Study to Compare Alisertib With Paclitaxel vs. Paclitaxel Alone in Metastatic or Locally Recurrent Breast Cancer

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

Inclusion Criteria:

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care, and signed Health
Insurance Portability and Accountability Act (HIPAA) form.

- Female subject (≥18 years old), who is either:

- post-menopausal for at least one year before the screening visit, or

- surgically sterilized, or

- willing to use an acceptable method of birth control (i.e., a hormonal
contraceptive, intra-uterine device, diaphragm with spermicide, or condom with
spermicide) for the duration of the study.

- Metastatic or locally recurrent breast cancer with histologic confirmation (on either
primary or metastatic tumor) of one of the following:

- ER+, HER2- invasive breast cancer (any progesterone receptor [PgR] status)

- Poorly differentiated and/or Grade 3 invasive TNBC, defined as:

- HER2 negative status (based on most recently analyzed biopsy) is defined as
immunohistochemistry (IHC) status of 0, 1+ or 2+ (if IHC 2+, a negative FISH test
is required, i.e., HER2 fluorescence in situ hybridization (FISH) ratio < 2.0
with an average HER2 copy number <4.0 signals/cell); ER-negative and PR-negative
status is defined as ER and PgR <1% nuclei positive by IHC

- Measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST)
(v1.1) or non-measurable lytic, bone-only disease (mixed blastic/lytic bone disease is
allowed); if patient has bone-predominant disease with no measurable disease, there
must be a lytic component to the bone metastases that is visible on plain X-ray or CT
scan that can be serially followed

- Absolute neutrophil count (ANC) > 1500/mm³, platelets > 100,000/mm³, Hgb > 9 g/dL.
Values must be obtained without need for myeloid growth factor or platelet transfusion
support within 14 days, however, erythrocyte growth factor is allowed as per published
American Society of Clinical Oncology (ASCO) guidelines (available at:
http://www.asco.org/quality-guidelines/asco-ash-clinical-practice-guideline-update-use
-epoetin-and-darbepoetin-adult).

- Total bilirubin ≤ 1.5 x upper limit of normal (ULN), serum glutamic-oxaloacetic
transaminase (SGOT) (AST) and serum glutamic-pyruvic transaminase (SGPT) (ALT) < 2.5 x
ULN. AST and/or ALT may be up to 5 x ULN if patient has known liver metastases

- Adequate renal function as defined by: Calculated creatinine clearance must be ≥ 30
mL/minute (see Cockcroft-Gault formula in Appendix 5)

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (refer to Appendix
4)

Exclusion Criteria:

- Previous radiation therapy covering the whole pelvis

- Suspected brain metastases, untreated brain metastases or current clinical or
radiologic progression of known brain metastases or requirement for steroid therapy
for brain metastases

- Patients with treated brain metastases are eligible if they have been stable and
off steroids for ≥ 3 weeks

- Prior allogeneic bone marrow or organ transplantation

- Known GI disease or GI procedures that could interfere with the oral absorption or
tolerance of alisertib. Examples include, but are not limited to partial gastrectomy,
history of small intestine surgery, and celiac disease

- 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.

- Requirement for administration of proton pump inhibitor, or for constant
administration of H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids
or H2 antagonists are allowed as described in Section 3.4.

- Systemic infection requiring IV antibiotic therapy within 14 days preceding the first
dose of study drug, or other severe infection.

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure (see Appendix 3), uncontrolled
angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence
of acute ischemia or active conduction system abnormalities. Prior to study entry, any
ECG abnormality at Screening has to be documented by the investigator as not medically
relevant.

- Female subject who is pregnant or breast-feeding. Confirmation that the subject is not
pregnant must be established by a negative serum B-human chorionic gonadotropin
(B-hCG) pregnancy test result obtained during screening, within 72 hours prior to
first dose of study drug(s). Pregnancy testing is not required for post-menopausal or
surgically sterilized women.

- Patient has received an investigational agent within 30 days before enrollment

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Other severe acute or chronic medical and/or psychiatric condition(s), including but
not limited to uncontrolled diabetes, malabsorption, resection of the pancreas or
upper small bowel, requirement for pancreatic enzymes, any condition that would modify
small bowel absorption of oral medications, or laboratory abnormalities that may
increase the risk associated with study participation or investigational product
administration or may interfere with the interpretation of study results and, in the
judgment of the investigator, would make the patient not eligible for enrollment for
this study.

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, or an in situ malignancy, or a stage I cancer with a 5-year Disease Free
Survival (DFS) of ≥ 90% (survival rates by stage are available for most cancers on the
American Cancer Society website).

- Treatment with clinically significant enzyme inducers, such as the enzyme-inducing
antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin,
rifapentine or St. John's wort within 14 days prior to the first dose of alisertib and
during the study.

- Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or
hepatitis C. Testing is not required in the absence of clinical findings or suspicion.
For guidance in defining active infection for hepatitis B, please refer to the WHO
guidelines. (World Health Organization, Global Alert and Response (GAR), Hepatitis B.
http://who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index4.html)

- Prior administration of an Aurora A kinase-targeted agent, including alisertib

- Need for ongoing therapeutic steroid therapy. Intermittent steroid use for the control
of nausea and vomiting is allowed. Premedication with dexamethasone prior to
paclitaxel administration is allowed. Topical steroid use is permitted. Inhaled
steroids are permitted. Replacement doses of hydrocortisone up to 15 mg/day are
allowed.

- Inability to swallow oral medication or inability or unwillingness to comply with the
administration requirements related to alisertib.

- Administration of myeloid growth factors or platelet transfusion within 14 days prior
to the first dose of study treatment.

- More than 1 previous chemotherapy regimen for metastatic disease

- No limit on previous endocrine therapy

- Previous mammalian target of rapamycin (mTOR) therapy, e.g., everolimus, is
allowed

- Prior adjuvant taxane therapy is allowed, provided the disease-free interval from
the end of (neo)adjuvant chemotherapy to the development of metastatic disease
was ≥ 1 year

- No prior taxane for metastatic disease

- Peripheral neuropathy > grade 1

- Known severe hypersensitivity to paclitaxel