAEs were reported in Study INK128-002 for 11 patients (28%). No 
SAE occurred in more than 1 patient. Overall, most SAEs were considered severity Grade 2 
or 3. Grade 4 SAEs were reported in 2 patients: hyperviscosity syndrome and 
hyponatremia were reported in 1 patient in the 2-mg QD dose group (both events resolved); 
and acute renal failure was reported in 1 patient in the 12-mg QD×3days per week dose 
group (resolved with sequelae). 
 
No SAEs were considered to be related to MLN0128 treatment, with the exception of 
3 events that were reported in 1 patient. This patient experienced Grade 2 pneumonia on 
Day 58 that resolved without sequelae on Day 60. On Day 121, the same patient 
experienced SAEs of pneumonia (Grade 2) and hypoxia (Grade 3). The 3 events improved 
by Day 125 and were resolved as of Day 142. All 3 events were considered by the 
investigator to be related to MLN0128. 
 
Treatment-Emergent Adverse Events 
All patients in Study INK128-002 experienced at least 1 TEAE. Overall, nausea was the 
most frequently reported preferred term (in 56% of patients), followed by fatigue (49%), 
hyperglycemia (38%), thrombocytopenia (36%), and diarrhea (28%). 
 
TEAEs of severity ≥ Grade 3 were reported in 24 patients (62%); of these, 18 patients (46%) 
experienced ≥ Grade 3 events that were considered related to study drug. The most common 


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study drug-related ≥ Grade 3 TEAEs were thrombocytopenia (in 15% of patients) and 
fatigue (10%). 
 
Events Leading to Study Discontinuation 
Overall, a total of 20 patients (51%) in Study INK128-002 discontinued due to progressive 
disease, 11 patients (28%) withdrew consent, and 6 (15%) discontinued due to investigator 
decision or other reasons. 
Most events leading to study discontinuation were considered nonserious. Fatigue was 
reported as resulting in study discontinuation in 2 patients; all other events were reported as 
leading to study discontinuation in 1 patient only.  
 
3.2.3  Study INK128-003 
Study INK128-003 is a phase 1, open-label, dose-escalation study of oral MLN0128 
administered in 4-week cycles in combination with paclitaxel in patients with advanced 
solid malignancies (lung, ovarian, endometrial, breast, pancreatic, prostate, etc).As of the 
clinical data cutoff date, the treatment period for the primary endpoint had completed and 
long-term treatment for 1 patient remained ongoing. 
 
In this study, 67 patients received ≥1 study drug dose under 1 of 3 dosing schedules: QW; 
QD×3days per week; and QD×5days per week. With each regimen, paclitaxel 80 mg/m2 was 
dosed on Days 1, 8, and 15 of each cycle. Patients who tested positive for HER2+ received 
the combination and also received trastuzumab QW. 
 
At total of 57% of the patients are women and 93% are white. At baseline, the median age 
was 60 years (range, 21-81 years).  
 
On the basis of dose escalation data, 8 mg of MLN0128 on the QD×3days per week 
schedule was selected for the dose expansion phase in patients with breast cancer. The 
QD×5days per week and QW schedules were abandoned before MTDs were declared, as 
they were viewed as being less convenient relative to the QD×3days per week schedule from 
the perspective of administering the paclitaxel and trastuzumab combination.  
 
Overall in the dose expansion phase, patients entered a median of 3.0 treatment cycles 
(range, 1-19 cycles) and a mean (SD) of 5.6 (6.07) cycles. The overall median duration of 
exposure was 7.5 weeks, with a duration over 2-fold greater (11.1 weeks) in the MLN0128 
8 mg QD×3days per week HER2- treatment group relative to the MLN0128 8 mg 
QD×3days per week HER2+ plus trastuzumab group (5.2 weeks). The median cumulative 
dose was 189.0 mg. Across treatment groups, patients received approximately 75% of their 
planned dose of MLN0128. 
 
Deaths 
As of the clinical data cutoff date, 9 patients in this study had died within 30 days of 
administration of their last dose of study drug. Of these patients, 6 died due to disease 
progression, 1 died due to failure to thrive, 1 died due to enlarging tumor mass causing 


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tracheal compression, and 1 died due to pneumonia. None of the events were considered 
related to MLN0128. 
 
Serious Adverse Events 
As of the clinical data cutoff date, 55 SAEs had been reported among 29 patients (43%) in 
this study. Overall, 23 patients (49%) reported ≥1 SAE during the Dose Escalation phase 
and 6 patients (30%) reported ≥1 SAEs during the Expansion phase. The most frequently 
reported SAEs overall were pneumonia (6 patients), vomiting (2 patients, plus hematemesis 
in 1 patient), small intestinal obstruction (3 patients), and stomatitis, esophageal carcinoma, 
sepsis, and failure to thrive in 2 patients each. SAEs reported in most patients (85%) were 
considered not study drug-related, including all of the fatal events. No SAE event terms 
were reported in >1 patient in the Dose Escalation phase. 
 
Treatment-Emergent Adverse Events 
All patients treated in Study INK128-003 reported at least 1 TEAE. The most common 
(≥10% of patients) TEAEs, regardless of causality, that were reported as of the clinical 
database cutoff include fatigue, nausea, and diarrhea, which were reported in 67%, 
60%, and 52% of patients, respectively. 
 
Regardless of causality, TEAEs reported in 54 patients (81%) overall were assessed as 
severity ≥Grade 3. The most commonly reported ≥Grade 3 TEAEs included neutropenia 
(21% of patients), hypophosphatemia (15%), diarrhea or hyperglycemia (12% of patients 
each), and fatigue, hypokalemia, and vomiting (10% of patients each).  
 
Events Leading to Study Discontinuation 
All but 1 patient had discontinued from MLN0128 treatment in Study INK128-003 as of the 
clinical data cutoff. Reasons for discontinuation for the other 66 patients included disease 
progression (54%), patient decision (24%), or ≥1 TEAE (21%). Events reported as leading 
to study discontinuation for more than 1 patient included fatigue (4 patients) and pneumonia, 
rash (erythematous or macular), failure to thrive, or vomiting (2 patients, each). A majority 
(52%) of the events were considered not related to MLN0128. A total of 9 events (43%) 
were considered serious and 12 were assessed as severity ≥Grade 3, including 3 fatal events. 
Ten events remained ongoing as of the last contact with the patients. 
 
3.2.4 Study C31001  
Study C31001 is a phase 1b/2 study of the safety and efficacy of MLN0128 in combination 
with exemestane or fulvestrant in women with ER+/HER2− advanced or metastatic breast 
cancer that has progressed on prior treatment with everolimus in combination with 
exemestane or fulvestrant. Patients in this study continue receiving their same prior therapy 
(either exemestane or fulvestrant) at the same dose, in combination with MLN0128.  
As of the clinical data cutoff date, 16 patients had received ≥1 MLN0128 dose along with 
either exemestane (7 patients) or fulvestrant (9 patients). A total of 88% of the women 
treated as of the data cut were white. At baseline, their median age was 56.5 years (range 
42-74 years). Of the original 16 patients, 12 remained ongoing as of data cutoff. 
 


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Deaths 
As of the clinical data cutoff date, no patient had died within 30 days of administration of 
their last dose of study drug.  
 
Serious Adverse Events 
As of the clinical data cutoff date, 3 treatment-emergent SAEs (ataxia, pneumonitis, and 
upper respiratory tract infection) had been reported in 3 patients (19%). The SAE of ataxia 
resulted in a dose delay, and no action was taken in response to the other events. All 
3 events were reported as being severity Grade 3 and all had resolved as of the data cut. 
Only the event of pneumonitis was considered related to study drug.  
 
Treatment-Emergent Adverse Events 
The most common (≥12% of patients) TEAEs, regardless of causality, include nausea, 
fatigue, and diarrhea or stomatitis, which were reported in 69%, 50%, and 44% of patients, 
respectively. 
Regardless of causality, the most common TEAEs considered severity ≥Grade 3 were 
alanine aminotransferase increased, diarrhea, fatigue, and nausea, each of which were 
reported in 2 patients 
 
Events Leading to Study Discontinuation 
Four patients had discontinued from MLN0128 treatment as of the clinical data cutoff. 
Reasons for discontinuation were disease progression (2 patients), patient decision (1), and 
≥1 TEAEs (1). The TEAE leading to discontinuation was Grade 3 nausea in a patient in the 
MLN0218+fulvestrant arm. The event was not considered related to study drug and had 
resolved as of data cutoff.   
 
3.2.5 Study C31002  
Study C31002 is a phase 1 open label, single-arm, multicenter study to evaluate the effect of 
a single dose of 40 mg MLN0128 on the QT/QTc (QT interval corrected for heart rate) in 
patients with advanced solid tumors. After completing the per-protocol PK/ECG 
assessments on Cycle 1, Day 3, patients may continue to receive MLN0128 if, in the opinion 
of the investigator, the patient is deriving clinical benefit, until they experience disease 
progression. Patients continuing treatment receive MLN0128 30 mg QW in 28-day cycles.  
As of the clinical data cutoff date, 19 patients had received ≥1 MLN0128 dose in this study 
and 3 had entered Cycle 2. A total of 53% are women and 74% are white. At baseline, their 
median age was 63.5 years (range, 46-76 years). Of the original 19 patients, 16 remained 
ongoing as of data cutoff. 
 
Deaths 
As of data cutoff, no reports of events having fatal outcomes had been reported to the 
clinical database as of data cutoff.  
 
Serious Adverse Events 
Serious adverse event information had not been reported to the clinical database as of the 
data cutoff date. 


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Treatment-Emergent Adverse Events 
The most common (≥10% of patients) TEAEs, regardless of causality, include nausea, 
fatigue, decreased appetite, and vomiting, which were reported in 53%, 42%, 32%, and 21% 
of patients, respectively. Information regarding severity of TEAEs had not been reported to 
the clinical database as of data cutoff. 
 
Events Leading to Study Discontinuation 
As of data cutoff, 2 patients had discontinued due to ≥1 AE. The preferred term for 1 event 
was pelvic pain. The other event had not been coded as of data cutoff;  Both events were 
reported as being Grade 4 in severity, had not yet resolved as of data cutoff, and were not 
considered study drug-related. 
 
4.       UPDATED MANUFACTURING PROCESS 
A new MLN0128 capsule containing milled active pharmaceutical ingredient (API) is 
available for new clinical studies in 1 mg, 3 mg and 5 mg strengths.  
 
The milled API, may result in faster absorption profile with possibly higher maximum 
concentration (Cmax), which could result in a different safety profile compared to the 
previous unmilled API capsules. Therefore, ongoing studies (C31001, C31002 and , 
MLN0128-1004 –A Phase I, open label study to evaluate the safety, tolerability, and 
pharmacokinetics of MLN0128 as a single agent and in combination with paclitaxel in 
adult patients with advanced non-hematologuical malignancies-), with the new milled API 
will determine the recommended phase 2 dose (RP2D) for single agent MLN0128 (QD 
and QW) and QD×3days per week in combination with paclitaxel, as well as the effect of 
high-fat meal on the PK of milled API. 
 
5.    
CLINICAL SUMMARY OF SAFETY 
5.1 Special Warnings and Precautions for Use 
5.1.1  Insulin and Glucose Levels 
Hyperglycemia and hyperinsulinemia are known toxicities associated with inhibition of 
mTOR and related pathways based on nonclinical studies. 
 
A rise in fasting plasma glucose has been observed as early as 1 to 2 days following oral 
administration of MLN0128. Daily in-home glucose monitoring and early initiation of 
treatment of the hyperglycemia are essential. For subject self-monitoring of blood glucose, 
a finding of fasting blood glucose ≥ 140 mg/dL measured by glucometer would initiate 
closer monitoring of serum glucose and possible intervention. Subjects with Grade 1 
hyperglycemia (fasting serum glucose [FSG] > the upper limit of the normal range 
≤ 160 mg/dL) are treated with oral hypoglycemic agents (eg, metformin), and subjects with 
≥ Grade 2 hyperglycemia (FSG > 160 mg/dL) are treated aggressively with oral 
hypoglycemic agents and/or insulin as clinically indicated. Daily home monitoring and 


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early treatment, have resulted in good control of glucose levels for the 
majority of MLN0128-treated subjects who developed hyperglycemia.  
 
5.1.2  Cardiac Effects 
Cardiac events (including QT interval corrected for heart rate prolongation and arrhythmias) 
have been infrequently observed in clinical studies of MLN0128. To date, there has been 
1 report of ventricular fibrillation and cardiac arrest postdose that had a fatal outcome and 
was assessed as related to MLN0128. Routine cardiac monitoring with baseline 
electrocardiogram (ECG) or multigated acquisition (MUGA) scan and on-study ECGs and 
physical examination constitute the core cardiac safety monitoring in all MLN0128 studies. 
 
For subjects showing any signs of cardiac instability after MLN0128 dosing, additional 
monitoring onsite before clinic discharge should be considered. 
 
5.1.3  Renal Function 
Elevations in creatinine (regardless of causality) have been observed in subjects receiving 
MLN0128, all of which have been reversible with drug interruption and/or supportive care 
with IV hydration. Further evaluation of the renal insufficiency with urine electrolytes 
suggested a pre-renal etiology with a low fractional excretion of sodium < 1%. However, the 
adverse event cases were confounded by multiple factors such as nausea, vomiting, 
hyperglycemia, concomitant medications with GI side effects such as metformin, and 
hydronephrosis, any of which may have also contributed to dehydration and elevated 
creatinine. Subjects should be encouraged to drink at least 20 ounces of fluids a day, 
especially on days requiring fasting (per protocol), with administration of IV fluids in the 
clinic as indicated to avoid dehydration. 
 
Baseline macroscopic urinalysis and routine serum chemistries along with other safety 
laboratory assessments are performed in all MLN0128 studies. Additionally, microscopic 
urinalysis, a 12-hour urine collection, spot urine electrolytes, protein and creatinine, and 
serum chemistry should be collected at any time when the serum creatinine is ≥ Grade 1, 
according to National Cancer Institute Common Terminology Criteria for Adverse Events 
version 4.0, to further evaluate possible etiologies for the renal dysfunction. 
 
5.1.4  Rash 
Rash observed in clinical studies of MLN0128 tends to be maculopapular and pruritic and 
has ranged from Grade 1 to 3. For the most part, rash and pruritus improve with 
antihistamines, topical steroid creams, and/or dose interruption. Some subjects have 
required pulse systemic steroids, dose reduction, and/or study treatment discontinuation. 
 


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5.1.5  Pneumonitis 
Pneumonitis is a known potential risk of mTOR inhibitors. Early recognition, prompt 
intervention, and a conservative risk management approach are recommended due to 
pneumonitis that has been observed with rapalog therapy and with MLN0128 
administration. Symptoms of pneumonitis will be closely monitored in all MLN0128 study 
subjects. 
 
5.2  Interactions With Other Medicaments and Other Forms of Interaction 
Clinical drug-drug interaction studies have not been conducted with MLN0128. At this 
time, there are no known drug interactions. In vitro data, including cytochrome P450 
induction/inhibition and transporter inhibition studies conducted for MLN0128, suggest a 
low risk for MLN0128 to precipitate a drug-drug interaction. Although potential drug-drug 
interactions with MLN0128 cannot be ruled out based on the known metabolism 
characteristics of MLN0128, the potential risk is considered low. 
 
6.  ALISERTIB (MLN8237) 
6.1  Aurora A Kinases and the Aurora A Kinase Inhibitor Alisertib (MLN8237) 
Alisertib (International Proprietary Name, also known as MLN8237) is a selective small 
molecule inhibitor of Aurora A kinase that is being developed for the treatment of advanced 
malignancies.  Aurora A kinase (AurA) belongs to a highly conserved family of 
serine/threonine protein kinases that also includes Aurora B and Aurora C.  AurA and 
Aurora B are expressed in all actively dividing cells, while Aurora C expression is largely 
restricted to dividing germ cells (15,16).  AurA localizes to centrosomes and the proximal 
mitotic spindle during mitosis where it functions in a diverse set of mitotic processes.  
 
The evidence supporting AurA kinase as a therapeutic target for the treatment of 
malignancies comes from several sources.  First, the AurA kinase gene is amplified, 
overexpressed, or both in many tumors, including colon, breast, pancreatic, and bladder 
cancers, as well as certain lymphomas, leukemias, and myeloma (16). AurA overexpression 
in human cancers has been correlated with increased aneuploidy and centrosome 
amplification (16,17). Second, forced overexpression of AurA kinase in experimental 
models results in the transformation of normal cells, suggesting that AurA overexpression 
may be oncogenic (15). Lastly, in a number of different experimental systems, AurA 
inhibition leads to mitotic delays and severe chromosome alignment and segregation defects, 
followed by cell death (18-20). Overall, the essential role of AurA in mitotic progression 
and its dysregulation in certain cancers makes it an attractive therapeutic target.   
 
Given the obligatory role of mitosis in tumor proliferation, an AurA inhibitor would be 
expected to have potential applications across a broad range of human tumors.  Indeed, 
alisertib has demonstrated activity against a variety of nonclinical solid tumor and 
hematological malignancy models grown in vitro and in vivo, as described below.  Alisertib 


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is also expected to be toxic to proliferating normal tissues, such as the bone marrow, 
gastrointestinal (GI) epithelium, and hair follicles because any cell that is in mitosis, where 
AurA is expressed and active, should be susceptible to the effects of an AurA kinase 
inhibitor. 
 
6.1.1  Alisertib In Vitro Studies 
Alisertib is an ATP-competitive and reversible inhibitor of AurA kinase in vitro with an 
inhibition constant (Ki) of 0.43 nM. The data from both enzymatic and cell-based assays 
demonstrated that alisertib is a selective and potent inhibitor of AurA kinase. Alisertib 
inhibited proliferation of a wide variety of tumor cell lines grown in culture. Moreover, 
treatment of tumor cell lines with alisertib induced phenotypes consistent with AurA kinase 
inhibition, including mitotic spindle defects, mitotic delay, and apoptosis (21-24). For 
further details, refer to the Investigators’ Brochure (IB).  
 
6.1.2     Alisertib In Vivo Studies 
Alisertib demonstrated antitumor activity when administered orally on a daily basis for 
approximately 21 days (maximal tumor growth inhibition [TGI] > 90%) in several 
experimental human solid and hematologic tumor models grown as xenografts in 
immunocompromised mice. The maximally efficacious dose (ED) for each model varied: 
between 10 and 30 mg/kg if given once daily (QD) and 20 mg/kg if given twice daily (BID). 
Studies in the HCT-116 colon tumor model showed that less frequent dosing (eg, 5 days on 
followed by 5 days off) was also efficacious, demonstrating that continuous dosing is not 
necessary for antitumor activity. A single oral dose of alisertib given to nude mice 
bearingsubcutaneous HCT-116 human colon tumors resulted in inhibition of activated AurA 
kinase and an increase in mitotic cells. Therefore, mitotic index (MI) can be used as a 
pharmacodynamic marker of alisertib in some in vivo settings. The relationship between 
pharmacokinetics (PK), pharmacodynamics, and efficacy was further studied in HCT-116 
xenografts using oral dosing and subcutaneous osmotic mini-pumps. Both a 
pharmacodynamic response and efficacy (antitumor activity) were achieved using either 
route of administration. The data from these studies suggest that the maximum 
pharmacodynamic effect (mitotic accumulation) and efficacy are achieved at steady state 
plasma concentrations of 1-µM. Moreover, the maximally efficacious oral doses of alisertib 
in the HCT-116 model (30 mg/kg QD) resulted in plasma concentrations of 1 µM for 8 to 12 
hours postdose. Plasma concentrations of alisertib associated with saturating levels of 
pharmacodynamic and antitumor activity (1 μM) were exceeded at the recommended phase 
2 dose (RP2D) of alisertib in patients (50 mg BID). 
 
To determine whether alisertib would enhance the antitumor effects of standard of care 
agents in solid and hematologic malignancies, nonclinical combination studies were 
performed. Combination therapy with alisertib and docetaxel resulted in additive or 
synergistic effects during the dosing period, with prolonged tumor growth delay in multiple 
solid tumor xenograft models after terminating treatment. These effects were also observed 
in alternative intermittent dosing schedules. In DLBCL xenograft models, combination 
therapy with alisertib and rituximab resulted in synergistic, additive, or subadditive effects 


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depending on the dose and model; however, prolonged tumor growth delays were observed 
in every case after terminating treatment, and in some cases complete cures were 
maintained. 
 
6.1.3    
Alisertib Safety Pharmacology, Toxicology, and Drug Metabolism 
Safety pharmacology studies with alisertib did not identify significant adverse effects in 
nonclinical studies, including in the central nervous system (CNS) and cardiovascular 
systems. No alisertib-related effects on clinical signs or physical examination findings 
indicative of impaired respiratory function (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. Alisertib exhibited minimal activity against the rapidly activating component of IKr, 
which is encoded by hERG (IC50 and Ki > 100 µM). Alisertib had in vitro activity against 
the GABAAα1 benzodiazepine binding site (Ki = 290 nM). 
 
The dose-limiting toxicities (DLTs) for alisertib in both rats and dogs after repeat daily oral 
dosing for 2 cycles (each cycle consisted of 7 consecutive days separated by a 14-day dose 
holiday) or for 6 cycles (each cycle consisted of 21 consecutive days of dosing separated by 
a 7-day dose holiday) were consistent with inhibition of AurA kinase by alisertib. 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 AurA kinase inhibition. No off-target effects were seen in the 
GLP-compliant toxicology studies.Alisertib was negative in the bacterial reverse mutation 
assay (Ames assay) both in the absence and presence of Aroclor™ 1254-induced rat liver S9 
fractions. In a rat bone marrow micronucleus assay, alisertib was considered to be equivocal 
for clastogenicity. 
 
Alisertib is metabolized by multiple phase I (cytochrome P450 [CYP]3A4, CYP2C9, 
CYP2C19, and CYP1A2) and phase II (uridine diphosphate glucuronosyltransferase [UGT] 
1A1, 1A3, and 1A8) enzymes.  Using human liver microsomes with the appropriate 
cofactors, the percent contribution of CYP and UGT was calculated to be 13.1% and 86.9%, 
respectively, showing that CYP isozymes play a minor role in the metabolism of MLN8237.  
MLN8237 is unlikely to inhibit the 5 major CYP enzymes, 1A2, 2C9, 2C19, 2D6, and 
3A4/5 (IC50 > 100 μM) when administered at the projected human efficacious dose.  
MLN8237 is not a mechanism-based inhibitor of CYP3A4/5.  Alisertib inhibited the P 
glycoprotein (Pgp)-mediated efflux of paclitaxel (Taxol®) in Caco 2 cells with an IC50 of 
4.0 μM.  Detailed information regarding the nonclinical pharmacology and toxicology of 
alisertib may be found in the IB. 
 
6.1.4 Alisertib Clinical Experience 
As of 29 March 2012, the following company-sponsored alisertib studies were in progress or 
completed: 6 single-agent phase 1 studies, 3 single-agent phase 2 studies, 1 single-agent 


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phase 1/2 study, and 3 combination studies.  Alisertib for clinical studies is being developed 
in 2 dosage formulations:  Enteric-coated-tablet (ECT) and oral solution (OS).  The dose-
escalation, phase 1 study, C14007, evaluated multiple dose levels from 10 to 60 mg BID for 
7 days in repeat, 21-day cycles and 50 mg BID has been determined to be the MTD. 
 
Alisertib is structurally related to the benzodiazepines (BZD) (eg, diazepam, lorazepam) and 
also has activity against the GABAAα1 BZD receptor.  BZD-like effects (eg, somnolence, 
confusion, memory loss) have been observed to be associated with the onset of maximal 
plasma concentration (eg, Tmax [time to maximum plasma concentration]).  CNS effects 
associated with peak plasma levels have been generally managed by administration of 
divided doses (eg, BID administration), although dose reductions have sometimes been 
required.  While CNS effects attributed to alisertib were also generally reversible and 
manageable by dose delay or reduction, the causal relationship, and thus optimal approach to 
management, were sometimes confounded by diverse causes including, but not limited to, 
concomitant medications (eg, narcotic analgesics, antianxiety medications), comorbidities 
(eg, infection, anemia, electrolyte abnormalities), or progressive malignancy (eg, brain 
metastases).  The clinical experience with alisertib includes treatment with multiple doses 
and schedules and is summarized in the IB.   
 
6.1.5  Alisertib Pharmacokinetics 
Upon oral administration to patients with advanced nonhematologic malignancies, 
absorption of alisertib was fast, with peak plasma concentrations generally achieved by 3 
hours postdose. Negligible urinary excretion of alisertib was observed in humans. The renal 
clearance of alisertib in humans was less than 0.1% of apparent oral clearance. 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. Overall mean steady 
state terminal half-life following multiple-dose administration in patients with 
nonhematologic malignancies was approximately 22 hours. The overall mean peak/trough 
ratios were 2.6 and 5.0 for BID and QD dosing, respectively. The overall mean 
accumulation ratios were 2.8 and 1.9 for BID and QD dosing, respectively. Pharmacokinetic 
steady-state conditions were approximately achieved by Day 7 following daily oral 
administration. The PK properties of alisertib in patients with hematologic malignancies 
were generally consistent with those observed in patients with nonhematologic 
malignancies. Based on PK and genotype data in patients with nonhematologic 
malignancies, there was a substantial overlap in exposures (dose-normalized steady-state 
area under the plasma concentration versus time curve [AUC]) of alisertib in patients with 0, 
1, or 2 copies of the UGT1A1 *28 allele, indicating the lack of readily apparent effects of 
UGT1A1 genotype on alisertib systemic exposure. 
 
Clinical pharmacokinetic data available as of 20 April 2012 are summarized in the IB. Upon 
oral administration to patients with advanced nonhematologic malignancies, absorption of 
alisertib was fast, with peak plasma concentrations generally achieved by 2 hours post dose. 
Negligible urinary excretion of alisertib was observed in humans. The renal clearance of 
alisertib in humans was less than 0.1% of apparent oral clearance. Steady-state plasma 
exposures of alisertib increased in an approximately dose proportional manner over the 


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range of 5 to 200 mg/day in patients with advanced solid tumors. Overall mean steady-state 
terminal half-life following multiple-dose administration in patients with nonhematologic 
malignancies was approximately 22 hours. The overall mean peak/trough ratios were 2.6 
and 5.0 for BID and QD dosing, respectively. The overall mean accumulation ratios were 
2.8 and 1.9 for BID and QD dosing, respectively. Pharmacokinetic steady-state conditions 
were approximately achieved by Day 7 following daily oral administration.  
 
Based on the results of a population PK analysis in 294 adult cancer patients, the apparent 
oral clearance of alisertib CL/F was unaffected by age, body weight, BSA, or the UGT1A1 
genotype (number of *28 alleles). These results support the use of a common fixed starting 
dose of alisertib independent of UGT1A1 genotype status, age or body size in the adult 
patient population, in the ongoing and planned clinical trials. 
 
The absolute bioavailability of alisertib in humans has not been determined; however, the 
single-dose pharmacokinetics of a prototype oral solution formulation of alisertib (25-mg 
dose) were characterized in a cross-over relative bioavailability evaluation in Study C14010 
in 15 patients with nonhematologic malignancies.  
 
The effect of a standardized high-fat meal on the PK of single dose alisertib administered as 
a 50-mg strength was evaluated in 14 patients with advanced solid tumors.  The lack of an 
effect of food on alisertib AUCinf observed in this study supports the conclusion of the lack 
of a clinically meaningful effect of food on the PK of alisertib.  The results of this study, 
therefore, support a recommendation that alisertib may be dosed without regard to the 
timing of meals in future clinical studies, unless otherwise specified in the clinical study 
protocol. 
 
6.1.6   Alisertib Potential Risks and Benefits 
Seven-hundred fourteen patients (excluding 13 patients from a company-sponsored, non-US 
IND study in Japan) have been treated with alisertib as of 29 March 2012. Clinical safety 
data includes experience from patients who received multiple cycles followed by treatment 
free periods between each cycle, and from patients who reduced or discontinued treatment. 
Based on the available clinical data, drug abuse, dependency, and drug withdrawal effects 
were not observed.  
 
To date, the observed risks associated with alisertib treatment, as detailed in the Safety 
Management Attachment of 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 transaminase [AST], alanine transaminase [ALT], bilirubin, alkaline phosphatase 
[ALP], and gamma glutamyl transferase [GGT]), and (9) rash, which may include bullous 
dermatitis, and palmar-plantar erythrodysaesthesia syndrome.While these toxicities are 
potentially associated with risk or discomfort to the patient, they are anticipated to be 


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reversible.   To mitigate the inherent risks in clinical studies of alisertib, patients are 
evaluated frequently while they are receiving treatment.   
 
Because alisertib inhibits AurA kinase, it is possible that alisertib may interfere with cancer 
growth and cause cancer cell death. Preclinical results indicate that alisertib is not a major 
substrate for efflux mechanisms that have been associated with cross-resistance between 
some types of anticancer agents. Thus, alisertib has potential through a potentially non-cross 
resistant pathway as compared to other agents the patients may have received.  The clinical 
utility of these effects will be investigated in current and future studies. 
 
This study will be conducted in compliance with the protocol, applicable regulatory 
requirements, and International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP), guidelines. 
6.2  Risk of MLN0128 and Alisertib Combination Therapy 
Overlapping toxicity is not expected with the combination of MLN0128 and alisertib, 
however, the risk of increased toxicity with combination therapy is possible. Dose limiting 
adverse events observed with MLN0128 treatment include mucositis, hyperglycemia, 
diarrhea and fatigue.  Dose limiting adverse events observed with alisertib treatment include 
myelosuppression and CNS depression. As described in Section 10.1 and Table 1, dosing 
will begin below the MTD for each agent in the dose escalation cohort.  Patients will be 
monitored for toxicity and management guidelines are provided to facilitate early detection 
and rapid, appropriate management of toxicity. 
7. 
STUDY RATIONALE 
7.1  Alisertib and MLN0128 in TNBC 
Metastatic TNBC is a biologically heterogeneous disease and the development of active 
targeted therapies in conjunction with effective biomarker selection strategies is an area of 
unmet clinical need (25,26).  AurA plays a critical role in mitosis including functions in 
chromosome alignment, spindle formation, and cytokinesis (27,28).  It functions as an 
oncogene through the promotion of genetic instability (15) and over-expression of AurA has 
been linked to inferior outcomes in patients with early stage breast cancer (29).  Aurora 
kinase inhibitors (AKIs) are a promising class of drugs for the treatment of TNBC based on 
their anti-mitotic mechanism of action and the high mitotic index observed in TNBC. (30). 
 
Alisertib is an orally bioavailable, second-generation selective AKI with broad 
antiproliferative and anti-tumor activity in preclinical in vitro and in vivo TNBC models 
(23).  Alisertib treatment resulted in a G2/M cell cycle arrest and the induction of apoptosis 
in a subset of p53 wildtype and mutant sensitive TNBC cell lines (23). TP53 is the most 
commonly mutated gene in TNBC with an incidence of approximately 85% (31).  While the 
majority of mutations are missense mutations in the DNA binding domain, more complex 
mutations (ie frameshift and nonsense mutations) occur at a higher frequency in TNBC as 
compared to luminal breast cancers (32).  Mutations in p53 may abrogate its tumor 
suppressor function resulting in impairment of cell cycle arrest, DNA repair and apoptosis 


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(33).  AurA over-expression may lead to increased p53 degradation via phosphorylation of 
p53 at Ser315, leading to increased ubiquitination by MDM2 (34). Furthermore, silencing of 
AurA results in stabilization of p53 and a characteristic G2/M cell cycle arrest (34).    
 
Sensitivity to the pro-apoptotic activity of alisertib in TNBC is mediated by both p53 and the 
p53 family member p73.  Knock-down (KD) of either p53 or p73 using shRNA in the p53 
wildtype CAL-51 TNBC cell line led to an increase in resistance to the antiproliferative and 
proapoptotic effects of MLN8237 (23). This shift to resistance was associated with an 
increase in senescence associated-β-galactosidase (SA-β-gal) activity and phenotypic 
features consistent with senescence (23). These findings support the induction of senescence 
as a mechanism for resistance to the anti-apoptotic effects of MLN8237 in cells lacking 
functional p53 or p73.   
 
Alisertib is active against TNBC xenograft and patient-derived tumor xenograft (PDX) 
models where apoptosis is observed in sensitive models as detected by cleaved caspase-3 
staining (23).  Senescence and upregulation of genes in the PI3K/AKT/mTor pathway were 
observed in PDX models treated with alisertib to resistance.  This finding is consistent with 
an emerging body of literature supporting a critical role for mTOR in oncogenic and DNA-
damage induced senescence (35). 
 
Based on the role of mTOR in senescence and upregulation of the PI3K/AKT/mTor pathway 
in TNBC models resistant to AKIs, we investigated the combination of alisertib and the 
Torc1/2 inhibitor MLN0128 in TNBC PDX models.  The combination of MLN8237 and 
MLN0128 resulted in greater TGI as compared to either agent alone (Figure 3A), 
accompanied by an increase in apoptosis as measured by BAX and DR5 expression (Figure 
3B) and a decreased senescence as evaluated by SA-β-gal and phenotypic changes (Figure 
3C).  
 
Figure 3. In vivo, combination therapy with alisertib (MLN8237) and MLN0128 significantly inhibits growth over monotherapies.  A. 
Tumor growth of TNBC PDX CU_TNBC_005 in vehicle or experimental agent-treated mice (n = 10/group) were plotted. Combination therapy 
significantly enhances tumor growth inhibition compared to vehicle (p < 0.0001) or single agents (p < 0.0001).  B. Cotreatment with alisertib 
(MLN8237) and MLN0128 enhances expression of pro-apoptotic proteins BAX and DR5 in tumors excised at Day 38. C. Treatment with 
MLN8237 induces SA-β-gal activity (blue stain) that is not observed with combination treatment.  
A 
B 
C 


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The purpose of this study is to evaluate the combination of alisertib and MLN0128 in 
patients with advanced solid tumors refractory to standard treatment followed by an 
expansion cohort of patients with metastatic TNBC and other solid tumors with exploratory 
correlative studies in select cohorts.  The starting dose of MLN0128 is 1 mg PO daily with 
continuous dosing.  This dose is 75% lower than the MTD of single agent milled MLN0128 
(4 mg) PO daily when administered in a continuous dosing schedule.  The starting dose of 
alisertib is 30 mg PO BID.  This dose is in the biologically active dose range and is 40% 
lower than the MTD of single agent alisertib (50 mg PO BID Days 1-7 repeat every 21 
days).   
7.2  Correlative Studies 
Serial tumor biopsies will be performed in the Expansion Cohort Group 1 and Group 2.  
Tumor tissue will be obtained prior to initiating study drug treatment, Cycle 1 Day 7, Cycle 
2 Day 7 and at the time of progression in patients with an initial response to treatment.  
Tissue samples will be processed, assayed and analyzed at the University of Colorado 
Cancer Center.  Testing will include immunohistochemistry (IHC), SA-β-gal staining, gene 
expression profiling and DNA mutation testing.  Other markers may be investigated 
depending on ongoing preclinical work. 
 
Functional Imaging with diffusion-weighted MRI (DWI) and 5-fluoro-deoxy-glucose-PET 
(FDG-PET) will be performed at the University of Colorado Cancer Center in a subset of 
patients enrolled in Dose Expansion Groups 1 and 2 depending on the presence of tumor 
lesions amenable to imaging evaluation.  Oncologic imaging has evolved and now 
represents a  key diagnostic platform for cancer diagnosis and treatment. In addition to 
capabilities in determining tumor size, molecular and physiologic imaging is now available 
in order to assess tumor metabolism, physiology and molecular targets non-invasively in  
real time. As such, Positron Emission Tomography (PET) plays a crucial role in assessing 
tumor metabolic aggressiveness by determining uptake rates of the 18F-radioactive glucose 
analogue (FDG) which is up-regulated in TNBC and is a sensitive marker for treatment 
response to novel targeted agents. Tumor cellularity can be assessed by measuring water 
tissue properties by diffusion-weighted MRI (DWI) which is clinically used to assess tumor 
response to chemotherapy as a marker of apoptosis (36,37). These studies will be performed 
and analyzed by Natalie Serkova, PhD (Associate Professor of Anesthesiology, 
Pharmacology and Radiology; Director, Colorado Clinical Translational Science Institute 
Imaging Core) and her staff. 


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8.    
STUDY OBJECTIVES 
8.1    Primary Objectives 
• To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) 
of the combination of MLN0128 and alisertib in adult patients with advanced solid 
tumors. 
8.2    Secondary Objectives 
• To determine the safety profile and tolerability of the combination of MLN0128 and 
alisertib in adult patients with advanced solid tumors. 
• To determine the pharmacokinetics of MLN0128 and alisertib in the combination. 
• To evaluate the pharmacodynamic effects of MLN0128 and alisertib in serial tumor 
biopsies and blood samples in patients with metastatic TNBC and other solid tumors 
enrolled in the expansion cohort at the MTD. 
• To estimate the objective response rate using RECIST 1.1 and time to progression in 
patients with advanced solid tumors treated with MLN0128 and alisertib. 
8.3    Tertiary/Exploratory Objectives  
• To explore biomarkers predictive of response to MLN0128 and alisertib including the 
investigation of mechanisms of acquired resistance to treatment in patients with 
metastatic TNBC and other solid tumors treated in the expansion cohort at the MTD. 
• To evaluate the pharmacodynamic effect of the combination of MLN0128 and alisertib 
on cellular metabolism using functional imaging with FDG-PET (5-fluoro-deoxy-
glucose-PET) and diffusion weighted magnetic resonance imaging (DWI-MRI). 
9.    
STUDY ENDPOINTS 
9.1    Primary Endpoints  
DLTs are defined according to the AE profile observed during the DLT assessment window 
of up to 28 days following the first dose of MLN0128 (Cycle 1 Day -7 to Cycle 1 Day 21) in 
the Dose Escalation portion of the trial (see Sections 10.1, 10.2 and 12.2).  Toxicity will be 
graded according to the NCI CTCAE Version 4.03.   
9.2    Secondary Endpoints 
• Safety:  Adverse events according to the NCI CTCAE v.4.03 that occur after the first 
dose of study drug. 
• Pharmacokinetics:  PK analysis will be performed only to evaluate the effects of 
MLN0128 and alisertib on the disposition of each other.  PK analysis will be 
obtained only during Cycle 1 of the Dose Escalation cohort. 


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• Efficacy:  Objective response rate based on imaging with CT or MRI will be 
evaluated using RECIST 1.1 criteria.  Time to progression as defined as the time 
from the first day of treatment to the first observation of disease progression will be 
determined. 
9.3    Tertiary/Exploratory Endpoints  
• Serial tumor biopsies will be performed in the Expansion Cohort Group 1 and Group 
2.  Tumor tissue will be obtained prior to initiating study drug treatment, Cycle 1 
Day 7, Cycle 2 Day 7 and at the time of progression in patients with an initial 
response to treatment.  Tissue samples will be tested and analyzed at the University 
of Colorado Cancer Center for the following: 
a. pHH3, Ki67, pAurA, p16, p4E-BP1, pS6 and pAKT (Immunohistochemistry 
[IHC]) 
b. p53 and mTor pathway target gene expression (gene expression profiling and 
RT-PCR) 
c. Senescence-associated beta-galactosidase staining (SA-β-gal) 
d. DNA mutation testing (baseline and time of progression only, Ion Ampliseq 
Cancer Hotspot Panel or similar platform depending on advancement of 
technology at the time of analysis) 
e. Possibly other markers depending on ongoing preclinical work 
• Functional Imaging with diffusion-weighted MRI (DWI) magnetic resonance 
imaging and 5-fluoro-deoxy-glucose-PET (FDG-PET) will be performed at the 
University of Colorado Cancer Center in a subset of patients enrolled in Dose 
Expansion Groups 1 and 2 depending on the presence of tumor lesions amenable to 
imaging evaluation.  These studies will be performed and analyzed by Natalie 
Serkova, PhD (Associate Professor of Anesthesiology, Pharmacology and 
Radiology; Director, Colorado Clinical Translational Science Institute Imaging Core) 
and her staff. 
10.    STUDY DESIGN  
10.1    Overview of Study Design 
This is a Phase Ib open-label, single institution, dose-escalation study designed to evaluate 
the safety, tolerability, and pharmacokinetics of MLN0128 administered by mouth (PO) in 
combination with alisertib administered PO to patients with advanced solid tumors and 
previously treated metastatic TNBC and other solid tumors in an expansion cohort.  The 
initial schedule of MLN0128 administration will be once daily with continuous dosing.  If 
this schedule is not tolerable in combination with alisertib, other schedules may be 
considered including once weekly dosing or other interrupted schedules.  The initial 
schedule of alisertib administration will be twice daily for 7 days of a 21 day cycle.  If this 
schedule is not tolerable in combination with MLN0128 then other interrupted dosing 
schedules may be considered.  
 
The dose escalation portion of the trial will be conducted using a standard 3 + 3 dose-
escalation design in patients with advanced solid tumors refractory to standard therapies or 
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maximum tolerated dose (MTD) / recommended phase II dose (RP2D) is identified, the dose 
expansion portion will be conducted in patients with previously treated metastatic TNBC 
and other solid tumors.  Exploratory correlative studies will be conducted in the expansion 
cohort including:  evaluation of pharmacodynamics markers in serial tumor biopsies and 
blood samples, exploration of predictive biomarkers using fresh and archival tissue samples, 
and evaluation of cellular metabolism using functional imaging.  
 
A total of 30 patients will be treated in the dose-expansion cohort at the MTD/RP2D (see 
Figure 2 for dose expansion cohort schema).  All patients in the expansion cohort group 1 
and 2, will be required to undergo fresh tumor biopsy prior to initiating treatment, Cycle 1 
Day 7, and Cycle 2 Day 7.  In expansion cohort Group 1, single agent alisertib will be 
administered at the MTD on Days 1-7 and MLN0128 will be administered on Days 8-21.  In 
Cycle 2 and beyond, dosing with both agents will begin on Day 1.  In expansion cohort 
Group 2, MLN0128 will be administered at the MTD in Cycle 1 Days 1-28 and alisertib will 
be administered at the MTD on Days 8-15.  An attempt will be made to obtain a repeat 
tumor biopsy at the time of progression in patients with an initial response to treatment in 
group 1 and 2.  
Table 1.   Planned Dose Levels 
Dose Level 
Number of 
Patients 
MLN01281 
Alisertib2  
-1 
3-6 
1 mg PO daily 
20 mg PO BID 
1(Starting Dose) 
3-6 
1 mg PO daily 
30 mg PO BID 
2 
3-6 
2 mg PO daily 
30 mg PO BID 
3 
3-6 
2 mg PO daily 
40 mg PO BID 
4 
3-6 
3 mg PO daily 
40 mg PO BID 
5 
3-6 
3 mg PO daily 
50 mg PO BID 
6 
3-6 
4 mg PO daily 
50 mg PO BID 
MTD 
20 
TBD 
TBD 
1.  MLN0128 will be administered orally once daily with continuous dosing.  A single dose of MLN0128 will 
be administered on Cycle 1 between Day -7 to Day -3.  Continuous dosing in Cycle 1 during the Dose 
Escalation Cohort will begin on Cycle 1 Day 2. 
2.  Alisertib will be administered orally twice daily days 1-7 of each 21 day cycle.  A single dose of alisertib 
will be administered on Cycle 1 Day 1 and BID dosing will be initiated on Cycle 1 Day 2. 
 
Based on an efficacy signal observed in a patient with metastatic pancreatic 
adenocarcinoma, an expansion cohort of 10 patients with previously treated, locally 
advanced or metastatic pancreatic adenocarcinoma will be treated at the MTD/RP2D. 
All patients will be followed carefully for adverse events during the study period and for at 
least 30 days after the last dose of MLN0128 or alisertib or until initiation of another cancer 
treatment.  Additionally, patients with unresolved adverse events or abnormal laboratory 
values related to MLN0128 or alisertib may be contacted by telephone for follow-up of 
these events.  Adverse events will be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.03.  Blood 
samples will be taken before and at predetermined times after a single dose of MLN0128 on 
Cycle 1 Day -7 to Day -3, after a single dose of alisertib on Cycle 1 Day 1, and after 


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combination treatment on Cycle 1 Day 7 and Day 1 of subsequent cycles to determine the 
PK properties of MLN0128 and alisertib. 
Disease status will be assessed using RECIST 1.1.  Patients will undergo tumor assessments 
at screening, at the end of Cycle 3 and every three cycles thereafter, or as clinically 
indicated.  Tumor status will be categorized as a complete response, partial response, stable 
disease, or progressive disease per RECIST 1.1.  An objective response will be considered 
confirmed once the same assessment is made by repeat evaluation > 4 weeks after the initial 
documentation, per RECIST 1.1. 
Protocol treatment will be discontinued in patients who experience disease progression or 
unacceptable toxicity or who are not compliant with the study protocol.  Treatment with 
MLN0128 or alisertib alone may be continued if the other agent is discontinued for 
unacceptable toxicity related to only one study agent.  A study completion visit will be 
performed within 30 days after the last dose of protocol treatment in all patients.  
In addition to the protocol, the Investigator should refer to the associated Investigator’s 
Brochure, the Study Procedures Manual, and the appendices of this clinical study protocol 
for further information regarding this investigational product or details of the procedures to 
be followed during the course of this study. 
10.2 Dose Escalation Cohort 
The starting dose for MLN0128 is 1 mg (milled formulation) PO once daily with continuous 
dosing.  This dose is 75% lower than the MTD of MLN0128 in the Ph1b/2 study C31001 
which is 4 mg (milled formulation).  The starting dose of alisertib is 30 mg PO BID Days 1-
7 repeat every 21 days.  This dose is 40% lower than the MTD of alisertib (50 mg) for this 
dosing schedule.  During Cycle 1 in the Dose Escalation Cohort only, a single dose of 
MLN0128 will be administered on Cycle 1 between Day -7 to -3 to allow for single agent 
MLN0128 PK analysis.  Continuous dosing with MLN0128 will begin Cycle 1 Day 2.  A 
single dose of alisertib will be administered on Cycle 1 Day 1 to allow for single agent 
alisertib PK analysis and BID dosing with alisertib will begin on Cycle 1 Day 2.   
 
DLTs will be assessed during the DLT assessment window of up to 28 days following the 
first dose of MLN0128 (Cycle 1 Day -7 to Cycle 1 Day 21).  Patients who withdraw from 
the study prior to completing the DLT assessment window for any reason other than a DLT 
will be replaced.  In addition, patients who miss a total of > 3 days of scheduled dosing for 
MLN0128 or alisertib during the DLT assessment window for reasons other than a DLT will 
be replaced.  See Section 12.2 for DLT definition. 
 
After dosing has been completed in each cohort, data pertaining to dose-escalation decisions 
for MLN0128 and alisertib will be reviewed by the Sponsor Investigator, Clinical Trial 
Manager and at least 2 other Phase I Oncologists (co-investigators). Available adverse event 
data, laboratory assessments, ECGs, dose administration logs and PK parameters (when 
available) will be used to determine whether dose escalation should continue and, if so, at 
what dose level and schedule (see Table 1).  The dose escalation schema may be altered if 
toxicity is observed related to one agent which would favor escalation of the other agent. 


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Dose escalation will procede in accordance with the following rules (see Figure 1): 
• A minimum of 3 patients will be treated in each cohort. 
• If 0 patients experience a DLT in a cohort, dose escalation will proceed. 
• If 1 of the first 3 patients in a cohort experiences a DLT then 3 additional patients 
will be enrolled in that cohort. 
• If less than 1/3 of the evaluable patients in a cohort experience a DLT then escalation 
will proceed 
• If 1/3 or more evaluable patients in a cohort experience a DLT, then the MTD has 
been exceeded and the preceding dose level will be expanded to 6 evaluable patients 
(If 6 patients have not already been evaluated at that level).  Intermediate dose levels 
may be evaluated at the discretion of the Sponsor Investigator after discussion with 
the study team. 
• If the MTD is exceeded in the first dosing cohort, lower doses or alternate schedules 
of MLN0128 or alisertib will be evaluated as guided by observed toxicities. 
• If the MTD is exceeded at a given dose level then the next highest dose at which less 
than 1/3 of at least 6 evaluable patients experiences a DLT will be declared the 
MTD. 
• If fewer than 1/3 of at least 6 evaluable patients experiences a DLT at the highest 
planned dose level then this dose level will be declared the RP2D. 
 
10.3  Study Procedures 
Refer to the Schedule of Events for timing of assessments.  Additional details are provided 
as necessary in the sections that follow. If a subject has an unscheduled clinic visit, data 
from procedures performed, per standard of care, may be collected and used for research 
purposes at the investigators discretion. 
 
10.3.1  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. 
 
10.3.2 Patient Demographics  
The date of birth, race, and ethnicity of the patient are to be recorded during screening. 
 
10.3.3  Medical History   
During the Screening period, a complete medical history will be compiled for each patient.  
The history will emphasize the background and progress of the patient’s malignancy and 
include a description of prior therapies for the disease.  ER, PR and HER2 status should be 
collected for breast cancer patients.   
 


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10.3.4  Physical Examination 
A physical examination will be completed per standard of care at the times specified in the 
Schedule of Events. 
Physical examination findings within the following categories will be assessed: 
• HEENT 
• Pulmonary 
• Cardiovascular 
• GI/abdomen 
• Extremities 
• Neurological 
• Skin and hair 
 
10.3.5  Vital Signs 
Vital signs include systolic and diastolic blood pressure, heart rate, respiratory rate, body 
temperature and weight.  Height will be measured only during screening. 
10.3.6  ECOG Performance Status 
The ECOG Performance Status (refer to Appendix 1) will be assessed at the times 
specified in the Schedule of Events. 
10.3.7  Concomitant Medications and Procedures 
Medications used by the patient and therapeutic procedures completed by the patient will 
be recorded in the eCRF from first dose of study drug through 30 days after the last 
dose.  See Section 12.5 and Section 12.6 for a list of medications and therapies that are 
prohibited and/or permitted during the study. 
Clinical laboratory evaluations will be performed locally.  Blood and urine samples for 
analysis will be obtained as specified in the Schedule of Events.  Results of hematology 
and clinical chemistry safety labs must be available and reviewed by the investigator 
before enrollment and initial administration of study drug.  Serum pregnancy tests will 
be performed in women of child bearing potential as specified in the Schedule of Events.  
A positive pregnancy test prior to dosing will exclude the patient from enrollment in the 
study.  Values for the following parameters will be obtained: 


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HEMATOLOGY 
CLINICAL CHEMISTRY 
URINALYSIS  
Hemoglobin 
Hematocrit 
Platelet Count 
White Blood Cell Count 
Differential, including: 
Neutrophils 
Lymphocytes 
Basophils 
Monocytes 
Eosinophils 
Total protein 
Albumin 
Creatinine 
Bilirubin (total) 
Alkaline phosphatase 
AST(SGOT) 
ALT (SGPT) 
Glucose 
Calcium 
Phosphorus 
Bicarbonate 
Chloride 
Sodium 
Potassium 
Magnesium 
 
Color/appearance 
Specific gravity 
pH 
Protein (qualitative) 
Glucose (qualitative) 
Ketones (qualitative) 
Bilirubin (qualitative) 
Blood (qualitative) 
Standard microscopic examination 
if above parameters are abnormal 
COAGULATION TESTS 
OTHER 
Prothrombin time (PT) or 
International Normalized Ratio (INR) 
Partial thromboplastin time (PTT) 
 
Serum Pregnancy Test  
Fasting Serum Glucose (patients are 
required to fast overnight as defined 
as nothing except water and/or 
medications after midnight or for a 
minimum of 8 hours) 
HbA1C 
  
FASTING LIPID PROFILE 
Total cholesterol 
Triglycerides 
High-density lipoprotein cholesterol 
(HDL) 
Low-density lipoprotein cholesterol 
(LDL) 
 
10.3.8  In-home fasting glucose monitoring 
Patients will be instructed to complete daily glucose monitoring at home after fasting 
overnight (nothing except water and/or medications after midnight or for a minimum of 
8 hours) for each of these measurements.  Patients will be instructed to bring the 
glucometer with them to each study visit so that the data collected can be reviewed and 
recorded into source documents.  
10.3.9  Pharmacokinetic measurements 
Pharmacokinetic studies will be performed at the timepoints outlined in the Schedule of 
Events including on the day of on treatment tumor biopsies.  Instructions for preparation, 
completion, and shipment of PK samples are included in the Study Procedure Manual. 
10.3.10  Tumor Biopsies 
All patients in the expansion cohort group 1 and 2, will be required to undergo fresh 
tumor biopsy prior to initiating treatment, Cycle 1 Day 7, and Cycle 2 Day 7 as outlined 
in the Schedule of Events and Figure 2.  Tumor biopsies will be performed as per local 
institutional guidelines. An attempt should be made to obtain a repeat tumor biopsy at 
the time of progression in patients with an initial response to treatment.   


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Instructions for preparation, completion, and processing of tumor biopsies are included 
in the Study Procedure Manual.   
Tumor biopsies will not be performed in the pancreatic adenocarcinoma expansion 
cohort.  
10.3.11  Functional Imaging 
DWI-MRI and FDG-PET/CT will be obtained on select patients as outlined in the 
Schedule of Events.  Instructions for functional imaging are included in the Study 
Procedure Manual. 
10.4 Number of Patients 
The total number of patients enrolled in the Dose Escalation Cohort will depend on the 
number of dose cohorts required to identify the MTD.  Escalation to the next dose cohort 
will depend on the probability of DLT at a given dose.  When 1 of 3 patients develops a 
DLT and the cohort is expanded to 6 patients, the proposed plan for dose escalation provides 
a 91% probability that dose escalation will proceed at doses associated with DLT probability 
of < 10%. 
 
A maximum of 6 patients can be enrolled at each dose level.  With 6 potential dose levels 
and an Expansion Cohort of 30 patients, the maximum number of patients that can be 
enrolled is 56 and the minimum number is 6.  Patients will be considered enrolled on the 
first day of MLN0128 or alisertib study drug treatment. 
10.5    Duration of Study 
Patients will continue to receive treatment with MLN0128 and alisertib until they experience 
disease progression or have an unacceptable drug-related toxicity.  There is no maximum 
duration of treatment.  The study will be terminated 6 months after the last patient completes 
the End-of-Treatment (EOT) study visit. 
 
11.    STUDY POPULATION 
11.1    Inclusion Criteria 
Each patient must meet all of the following inclusion criteria to be enrolled in the study: 
1. Male or female patients 18 years or older.  
2. Dose Escalation Cohort:  Patients must have a diagnosis of a histologically 
confirmed solid tumor that is incurable and refractory to standard therapy or for 
which no standard therapy exists. 
 
3. Dose Expansion Cohort Group 1 and 2: Patients must have a diagnosis of 
histologically confirmed metastatic TNBC defined as negative for estrogen receptor, 


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progesterone receptor and HER2. Patients must have received either adjuvant 
chemotherapy or first line chemotherapy for metastatic disease.  Negative for Estrogen 
and Progesterone Receptor includes the following: 
• Local Pathology report classifies them as negative 
• Allred Score of 2 or below 
• <1% positive staining 
Subjects with solid tumor types other than TNBC may also be enrolled after 
discussion with the Sponsor.  These subjects must have a diagnosis of a 
histologically confimed solid tumor that is incurable and refractory to standard 
therapy or for which no standard therapy exists. 
 
4. Pancreatic Cancer Cohort: Patients must have a diagnosis of locally advanced or 
metastatic pancreatic adenocarcinoma previously treated with or not a candidate 
for standard of care systemic therapy. 
 
5. Dose Expansion Cohort Group 1 and 2:  At least one tumor lesion amenable to repeat 
core needle biopsy or punch biopsy without unacceptable risk of a major procedural 
complication. 
6. Eastern Cooperative Oncology Group (ECOG) performance status < 1 (See 
Appendix 1) 
7. Three weeks or 5 half-lives (whichever is shorter) from previous systemic anticancer 
therapy; at least 4 weeks from major surgery and recovered; at least 2 weeks from 
palliative radiation and recovered. No more than 450 mg/m2 cumulative dose of 
doxorubicin or equivalent anthracycline dose is allowed.   
8. All acute treatment-related toxicities from prior therapy must have resolved to Grade 
< 1 prior to study entry excluding alopecia. 
9. For women: 
• 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, at the same time, from the time of signing the informed consent  
through 90 days after the last dose of study drug OR agree to practice true 
abstinence, when this is in line with the preferred and usual lifestyle of the 
patient (Periodic abstinence [e.g, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of 
contraception 
For men, even if surgically sterilized (ie, status post-vasectomy), they must: 
• Agree to practice effective barrier contraception during the entire study treatment  
period and through 120 days after the last dose of study drug, OR agree to 
practice true abstinence, when this is in line with the preferred and usual lifestyle 


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of the patient (Periodic abstinence [e.g, calendar, ovulation, symptothermal, 
postovulation methods for the female partner] and withdrawal are not acceptable 
methods of contraception 
• Agree not to donate sperm during the course of this study or 120 days after 
receiving their last dose of study drug 
10. Screening clinical laboratory values as specified below:  
a) Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 
x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL. Values must be 
obtained without the need for myeloid growth factor support, platelet or 
PRBC transfusion support within 14 days. 
b) Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN), transaminases 
(aspartate aminotransferase/serum glutamic oxaloacetic transaminase-
AST/SGOT and alanine aminotransferase/serum glutamic pyruvic 
transaminase-ALT/SGPT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are 
present); 
c) Renal: Creatinine < 1.5 X ULN or creatinine clearance ≥ 50 mL/min based 
either on Cockroft-Gault estimate or based on urine collection (12 or 24 
hour)(Appendix 2); 
d) Metabolic: Glycosylated hemoglobin (HbA1c)<7.0%, fasting serum glucose 
(≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL;  
e) For patients undergoing serial tumor biopsies, INR and activated partial 
thromboplastin time (PTT) must be within 1.5 X the upper limit of normal.    
11. Left ventricular ejection fraction (LVEF) > LLN of the institutional standard of 
normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan 
(MUGA) within 4 weeks prior to first study drug administration. 
12. Ability to swallow oral medications.  
13. 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. 
14. Patients who have a history of brain metastasis are eligible for the study provided 
that all the following criteria are met: 


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a) Brain metastases which have been treated 
b) No evidence of disease progression for ≥ 4 weeks or hemorrhage after 
treatment 
c) Off-treatment with dexamethasone for 2 weeks before administration of the 
first dose of MLN0128 
d) No ongoing requirement for dexamathasone or anti-epileptic drugs 
11.2 Exclusion Criteria 
Patients meeting any of the following exclusion criteria are not to be enrolled in the study: 
1. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, 
active central nervous system disease, active infection, or any other condition that 
could compromise the patient’s participation in the study. 
2. Known human immunodeficiency virus infection. 
3. Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is 
considered to be over 25%. 
4. Known history of uncontrolled sleep apnea syndrome and other conditions that 
could result in excessive daytime sleepiness, such as severe chronic obstructive 
pulmonary disease; requirement for supplemental oxygen. 
5. Systemic infection requiring IV antibiotic therapy within 14 days preceding the first 
dose of study drug, or other severe infection. 
6. Known hepatitis B surface antigen-positive, or known or suspected active hepatitis 
C infection. 
7. Any serious medical or psychiatric illness that could, in the investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 
8. Diagnosed or treated for another malignancy within 2 years before administration of 
the first dose of study drug, or previously diagnosed with another malignancy and 
have any evidence of residual disease. Patients with nonmelanoma skin cancer or 
carcinoma in situ of any type are not excluded if they have undergone complete 
resection. 
9. Breast feeding or pregnant. 


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10. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI 
disease, or for an unknown reason that may alter the absorption of MLN0128. In 
addition, patients with enteric stomata are also excluded. 
11. Treatment with any investigational products within 3 weeks before the first dose of 
study drug. 
12. History of any of the following within the last 6 months before administration of the 
first dose of the drug: 
• Ischemic myocardial event, including  angina requiring therapy  and artery 
revascularization procedures   
• Ischemic cerebrovascular event, including transient ischemic attack and artery 
revascularization procedures 
• Requirement for inotropic support (excluding digoxin) or serious 
(uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, 
ventricular fibrillation or ventricular tachycardia)  
• Placement of a pacemaker for control of rhythm 
• New York Heart Association (NYHA) Class III or IV heart failure (See 
Appendix 3)   
• Pulmonary embolism  
13. Significant active cardiovascular or pulmonary disease including: 
• Uncontrolled hypertension (i.e., systolic blood pressure >180 mm Hg, 
diastolic blood pressure > 95 mm Hg). Use of anti-hypertensive agents to 
control hypertension before Cycle1 Day 1 is allowed. 
• Pulmonary hypertension   
• Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or 
pulse oximetry on room air    
• Significant valvular disease; severe regurgitation or stenosis by imaging 
independent of symptom control with medical intervention, or history of valve 
replacement   


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• Medically significant (symptomatic) bradycardia    
• History of arrhythmia requiring an implantable cardiac defibrillator   
• Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated 
demonstration of QTc interval > 480 milliseconds, or history of congenital 
long QT syndrome, or torsades de pointes)  
14. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, 
CYP2C19 or CYP2C19 within 1 week preceding the first dose of study drug. 
15. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding 
inhalers or low-dose hormone replacement therapy) within 1 week before 
administration of the first dose of study drug. 
16. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI 
within 7 days before receiving the first dose of study drug 
17. For patients undergoing serial tumor biopsies, known bleeding diathesis or history of 
abnormal bleeding or require anti-coagulation therapy which cannot be interrupted 
for biopsy. 
 
12.    STUDY DRUG 
12.1    Study Drug Administration 
All protocol-specific criteria for administration of MLN0128 and alisertib must be met and 
documented before drug administration. Study drug will be administered only to eligible 
patients under the supervision of the investigator or identified subinvestigator(s). 
 
MLN0128 will be administered orally on an empty stomach once daily. Patients should be 
instructed to refrain from eating and drinking (except for water and prescribed medications) 
for 2 hours before and 1 hour after each dose.  Alisertib will be administered orally twice 
daily for 7 days of a 21 day dosing schedule.  The doses of MLN0128 and alisertib will be 
determined as outlined in Sections 10.1 and 10.2.  On days when MLN0128 and alisertib are 
both administered, the first dose of alisertib should be administered in the morning with the 
MLN0128 dose.  The second dose of alisertib should be administered approximately 12 
hours later with or without food. 
 
Patients should be instructed to take their study medication at approximately the same time 
on each scheduled dosing day and not to take more than the prescribed dose at any time. 
Patients should swallow the study medication whole and not chew it, open it, or manipulate 
it in any way before swallowing. If a patient does not take their MLN0128 or alisertib dose 
within the time frame specified (+/- 8h for MLN0128 or +/- 4 hours for alisertib), then the 
dose should be skipped and considered a missed dose. Patients should record any missed 


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doses in their diary  and resume drug administration at the next scheduled time with the 
prescribed dosage. Under no circumstance should a patient repeat a dose or double-up doses. 
12.2 Definitions of Dose-Limiting Toxicity  
Dose limiting toxicities are defined according to the AE profile observed during the first 
28 days of study drug administration in the dose escalation portion of the study and as 
described below. All AEs should be considered possibly related to the study drug unless 
such relationship can be definitively excluded.  
 
Toxicity will be evaluated according to NCI CTCAE Version 4.03 . A DLT will be defined 
as any of the following events that are considered by the investigator to be at least possibly 
related to treatment with MLN0128 or alisertib: 
 
• Grade 3 or higher nonhematologic toxicity, despite adequate treatment, except for the 
following: 
1. Grade 3 hyperglycemia lasting ≤ 72 hours (all patients should receive optimal 
antiglycemic treatment, including insulin, as clinically indicated). 
2. Grade 3 rash that resolves to ≤ Grade 1 within 3 days (all patients should receive 
topical steroid treatment, oral antihistamines, and oral steroids, if necessary). 
3. Inadequately treated Grade 3 nausea and/or vomiting and Grade 3 diarrhea (all 
patients should receive optimal antiemetic and/or antidiarrheal prophylaxis and/or 
treatment). 
4. Grade 3 nausea, vomiting and/or diarrhea lasting < 72 hours despite maximal 
supportive therapy. 
• Grade 4 neutropenia lasting > 7 days in the absence of growth factor support. 
• Grade 3 neutropenia of any duration accompanied by fever ≥ 38.5°C and/or systemic 
infection. 
• Thrombocytopenia with clinically significant bleeding. 
• Any other ≥ Grade 4 hematologic toxicity. 
• Inability to administer at least 75% of planned doses of MLN0128 or alisertib within 
Cycle 1, due to study drug-related toxicity. 
• Any clinically significant occurrence that the investigator and sponsor agree would place 
patients at an undue safety risk. 
 
Patients who experience an AE that meets the definition of a DLT during or after completing 
Cycle 1 should have their study drug treatment interrupted. If the event resolves to Grade 1 
or baseline values within 2 weeks of interrupting planned therapy, and in the opinion of the 
investigator the benefits of continuing treatment outweigh the risks posed by the toxicity, 
patients may continue study treatment with MLN0128 and alisertib with dose reduction of 
the agent responsible for toxicity. 
 


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12.3  MLN0128 Dose modification Guidelines 
MLN0128 should be administered in continuous cycles, which should continue unless the 
patient has a Grade 3 or greater MLN0128 -related event. Guidelines for dose interruption 
and for dose reduction are as follows: 
 
Criteria for Dose Interruption and Dose Modification During a Cycle  
Administration of MLN0128 should be withheld for MLN0128 treatment-related toxicities 
that are Grade 3 or higher, despite supportive treatment per standard clinical practice.  
The following nonhematologic toxicities attributed to MLN0128 would not require dose 
interruption: 
 
• Grade 3 or higher nausea and/or emesis in the absence of optimal anti-emetic 
prophylaxis. (Optimal anti-emetic prophylaxis is defined as an anti-emetic regimen that 
employs both a 5-HT3 antagonist and a corticosteroid given in standard doses and 
according to standard schedules.) 
• Grade 3 or higher diarrhea that occurs in the absence of optimal supportive therapy. 
 
 
If the event resolves to Grade 1 or baseline values within 2 weeks of interrupting treatment, 
the patient may resume study treatment at a dose reduced by 1 level (see Table 1). Two dose 
reductions of MLN0128 will be allowed according to Table 1.  If further dose reduction is 
required from 1 mg PO daily, then the dosing schedule can be modified to 5 days of 
treatment followed by 2 days rest without dosing.  Dosing interruptions/delays of up to 14 
days will be allowed for recovery from toxicities or inter-current illness. Longer 
interruptions can be considered if the patient is benefiting from therapy with 
MLN0128.Guidance for the management of common toxicities observed with MLN0128 
hyperglycemia, hyperlipidemia, oral mucositis, rash, nausea/vomiting, and non-infectious 
pneumonitis are outlined in Section 12.8.   
 
Table 2:  Recommended Dose Interuptions and Dose Reductions for Toxicities Related 
to MLN0128 (except hyperglycemia, hyperlipidemia, oral mucositis, rash, 
nausea/vomiting and non-infectious pneumonitis) 
Grade 
MLN0128 Dose 
Interruption 
MLN0128 Dose 
Modification 
1-2 
Treat on time 
No change 
3 
Delay until < Grade 1 or 
baseline 
Reduce 1 dose level. 
4 
Delay until < Grade 1 or 
baseline 
Reduce 1 dose level.  
Permanent discontinuation 
can be considered at the 
treating Investigator’s 
discretion. 


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12.4  Alisertib Dose Modifications Guidelines  
Treatment with alisertib will be repeated every 21 days.  In order for a new cycle of therapy 
to begin, the patient must meet the following criteria: 
• ANC must be  ≥ 1,500/mm3 
• Platelet count must be ≥ 75,000/mm3.   
• In addition, all toxicities considered by the investigator to be related to therapy with 
alisertib must have resolved to ≤ Grade 1 or to the patient’s baseline values before a 
new cycle of therapy may begin. 
If the patient fails to meet the above-cited criteria for retreatment, then initiation of the next 
cycle of therapy should be delayed for up to 1 week.  At the end of that week, the patient 
should be re-evaluated to determine whether the criteria for retreatment have been met.  
Should treatment need to be delayed for more than 1 week (ie, a rest period of more than 21 
days) because of incomplete recovery from treatment-related toxicity, the dose of alisertib 
should be reduced by one dose level (Table 1) when therapy resumes.  A second dose 
reduction may occur should treatment need to be delayed for more than 1 week because of 
incomplete recovery from treatment-related toxicity on the reduced dosage of alisertib.  If 
further dose reduction is required from 20 mg PO BID, then the dosing schedule can be 
modified to 3 days of treatment followed by 4 days rest without dosing.  Only 2 dose 
reductions of alisertib will be allowed according to Table 1. Dosing interuptions/delays of 
up to 14 days will be allowed for recovery from toxicities or inter-current illness.  Longer 
interuptions can be considered if the patient is benefiting from therapy with alisertib. 
Growth factor support is permitted at the treating Investigator’s discretion following delay 
or neutropenic fever, but should not be used prophylactically during Cycle 1. 
12.4.1  Dose Modifications for Hematological Toxicity 
If a patient experiences any of the following hematological toxicities during the dosing 
period, dosing with alisertib will be discontinued for the remainder of that cycle and the 
dose will be decreased 1 level for all subsequent cycles of treatment. 
• Grade 4 neutropenia (ANC < 500 cells/mm3) lasting more than 7 consecutive days 
• Grade 4 thrombocytopenia (platelet count < 25,000/µL) lasting more than 
7 consecutive days 
• Platelet count less than 10,000/µL at any time 


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• Grade 3 neutropenia with fever or infection, or both, where fever is defined as an 
oral temperature greater than 38.5°C 
• Any thrombocytopenia with clinically significant bleeding 
12.4.2    Dose Modifications for Non-Hematological Toxicities 
If a patient experiences any of the following toxicities that are at least possibly related to 
alisertib during the dosing period, dosing will be discontinued for the remainder of that cycle 
and the dose will be decreased 1 level for all subsequent cycles of treatment, and treatment 
may resume after drug-related toxicities have resolved to ≤ Grade 1 or to baseline. 
• Any Grade 3 nonhematological toxicity that is considered by the investigator to be 
related to alisertib other than: 
o Grade 3 or greater nausea or emesis, or both, that occurs in the absence 
of optimal antiemetic therapy (5-hydroxytryptamine 3 [5-HT3] 
serotonin receptor antagonist); 
o Grade 3 or greater diarrhea that occurs in the absence of optimal 
supportive therapy with loperamide or a comparable anti-diarrheal; 
• Grade 2 non-hematological toxicities that are considered by the investigator to be 
related to study drug and in the opinion of the investigator require dose reduction. 
In general, study drug treatment should be discontinued if a patient experiences a Grade 4 
toxicity.  If, in the opinion of the investigator and study sponsor it is in the patient’s interest 
to continue therapy with alisertib, then after recovery from the toxicity or toxicities in 
question to ≤ Grade 1 or to baseline values, the dose of alisertib should be reduced by at 
least 1 dose level with subsequent cycles of therapy. 
When a dose reduction of alisertib is required, no re-escalation of dose will be permitted.  If 
a patient requires more than 2 dose reductions, therapy with alisertib will be discontinued. 
See also Section 12.8 Management of Clinical Events Related to MLN0128 and alisertib 
for management of oral mucositis, rash, and nausea/vomiting which may be 
overlapping toxicities related to both agents.   
 


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12.5  Excluded Concomitant Medications and Procedures and potential Drug-Drug 
interactions 
The following medications and procedures are prohibited during the study: 
• Other investigational agents including mTOR, PI3Kinase and AKT inhibitors 
• Other anticancer therapies including chemotherapy, immunotherapy, 
radioimmunotherapy, targeted agents, radiation or surgery (subjects can have palliative 
radiation or surgery in the study for pre-existing lesions) 
• Systemic corticosteroids (either IV or oral steroids, excluding inhalers), unless necessary 
for treatment of MLN0128 related AE, ie, rash.  
• Anti-epileptic drugs for subjects with treated brain metastasis 
• Concomitant administration of any PPI is not permitted during the study. Patients 
receiving PPI therapy before enrollment must stop using the PPI for 7 days before their 
first dose of study drugs. Examples of PPIs include omeprazole, esomeprazole, 
pantoprazole, lansoprazole, and rabeprazole. 
• Consumption of grapefruit or grapefruit juice is not permitted during the study. Patients 
should not consume food or beverages containing the fruit or juice of grapefruits or 
Seville oranges within 7 days before the first dose of study drug and throughout the 
study (See Appendix 4).  
• Histamine-2 (H2) receptor antagonists are not permitted within 12 hours before and 
within 6 hours after MLN0128 or alisertib administration.  Patients receiving histamine 
H2 receptor antagonists before enrollment must stop using these medications for at least 
24 hours before their first dose of study drug. Examples of histamine H2 receptor 
antagonists include ranitidine, famotidine, nizatidine, and cimetidine. 
• Neutralizing antacids and calcium preparations are not permitted within 2 hours before 
and 2 hours after MLN0128 or alisertib administration. Some anti-gas preparations may 
also have antacid properties, and should also not be permitted from 2 hours before until 
2 hours after MLN0128 or alisertib administration. 
 
12.6  Permitted Concomitant Medications and Procedures  
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications is encouraged, 
and these may be administered before the first dose and subsequent doses of study drug, as 
needed throughout the study, and as clinically indicated per standard practice. When 
selecting an anti-emetic agent, drugs that do not have an effect on the QT interval, such as 
palonosetron, are preferred. 
 
Histamine H2 receptor antagonists may be allowed, if needed provided that the histamine 
H2 receptor antagonist is not taken within 12 hours before and within 6 hours after study 
drug administration. Patients receiving histamine H2 receptor antagonists before enrollment 
must stop using these medications for at least 24 hours before their first dose of study drug. 
Examples of histamine H2 receptor antagonists include ranitidine, famotidine, nizatidine, 
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Neutralizing antacid preparations (acid neutralizers) and calcium supplements may be taken 
as needed except from 2 hours before until 2 hours after MLN0128 or alisertib 
administration. Some anti-gas preparations may also have antacid properties, and should 
also not be permitted from 2 hours before until 2 hours after study drug administration. 
Strong CYP3A4 and CYP2C19 inducers and/or inhibitors and moderate inhibitors of 
CYP2C9 should only be administered with caution, at the discretion of the investigator (see 
Appendix 4): 
CYP3A, 2C9, and 2C19 inducers: rifampin, rifapentine, rifabutin, phenytoin, 
carbamazepine, oxcarbazepine, phenobarbital, primidone, St. John’s Wort, bosentan, 
nafcillin, modafinil. 
CYP3A, 2C9, and 2C19 inhibitors: ketoconazole, itraconazole, voriconazole, 
posaconazole, boceprevir, telaprevir, fluconazole, clarithromycin, telithromycin, 
troleandomycin, erythromycin, nefazodone, mibefradil, conivaptan, diltiazem, 
verapamil, dronedarone, aprepitant, casopitant, tofisopam, ciprofloxacin, 
amiodarone, fluvoxamine, and ticlopidine. 
 
Other medications considered necessary for the safety and wellbeing of the patient 
may be administered at the discretion of the investigator. 
 
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. 
Treatment with myeloid growth factors is permitted at the treating Investigator’s discretion 
following delay or neutropenic fever, but should not be used prophylactically during Cycle 
1. 
12.7 Precautions and Restrictions  
Patients who show evidence of hyperglycemia during the study should be encouraged to 
follow a low carbohydrate diet. 
 
Patients should not drive, operate dangerous tools or machinery, or engage in any other 
potentially hazardous activity that requires full alertness and coordination if they experience 
sedation while enrolled in this study. 
Patients are to be instructed to limit the use of alcohol while enrolled in this study.  Patients 
should consume no more than 1 standard unit of alcohol per day during the study and for 
30 days from the last dose of alisertib.  A standard unit of alcohol is defined as a 12 oz beer 
(350 mL), 1.5 oz (45 mL) of 80-proof alcohol, or one 6-oz (175 mL) glass of wine. 
It is not known what effects MLN0128 or alisertib have on human pregnancy or 
development of the embryo or fetus. Therefore, women participating in this study should 


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avoid becoming pregnant, and men should avoid impregnating a female partner or donating 
sperm. Women of childbearing potential and men should use effective methods of 
contraception during and through 90 days after the last dose  of study drug, as specified 
below. 
Women 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 (ICF) through 90 
days after the last dose of study drug, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods] and withdrawal are not acceptable methods of contraception.) 
Men, 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 120 days after the last dose of study drug, OR 
• Agree to practice true abstinence, when this is in line with the preferred and usual 
lifestyle of the patient. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
postovulation methods for the female partner] and withdrawal are not acceptable 
methods of contraception.) 
• Agree not to donate sperm during the course of this study or 120 days after receiving 
their last dose of study drug. 
 
12.8  Management of Clinical Events Related to MLN0128 and Alisertib 
12.8.1 Management of Hyperglycemia 
In addition to obtaining fasting serum glucose (FSG) levels at clinic visits, all subjects will 
be given a glucometer to monitor their daily pre-dose fasting blood glucose (FBG) levels at 
home.  Subjects will be instructed to notify the study staff immediately with any abnormal 
readings (ie, ≥ 150 mg/dL) for further instructions on the management of their 
hyperglycemia.  Hyperglycemia observed during home glucose monitoring should be 
confirmed in the clinic.  Investigators will be responsible for reviewing the home glucose 
monitoring logs for hyperglycemia.  If no irregularities in the fasting blood glucose level are 
observed during a minimum of 6 consecutive months, then the frequency of in-home fasting 
glucose testing may be reduced to twice weekly if the investigator approves.  Subjects will 
continue to notify the investigator of fasting blood glucose levels that exceed 150 mg/dL 
and, if blood glucose levels are not well-controlled, or if the subject requires either oral 
hypoglycemic agents or insulin to control blood glucose levels, then the frequency of in-
home testing of fasting blood glucose levels will be reinstated to daily. 


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In the event that any FSG reading performed at the site indicates hyperglycemia (> upper 
limit of normal [ULN] or ≥ 110 mg/dL), the study staff should first ascertain that the subject 
was fasting at the time of the blood draw (ie, nothing by mouth for at least 8 hours prior to 
blood being obtained), had continued to take their concomitant antiglycemic medications 
should the subject have underlying diabetes mellitus, and repeat the FSG as needed.  If the 
repeat FSG continues to demonstrate hyperglycemia, investigators should initiate steps to 
aggressively manage the hyperglycemia per standard clinical practice.  The following 
guidelines are provided to aid the investigator in initiating antiglycemic therapies. 
Based on the clinical experience from MLN0128 trials, most episodes of hyperglycemia 
observed have been Grade 1 or 2 that have responded quickly to oral metformin.  
Hyperglycemia has not been dose-limiting since instituting a standard regimen for early 
treatment of hyperglycemia.  All subjects developing hyperglycemia on the study should 
have their glucose closely monitored by study staff.  The investigator may choose either to 
continue close monitoring of subjects who develop Grade 1 hyperglycemia 
(FSG > ULN ≤ 160 mg/dL) or, alternatively, consider initiating treatment with an oral 
hypoglycemic agent, such as metformin.  All subjects with Grade ≥ 2 hyperglycemia 
(FSG > 160 mg/dL) must be treated aggressively with oral hypoglycemic agents and/or 
insulin as clinically indicated while continuing on MLN0128.  The investigator should 
consult an endocrinologist if needed to aid in optimizing the subject’s hyperglycemia 
treatment plan. 
It is recommended that subjects be treated initially with a fast acting, insulin sensitizer, such 
as metformin at 500 mg PO QD, and titrate up to a maximum of 1000 mg PO BID as 
needed.  Concurrent addition to metformin of DPP-4 inhibitors (eg, sitagliptin or 
vildagliptin) and/or insulin should also be considered.  Oral sulfonylureas (eg, glipizide or 
glyburide) should be used with caution due to the higher risk of inducing hypoglycemia in 
subjects.  The dose of oral hypoglycemic agents should be adjusted in subjects with renal 
insufficiency. In addition, patients should also be encouraged to follow a low carbohydrate 
diet once hyperglycemia is first observed. 
 
Guidance on study drug dose modification for patients with hyperglycemia is provided in 
the following table 
Table 3  Management of Hyperglycemia 
Grade 
Description 
Treatment 
Dose Modification 
1 
Fasting blood sugar 
>ULN to 160 mg/dL 
• Continue close monitoring of blood 
sugar. 
• Initiate oral hypoglycemic agent. 
None 
2 
>160 to 250 mg/dL 
• Initiate oral hypoglycemic agent 
and/or insulin if not well controlled 
on oral agent. 
None 
≥3 
>250 mg/dL 
• Initiate oral hypoglycemic agent 
and/or insulin. 
Hold MLN0128 until ≤Grade 
1.  
Resume MLN0128 based on 
timing of recovery after 
maximal treatment: 


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Table 3  Management of Hyperglycemia 
Grade 
Description 
Treatment 
Dose Modification 
• ≤1 week: resume 
MLN0128 at same dose 
and schedule. 
• >1 but ≤2 weeks: reduce 
MLN0128 by 1 dose level 
• >3 weeks: permanently 
discontinue MLN0128 
Prevention/Prophylaxis: 
• 
Follow fasting glucose levels during clinic visits. 
• 
Monitor home glucometer test results. 
• 
Check HbA1c levels every 3 months during therapy. 
• 
Most episodes of Grade 1 or 2 hyperglycemia respond quickly to oral metformin. Early initiation of 
therapy at the lowest therapeutic dose is recommended to prevent higher grade hyperglycemia. 
• 
Fasting blood glucose levels ≥150 mg/dL by glucometer should be followed by closer monitoring of 
serum glucose and possible intervention.  
HbA1c=glycosylated hemoglobin, ULN=upper limit of normal. 
  
 
12.8.2    Management of Hyperlipidemia 
Guidance on study drug dose modification for patients with hyperlipidemia is provided 
below 
Table 4 Management of Hyperlipidemia 
Grade 
Description 
Treatment 
Dose Modification 
1 
Cholesterol >ULN to 300 mg/dL 
Triglycerides >150 to 300 mg/dL 
None 
None 
2 
Cholesterol >300 to 400 mg/dL 
 
 
Triglycerides >300 to 500 mg/dL 
• 
Treat hyperlipidemia 
according to standard 
guidelines. 
• 
Triglycerides 
≥500 mg/dL should be 
treated urgently, due to 
risk of pancreatitis. 
• 
Maintain dose, if 
tolerable. 
• 
If toxicity becomes 
intolerable, interrupt 
MLN0128 until recovery 
to ≤Grade 1. Re-initiate 
MLN0128 at the same 
dose level 
3 
Cholesterol >400 to 500 mg/dL 
 
Triglycerides >500 to 
1000 mg/dL 
Same as for Grade 2. 
Hold MLN0128 until 
recovery to ≤Grade 1, then 
reinitiate MLN0128 at a dose 
reduced by 1 level  
4 
Cholesterol >500 mg/dL 
Triglycerides >1000 mg/dL 
Same as for Grade 2. 
Same as for Grade 3. 


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Prevention/Prophylaxis: 
Life-style modifications, as appropriate (balanced diet, limit alcohol consumption, increase physical 
activity) 
ULN=upper limit of normal. 
 
 
12.8.3 Management of Oral Mucositis 
Guidance on study drug dose modification for patients with oral mucositis 
Table 6 
Management of Oral Mucositis 
Grade 
Description 
Treatment 
Dose Modification 
1 
Asymptomatic or mild 
symptoms. 
• 
Nonalcoholic mouth wash, or 
0.9% salt water rinse. 
• 
Consider topical 
corticosteroids at earliest signs 
of mucositis. 
None 
2 
Moderate pain, not 
interfering with oral 
intake. 
Modified diet indicated. 
• 
Topical analgesic mouth 
treatments. 
• 
Topical corticosteroids. 
• 
Initiate antiviral or antifungal 
therapy, if indicated. 
• 
Maintain alisertib and 
MLN0128 dose if 
tolerable 
• 
Hold alisertib* and 
MLN0128 if intolerable 
until recovery to ≤Grade 
1, then restart at same 
dose. 
3 
Severe pain, interfering 
with oral intake. 
• 
Same as for Grade 2. 
• 
Consider intralesional 
corticosteroids. 
• 
Hold alisertib* and 
MLN0128 until recovery 
to ≤Grade 1, then restart 
alisertib* and MLN0128 
at a dose reduced by 
1 level  
4 
Life-threatening 
consequences. 
• 
Same as for Grade 2 
• 
Consider intra-lesional 
corticosteroids 
• 
Stop alisertib* and 
MLN0128  
Prevention/Prophylaxis: 
• 
Initiation of a nonalcoholic mouth wash, or 0.9% salt water rinses 4 to 6 times daily is strongly 
recommended at the start of therapy before signs of mucositis develop. 
• 
Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of 
stomatitis, as they may worsen mouth ulcers. 
*Only if oral mucositis developed during alisertib treatment or is felt to be at least possibly related to 
alisertib treatment 
 
12.8.4 Management of Rash 
Guidance on study drug dose modification for patients with rash is provided below 


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Table 7  Management of Rash 
Grade 
Description 
Treatment 
Dose Modification 
≤2 
Macules/papules covering 
≤30% body surface area 
with or without 
symptoms. 
Consider treatment with topical 
steroid cream/ointment and/or 
oral anti-histamines or 
antibiotics. 
None 
≥3 
Macules/papules covering 
>30% body surface area 
with or without 
symptoms. 
Consider treatment with topical 
steroid cream/ointment, oral 
anti-histamines, oral antibiotics, 
and/or pulsed steroids. 
Hold alisertib* and MLN0128 
until ≤Grade 1 
 
Resume alisertib* and MLN0128 
based on timing of recovery to 
<Grade 2: 
• 
≤3 weeks: reduce alisertib 
and MLN0128 by 1 dose 
level  
• 
>3 weeks: stop alisertib and 
MLN0128 and discontinue 
patient from the study 
Prevention/Prophylaxis: 
• 
Rash should be managed aggressively. The investigator should consider consulting a dermatologist or 
other specialist, if needed. 
• 
A skin biopsy at the site of rash should be considered as soon as possible after the initial episode. 
*Only if rash developed during alisertib treatment or is felt to be at least possibly related to alisertib 
treatment 
 
12.8.5  Management of Nausea/Vomiting 
Guidance for patients with nausea and/or vomiting is provided in the table below 
Table 8 Management of Nausea/Vomiting 
Grade 
Description 
Treatment 
Dose Modification 
≤2 
Loss of appetite with or 
without decreased oral intake;  
1 to 5 episodes of vomiting 
within 24 hours. 
• 
Maximize anti-emetic 
therapy. 
• 
Consider IV fluid 
hydration. 
None 
≥3 
Inadequate oral intake;  
≥6 episodes of vomiting 
within 24 hours. 
• 
Maximize anti-emetic 
therapy. 
• 
Initiate tube feeding, IVF 
or TPN. 
Hold alisertib* and MLN0128 
until ≤ Grade 1, then resume 
treatment without dose 
modification 
Prevention/Prophylaxis: 
Prophylactic use of anti-emetic, antinausea, and antidiarrheal medications are encouraged and may be used 
before each MLN0128 dosing as needed throughout the study. Because of the potential of benzodiazepines 


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to cause sedation, the use of benzodiazepines for antiemetic prophylaxis should be reserved for patients who 
cannot be satisfactorily managed otherwise. 
IV=intravenous, IVF=intravenous fluids, TPN=total parental nutrition. 
*Only if nausea/vomiting developed during alisertib treatment or is felt to be at least possibly related 
to alisertib treatment 
 
12.8.6  Management of Cardiac Abnormalities 
Management of Patients With Possible Cardiac Instability 
For patients showing signs of cardiac instability after MLN0128 administration, additional 
monitoring onsite before clinic discharge should be considered. 
Management of Patients With Left Ventricular Dysfunction 
Guidance for MLN0128 dose adjustment for patients with left ventricular dysfunction is 
provided below. 
 
Table 9   Management of Left Ventricular Dysfunction 
Grade 
Description 
Dose Modification 
1 
Asymptomatic decline in: 
LVEF >15% from baseline values, OR 
LVEF >10% to 15% from baseline values and 
is below institution’s LLN. 
No change; continue MLN0128 at the same 
dose and schedule 
≥2 
Symptomatic cardiac dysfunction/congestive 
heart failure. 
Discontinue treatment. 
LLN=lower limit of normal, LVEF=left ventricular ejection fraction. 
  
Management of Patients with QTc Prolongation 
Guidance for MLN0128 dose adjustment for patients exhibiting a prolonged QTc interval is 
provided below. 
Table 10 Management of QTc Prolongation 
Grade 
Description 
Treatment 
Dose Modification 
2 
480 msec 
<QTc <501 
msec 
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication, etc). 
None; continue MLN0128 at the same 
dose and schedule. 


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Table 10 Management of QTc Prolongation 
Grade 
Description 
Treatment 
Dose Modification 
≥3 
QTc 
≥501 msec 
Evaluate for other possible causes (eg, 
electrolyte disturbance, concomitant 
medication).(a) 
Consider a formal consult by a 
cardiologist; 
Notify the study doctor; 
Additional ECGs may be performed at 
intervals that the treating physician 
deems clinically appropriate until 
repeated QTc measurements fall or are 
below the threshold interval that 
triggered the repeat measurement. 
Hold MLN0128 
 
The decision whether to reinitiate 
MLN0128 with or without dose 
reduction and additional monitoring in 
those patients who had asymptomatic 
prolonged QTc ≥501 msec (Grade 3) 
that has reverted to an acceptable 
interval, have previously tolerated 
MLN0128, and appear to have 
benefitted from treatment with either 
disease control or response, will be 
agreed to by the investigator and the 
study doctor  on a case-by-case basis. 
ECG=electrocardiogram, IV=intravenous, msec=milliseconds, QTc=QT interval corrected for heart rate. 
(a) A list of medications known to prolong QTc can be found at https://www.crediblemeds.org/new-drug-
list/  
 
 
 
12.8.7  Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness and Fatigue) 
Guidance on dose adjustment for patients with other nonhematologic toxicities is provided 
below 
Table 11  Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue) 
Grade 
Description 
Treatment 
Dose Modification 
1 
Mild; asymptomatic or mild 
symptoms; clinical or 
diagnostic observations only; 
intervention not indicated. 
Initiate appropriate medical 
therapy and monitor. 
If tolerable, then no adjustment is 
required. 
2 
Moderate; minimal, local or 
noninvasive intervention 
indicated. 
Initiate appropriate medical 
therapy and monitor. 
• 
If tolerable, no adjustment 
required. 
• 
If toxicity becomes 
intolerable, hold MLN0128 
until recovery to ≤Grade 1, 
then reinitiate at same dose.  


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Table 11  Management of Other Nonhematologic Toxicities (Including Asthenia, 
Weakness, and Fatigue) 
Grade 
Description 
Treatment 
Dose Modification 
≥ 3 
Severe or medically 
significant but not 
immediately life-threatening; 
hospitalization or 
prolongation of 
hospitalization indicated 
 
Hold MLN0128  until recovery to 
≤ Grade 1. Reinitiate MLN0128 at 
dose reduced by 1 level.  
 
 
If asthenia, weakness or fatigue occurs during alisertib dosing or is considered to be at 
least possibly related to alisertib treatment, then see Section 12.4.2 Dose Modifications 
for Non-Hematologic Toxicities for alisertib dose modifications. 
 
12.8.8      Management of Aspartate Aminotransferase/Alanine Aminotransferase 
Elevations 
Guidance on dose adjustment for patients with AST/ALT elevations is provided below 
Table 12        Management of Aspartate Aminotransferase/Alanine 
Aminotransferase Elevations 
Grade 
Description 
Treatment 
Dose Modification 
1 
>ULN to 3×ULN 
None 
None 
2 
Asymptomatic with levels 
3 to 5×ULN; >3×ULN with 
the appearance of worsening 
fatigue, nausea, vomiting, 
right upper quadrant pain or 
tenderness, fever, rash, or 
eosinophilia. 
• 
Closely monitor LFTs at 
least weekly or more 
frequently as indicated. 
• 
Assess patient for other 
causes of transaminitis (eg, 
past medical history, 
concomitant medications). 
None 
3 
>5 to 20×ULN; >5×ULN 
for >2 weeks 
Same as for Grade 2. 
Hold MLN0128 until ≤Grade 1; 
Restart MLN0128 at the same 
dose; 
4 
>20×ULN 
Same as for Grade 2. 
Stop MLN0128 and discontinue 
patient from the study. 
Prevention/Prophylaxis: 
Ensure proper screening of patients for study participation. 
LFTs=liver function tests, ULN=upper limit of normal. 
 
 
12.8.9  Management of Non-infectious Pneumonitis 
Guidance for the management of pneumonitis is provided below 


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Table 13    Management of Non-infectious Pneumonitis 
Grade 
Description  
Treatment 
MLN0128 Dose 
Modification 
1 
Asymptomatic: Radiographic findings 
only. 
Rule out infection and 
closely monitor. 
None 
2 
Symptomatic: 
Not interfering with activities of 
daily living. 
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1. 
Interrupt MLN0128 
• When symptoms 
≤Grade 1, reinitiate 
MLN0128 at a dose 
reduced by 1 level. 
If no recovery 
within 4 weeks, then 
discontinue 
MLN0128.  
3 
Symptomatic: 
Interfering with activities of daily 
living; 
Requires administration of oxygen. 
Rule out infection and 
consider treatment with 
corticosteroids until 
symptoms improve to 
≤Grade 1. 
Interrupt MLN0128 until 
symptoms resolve to 
≤Grade 1.  
• Consider reinitiating 
MLN0128 at a dose 
reduced by 1 level . 
• If toxicity recurs at 
Grade 3, discontinue 
MLN0128. 
4 
Life-threatening: 
Ventilatory support indicated. 
Rule out infection and 
consider treatment with 
corticosteroids. 
Discontinue MLN0128. 
 
 
 
12.9  Management of Clinical Events Related to alisertib 
12.9.1  Management of Central Nervous System Effects 
If a patient experiences excessive sedation believed to be related to alisertib, treatment with 
alisertib should be interrupted.  Patients whose sedation is not considered immediately life-
threatening should be carefully monitored and given appropriate supportive care. 
If the patient’s level of consciousness is considered to be life-threatening, necessary 
measures should be instituted to secure the airway, ventilation, and intravenous access.  
Flumazenil (Romazicon®) is a selective benzodiazepine receptor antagonist that is intended 
as an adjunct to, not as a substitute for, the proper management of benzodiazepine overdose.  
Although there is neither preclinical nor clinical experience with flumazenil and alisertib, 
the use of flumazenil should be considered if the level of alisertib-associated sedation is 
considered to be life-threatening.  Patients treated with flumazenil should be monitored for 
resedation, respiratory depression, and other residual benzodiazepine effects for an 
appropriate period after treatment.  Continued monitoring is particularly important in the 


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case of alisertib given its half-life and the comparatively brief half-life of flumazenil in the 
CNS (20-30 minutes).  Flumazenil should be administered according to its label. 
 
12.10 Description of Investigational Agents 
12.10.1  MLN0128 
MLN0128 will be supplied as capsules for oral administration. The study drug is available 
in 3 dose strengths, 1 mg, 3 mg, and 5 mg, each containing 1 mg, 3 mg, and 5 mg of 
MLN0128, respectively, in addition to the following inactive ingredients: microcrystalline 
cellulose (solid filler/diluents), magnesium stearate (lubricant), and hard gelatin capsule. All 
3 dose strengths are formulated into size 2 capsules, and each dose strength is differentiated 
by color, as listed below: 
• MLN0128 capsules, 1 mg - white opaque color 
• MLN0128 capsules, 3 mg – orange opaque color; and/or 
• MLN0128 capsules, 5 mg – grey opaque color  
12.10.2  Alisertib 
Alisertib drug product is supplied as the ECT dosage form in 10 mg strength, with dose 
strength expressed as the milligrams of active drug (free acid).  The key formulation 
excipients of the alisertib tablet formulation that aid in the in vivo absorption of the drug are 
the buffer (sodium bicarbonate), the surfactant (sodium lauryl sulfate), and the enteric 
coating. 
12.11 Preparation, Reconstitution, and Dispensation 
12.11.1  MLN0128 
MLN0128 study drug will be provided in labeled bottlesd in accordance with all applicable 
regulations. Materials provided by the sponsor should be dispensed to patients 
with clear administration instructions from the investigator. 
 
MLN0128 is an anticancer drug and, as with other potentially toxic compounds, caution 
should be exercised when handling MLN0128 capsules. 
 
12.11.2  Alisertib 
Alisertib ECT are packaged in a 60-cc high-density polyethylene (HDPE) bottle with a 
rayon coil, induction seal, desiccant packs, and a polypropylene child-resistant cap. 
Alisertib is an anticancer drug, and as with other potentially toxic compounds, caution 
should be exercised when handling alisertib.  It is recommended that gloves and protective 
garments be worn during preparation. 


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12.12  Packaging and Labeling 
12.12.1  MLN0128 
MLN0128 will be provided by Millennium and will be handled at the investigative site as 
open-label material. Sites must store according to the labeled conditions.  
MLN0128 capsules are packaged in HDPE bottles with polypropylene, child-resistant caps 
and induction seal. For all dose strengths, each bottle contains 30/60 capsules. 
 
12.12.2  Alisertib 
The packaged and labeled study drug, alisertib ECT, will be provided by Millennium and 
will be handled at the investigative site as open-label material.  The labels on the study drug 
will fulfill all requirements specified by governing regulations.  Ten alisertib ECT are 
packaged into each 60-cc HDPE bottle.  Alisertib will be supplied as ECT 10 mg strength.  
The bottles will have a child-resistant cap and be labeled for take-home use.  Patients will 
receive instructions for home use of alisertib, including the requirement that alisertib be 
administered as intact tablets. 
As required by local regulations, any modifications to the plan for drug supply or storage 
will be communicated to the investigator and detailed in the Study Manual. 
12.13 Storage, Handling, and Accountability 
12.13.1  MLN0128 
Upon receipt at the investigative site, drug should be stored in the original bottles until use 
and stored at room temperature from 15°C to 30°C (59°F to 86°F). All temperature 
excursions will be reported  for assessment and authorization for continued use. All 
investigational supplies must be stored in a secure area with controlled access and will be 
stored in original packaging. All drug  supplies should be used before the retest expiry date.  
Because MLN0128 is an investigational agents, it should be handled with due care. In case 
of contact with broken capsules, raising dust should be avoided during the clean-up 
operation. The product may be harmful if inhaled, ingested, or absorbed through the skin. 
Gloves and protective clothing should be worn during the clean-up 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 capsule), the 
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 will receive instructions for home storage and administration of MLN0128. 
. 
Accountability for MLN0128 at all study sites is the responsibility of the sponsor-
investigator.  
 


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12.13.2 Alisertib 
Tablets should remain in the bottle provided until use.  The container should be stored at the 
investigative site at controlled room temperature (20-25°C; 68-77°F; excursions are 
permitted from 15-30°C; 59-86°F) and used before the retest expiry date provided by 
Millennium.  Containers should be kept closed during storage. 
Because alisertib is an investigational agent, it should be handled with due care. In case of 
contact with broken tablets, raising dust should be avoided during the cleanup operation. 
The product may be harmful by inhalation, ingestion, or skin absorption.  Gloves and 
protective clothing should be worn during preparation and 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. 
12.14  Study Compliance 
Study drug will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified sub-investigator(s).  The appropriate study personnel will 
maintain records of study drug receipt and dispensing. 
12.15 Treatment Assignment  
Treatment in the dose escalation cohort will be assigned based on the dose escalation 
scheme of the study as described in Section 10.   Once the dose escalation portion of the 
study is complete, enrollment to the dose expansion cohorts will begin.  
12.16  Termination of Treatment and/or Study Participation 
Patients will be informed that they have the right to withdraw from the study at any time for 
any reason, without prejudice to their medical care.  The investigator also has the right to 
withdraw patients from the study for any of the following reasons: 
• Adverse event 
• Protocol violation 


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• Lost to follow-up 
• Progressive disease 
• Study terminated  
• Other 
Patients withdrawn from the study in the dose escalation cohort during cycle 1 will be 
replaced unless they are withdrawn due to an adverse event.  Patients enrolled in the dose 
expansion cohort who withdraw prior to completing the correlative studies will be replaced. 
At the time of withdrawal, all study procedures outlined for the End of Study visit should be 
completed. The primary reason for patient’s withdrawal from the study should be recorded 
in the source documents and CRF. 
13.    STATISTICAL AND QUANTITATIVE ANALYSES 
13.1    Statistical Methods 
Primary Objective:   
The MTD will be defined as the highest dose level evaluated in which 0 or 1 patient out of 6 
patients experiences DLT. 
Secondary Objectives: 
1. 
Safety:  Adverse events will be tabulated by type and grade. 
2. 
Pharmacokinetics:  The AUC and Cmax will be determined for MLN0128 and 
MLN8237.  The distribution of these parameters for MLN0128 when administered with 
MLN8237 and for MLN8237 when administered with MLN0128 will be compared to the 
appropriate single agent administration control data. 
3. 
Translational Endpoints:  All analyses with respect to the translational component of 
this study are intended to be hypothesis-generating and descriptive in manner.  Biologic 
correlates will be obtained from tumor biopsies as outlined above.  Baseline levels of these 
markers will be correlated with clinical outcome (i.e. response, time to progression, and 
adverse events) using regression methods (Cox model for tie to event, logistic regression for 
binary outcome, Poisson regression for counts).  Additionally, the dynamic change in 
markers will be assessed from baseline to Cycle 1 Day 7 and Cycle 2 Day 7 in both 
Expansion Cohort Groups using repeated measures/mixed models analysis.  For the 
functional imaging performed in select patients in the Dose Expansion Groups, FDG-PET 
images will be analyzed with AsiProVM and mean change in SUV will be compared to 
baseline.  For DCE-MRI analysis, the AUC for the gadolinium versus time curve and the 
initial AUC will be calculated using the trapezoidal rule in Microsoft Excel.  Data will be 


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fitted to a two-compartment model to estimate Ktrans and Kep which will be compared to 
baseline. 
4. 
Efficacy:  Analysis of efficacy measures will be descriptive.  The best overall 
response will be summarized using the number and percent of patients in each tumor 
response category along with the two-sided exact binomial 95% confidence intervals. Time 
to progression will be defined as the time from the first day of treatment to the first 
observation of disease progression.  If a patient dies without documentation of disease 
progression, the patient will be considered to have had tumor progression at the time of their 
death unless there is sufficient documented evidence to conclude no progression occurred 
prior to death.  The distribution of disease-free survival will be estimated using the method 
of Kaplan and Meier.  The median time and its 95% confidence interval will be reported. 
13.1.1     Determination of Sample Size 
The total number of patients enrolled in the Dose Escalation Cohort will depend on the 
number of dose cohorts required to identify the MTD. Design considerations were not made 
with regard to explicit power and  type I error considerations, but to obtain preliminary safety , PK, 
and efficacy information  in this patient population. Escalation to the next dose cohort will 
depend on the probability of DLT at a given dose.  When 1 of 3 patients develops a DLT 
and the cohort is expanded to 6 patients, the proposed plan for dose escalation provides a 
91% probability that dose escalation will proceed at doses associated with DLT probability 
of < 10%. 
 
A maximum of 6 patients can be enrolled at each dose level.  With 6 potential dose levels 
and an Expansion Cohort of 30 patients with TNBC, the maximum number of patients that 
can be enrolled is 56 and the minimum number is 6. 
 
The total planned enrollment in the expansion study is up to approximately 30 patients in 
three cohort groups. This sample size will provide a reasonable chance (> 75%) of  
observing at least one or more adverse events when the true frequency of the adverse  
event is between 10%−15% at the given dose level. Specifically, for a given adverse event  
with a true rate of 15%, 10%, 5%, or 1%, the probability of observing at least one such  
adverse event in the combined cohort of 20 patients is 99%, 86%, 64%, or 18%, respectively 
In addition, assessment of the response rate in 20 patients will exclude with 95% 
confidence,  a true response rate of 15% or higher if no response is observed. 
13.1.2    Randomization and Stratification   
Randomization and stratification will not be used in this trial. 
13.1.3    Populations for Analysis 
Safety, PK and efficacy  analysis will be based on patient data collected through study 
discontinuation. The analyses will all be based on all patients receiving at least 1 dose of 
study drug.  
 


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13.1.4    Procedures for Handling Missing, Unused, and Spurious Data 
Missing values will not be estimated or imputed given the small sample size. All available  
data will be included in data listings. Repeated measures analyses of dynamic changes in  
biomarkers will use maximum likelihood methods which are robust to data being missing at 
random.   
 
Sensitivity analyses will be used to assess impact on spurious observations on statistical 
summaries. 
 
13.1.5    Demographic and Baseline Characteristics 
Demographic and baseline data will be summarized by dose level.  No formal statistical 
analysis will be performed on these data. 
13.1.6   Efficacy Analysis 
Best overall response rate will be computed with an exact 95% Binomial confidence interval 
for each tumor response category.  Progression free survival will also be analyzed using 
Kaplan Meier methods including 95% confidence interval for median PFS. 
 
Efficacy will be performed using all the patients who received at least one cycle of study drug 
or were withdrawn during cycle 1 for progression.  
 
13.1.7    Pharmacokinetics  
Pharmacokinetic parameters will be derived from the blood PK samples and will be 
analyzed using descriptive statistics, including the median, mean and 95% confidence 
intervals around parameter estimates by dose level and time point. PK analyses will be 
conducted on all patients that received at least one dose of the drug and provide at least one 
post-treatment sample.  
 
13.1.8    Safety Analysis 
The safety evaluation will be based on all patients that received at least one dose of the drug 
and will include AEs, SAEs, and changes from baseline in laboratory evaluations, vital 
signs, and physical examinations. Summaries will be provided overall and by does group. 
The number and percentage of subjects reporting treatment-emergent AEs (TEAE) will be 
summarized overall and by the worst CTCAE grade, with a breakdown by dose . Similarly, 
the number and percentage of subjects reporting TEAEs considered related to each study 
drug will be summarized. 


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14. ADVERSE EVENTS   
14.1    Definitions 
14.1.1    Adverse Event Definition 
Adverse event (AE) means any untoward medical occurrence in a patient or subject 
administered a pharmaceutical product; the untoward medical occurrence does not 
necessarily have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product whether 
or not it is related to the medicinal product.  This includes any newly occurring event, or a 
previous condition that has increased in severity or frequency since the administration of 
study drug. 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 
considered by the investigator to be a clinically significant change from baseline.   
14.1.2    Serious Adverse Event Definition 
Serious AE (SAE) means any untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (refers to an AE in which the patient was at risk of death at the 
time of the event.  It does not refer to an event which hypothetically might have 
caused death if it were more severe). 
• Requires inpatient hospitalization or prolongation of an existing hospitalization 
(see clarification in the paragraph below on planned hospitalizations). 
• Results in persistent or significant disability or incapacity. (Disability is defined 
as a substantial disruption of a person’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect. 
• Is a medically important event.  This refers to an AE that may not result in death, 
be immediately life threatening, or require hospitalization, but may be considered 
serious when, based on appropriate medical judgment, may jeopardize the patient, 
require medical or surgical intervention to prevent 1 of the outcomes listed above, or 
involves suspected transmission via a medicinal product of an infectious agent.   
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse; any organism, virus, or infectious particle (eg, prion protein transmitting 
Transmissible Spongiform Encephalopathy), pathogenic or nonpathogenic, is 
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Clarification should be made between a serious AE (SAE) and an AE that is considered 
severe in intensity (Grade 3 or 4), because the terms serious and severe are NOT 
synonymous.  The general term severe is often used to describe the intensity (severity) of a 
specific event; the event itself, however, may be of relatively minor medical significance 
(such as a Grade 3 headache).  This is NOT the same as serious, which is based on 
patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function.  A severe AE (Grade 3 or 4) 
does not necessarily need to be considered serious.  For example, a white blood cell count of 
1000/mm3 to less than 2000 is considered Grade 3 (severe) but may not be considered 
serious.  Seriousness (not intensity) serves as a guide for defining regulatory reporting 
obligations. 
14.2    Procedures for Reporting Serious Adverse Events 
Adverse Events may be spontaneously identified by the patient and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or 
other diagnostic procedures.  Any clinically relevant deterioration in laboratory assessments 
or other clinical finding is considered an AE.  When possible, signs and symptoms 
indicating a common underlying pathology should be noted as one comprehensive event.   
Adverse Events which are serious must be reported to Millennium Pharmacovigilance (or 
designee) from the time of consent up to and including 30 days after administration of the 
last dost of MLN0128 or alisertib. Any SAE that occurs at any time after completion of 
MLN0128 treatment or after the designated follow-up period that the sponsor-investigator 
and/or sub-investigator considers to be related to any study drug must be reported to 
Millennium Pharmacovigilance (or designee).  Planned hospital admissions or surgical 
procedures for an illness or disease that existed before the patient was enrolled in the trial 
are not to be considered AEs unless the condition deteriorated in an unexpected manner 
during the trial (e.g., surgery was performed earlier or later than planned).  All SAEs should 
be monitored until they are resolved or are clearly determined to be due to a patient’s stable 
or chronic condition or intercurrent illness(es). 
Since this is an investigator-initiated study, the sponsor-investigator Jennifer R. Diamond, 
MD, also referred to as the sponsor-investigator, is responsible for reporting serious adverse 
events (SAEs) to any regulatory agency and to the sponsor- investigator’s EC or IRB.   
Regardless of expectedness or causality, all SAEs must also be reported in English to 
Millennium Pharmacovigilance or designee: 
• Fatal and Life Threatening SAEs: within 24 hours of the sponsor-investigator’s 
observation or awareness of the event 
• All other serious (non-fatal/non life threatening) events: within 4 calendar days 
of the sponsor-investigator’s observation or awareness of the event  
The Sponsor will send all SAE reports to Millennium Pharmacovigilance (or designee) 
within 24 hours but no later than 4 calendar days as per any agreements.  
The SAE report must include at minimum: 
• Event term(s) 


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• Serious criteria 
• Intensity of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination.  Intensity for each SAE, including any lab abnormalities, will 
be determined by using the NCI CTCAE version specified in the protocol, as a 
guideline, whenever possible.  The criteria are available online at 
http://ctep.cancer.gov/reporting/ctc.html. 
• Causality of the event(s): Sponsor-investigator’s or sub-investigator’s 
determination of the relationship of the event(s) to MLN0128 and alisertib 
administration.  
Follow-up information on the SAE may be requested by Millennium Pharmacovigilance (or 
designee).   
In the event that this is a multisite study, the sponsor-investigator is responsible to ensure 
that the SAE reports are sent to Millennium Pharmacovigilance (or designee) from all sites 
participating in the study.  Sub-investigators must report all SAEs to the sponsor-
investigator so that the sponsor-investigator can meet his/her foregoing reporting obligations 
to the required regulatory agencies and to Millennium Pharmacovigilance, unless otherwise 
agreed between the sponsor-investigator and sub-investigator(s).   
Relationship to all study drugs for each SAE will be determined by the investigator or sub-
investigator by responding yes or no to the question: Is there a reasonable possibility that the 
AE is associated with the study drug(s)? 
US and Canada 
Toll-Free Fax #: 1-800-963-6290 
E-mail: takedaoncocases@cognizant.com 
 
All other countries (Rest of World) 
Fax #: 1 202 315 3560 
E-mail: takedaoncocases@cognizant.com 
 
Suggested Reporting Form:   
• 
SAE Report Form (a sample will be provided) 
• 
US FDA MedWatch 3500A:  
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
• 
Any other form deemed appropriate by the sponsor-investigator 
14.3   Procedures for Reporting Drug Exposure During Pregnancy and Birth Events 
If a woman becomes pregnant or suspects that she is pregnant while participating in this 
study, she must inform the investigator immediately and permanently discontinue study 
drug.  The sponsor-investigator must fax a completed Pregnancy Form to the Millennium 
Pharmacovigilance or designee immediately (see Section 12.2).  The pregnancy must be 
followed for the final pregnancy outcome (i.e., delivery, still birth, miscarriage) and 


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Millennium Pharmacovigilance or designee will request this information from the sponsor-
investigator. 
If a female partner of a male patient becomes pregnant during the male patient’s 
participation in this study, the sponsor-investigator must also immediately fax a completed 
Pregnancy Form to the Millennium Pharmacovigilance or designee (see Section 12.2).  
Every effort should be made to follow the pregnancy for the final pregnancy outcome. 
Suggested Pregnancy Reporting Form: 
Pregnancy Report Form (a sample will be provided)   
 
15.    ADMINISTRATIVE REQUIREMENTS 
15.1   Product Complaints   
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product.  Individuals 
who identify a potential product complaint situation should immediately contact Millennium 
(see below) and report the event.  Whenever possible, the associated product should be 
maintained in accordance with the label instructions pending further guidance from a 
Millennium Quality representative. 
For Product Complaints, call  
1-844-ONC-TKDA (1/844-662-8532) 
email: GlobalOncologyMedinfo@takeda.com 
 
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 Millennium Pharmacovigilance (refer to 
Section 12.2).  
16.  DATA AND SAFETY MONITORING 
The Sponsor Investigator will be responsible for monitoring the trial per the trial monitoring 
plan, in addition to overseeing the safety and efficacy of the trial, executing the DSM plan, 
and complying with all reporting requirements to local and federal authorities. This 
oversight will be accomplished through additional oversight from the Data and Safety 
Monitoring Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer 
Center).  The DSMC is responsible for ensuring data quality and patient safety for all 
clinical studies at the CU Cancer Center.   A summary of the DSMC’s activities is as 
follows: 
• Conduct of internal audits 
• Ongoing review of all serious adverse events (SAEs), unanticipated problems (UAPs) 
and reportable adverse events (AEs) 
• Has the authority to close and/or suspend trials for safety or trial conduct issues 


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• May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee 
 
Per the CU Cancer Center Institutional DSM Plan, SAEs, UAPs and reportable AEs are 
reported to the DSMC, IRB and the sponsor per protocol.  All SAEs, UAPs and reportable 
AEs are to be reported to the DSMC within 5 business days of receiving notification of the 
occurrence. 
 
Each subject’s treatment outcomes will be discussed by the Investigators and Clinical 
Research Coordinators (CRCs) at weekly disease-oriented working group meetings.  Data 
regarding number of subjects, significant toxicities, dose modifications, and treatment 
responses will be discussed and documented in the meeting’s minutes. 
 
The Sponsor Investigator will provide a DSM report to the CU Cancer Center DSMC on a 
six month basis. The DSM report will include a protocol summary; current enrollment 
numbers; summary of toxicity data to include specific SAEs, UAPs and AEs; any dose 
modifications; all protocol deviations; and protocol amendments. The DSM report to the 
DSMC will also include, if applicable, the results of any efficacy data analysis conducted, as 
well as any internal DSMB reports. Results and recommendations from the review of this 
six month report by the DSMC will then need to be submitted by the site to the IRB of 
record at the time of continuing review. 


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18.    APPENDICES 
Appendix 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, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5 (6):649-55.(36) 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: Cockcroft-Gault Equation 
For men: 
Creatinine Clearance = 
 (140-age [years])×weight [kg] 
72×(serum creatinine [mg/dL]) 
OR 
Creatinine Clearance = 
 (140-age [years])×weight [kg] 
0.81×(serum creatinine [µmol/L]) 
 
For women: 
Creatinine Clearance = 
0.85 (140-age [years])×weight [kg] 
72×(serum creatinine [mg/dL]) 
OR 
Creatinine Clearance = 
0.85 (140-age [years])×weight [kg] 
0.81×(serum creatinine [µmol/L]) 
• Source: Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976;16(1):31-41 (37). 
 
 
 
 


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Appendix 3: New York Heart Association Classification of Cardiac Disease 
Class 
Functional Capacity 
Objective Assessment 
I 
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation, dyspnea, or anginal pain. 
No objective evidence of 
cardiovascular disease. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary 
physical activity results in fatigue, palpitation, dyspnea, or 
anginal pain. 
Objective evidence of minimal 
cardiovascular disease. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than 
ordinary activity causes fatigue, palpitation, dyspnea, or anginal 
pain. 
Objective evidence of moderately 
severe cardiovascular disease. 
IV 
Patients with cardiac disease resulting in inability to carry on 
any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest. If 
any physical activity is undertaken, discomfort is increased. 
Objective evidence of severe 
cardiovascular disease. 
• Source: The Criteria Committee of New York Heart Association. Nomenclature 
and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. Ninth Ed. 
Boston, MA: Little, Brown & Co; 1994:253-256.(38) 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4: List of Relevant Cytochrome P450 Inhibitors and Inducers 
Strong CYP2C19 Inhibitors 
fluconazole 
fluvoxamine 
ticlopidine 
Moderate CYP3A4 Inhibitors 
amprenavir  
darunavir/ritonavir 
fosamprenavir 
aprepitant 
diltiazem 
grapefruit juice (a) 
atazanavir 
erythromycin 
imatinib 
ciprofloxacin 
fluconazole 
verapamil 
Strong CYP3A4 Inhibitors 
boceprevir 
ketoconazole 
ritonavir 
clarithromycin 
lopinavir/ritonavir 
saquinavir 
conivaptan 
mibefradil (b) 
telaprevir 
grapefruit juice (a) 
nefazodone 
telithromycin 
indinavir 
nelfinavir 
voriconazole 
itraconazole 
posaconazole 
 
Clinically Significant Enzyme Inducers 
carbamazepine 
rifabutin 
St. Johns Wort 
phenobarbital 
rifampin 
 
phenytoin 
rifapentine 
 
 
Source:  fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ 
ucm093664.htm.   
Note that these lists are not exhaustive.   
(a) The effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent.  Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used (eg, high dose, double strength) or as a “moderate CYP3A inhibitor” when another 
preparation was used (eg, low dose, single strength). 
(b) Withdrawn from the United States market because of safety reasons.