Alisertib With or Without Fulvestrant in Treating Patients With Locally Advanced or Metastatic, Endocrine-Resistant Breast Cancer

PRIMARY OBJECTIVES:

I. To assess the impact on objective tumor response rate (using Response Evaluation Criteria
in Solid Tumors [RECIST] criteria) with the addition of fulvestrant to alisertib in women
with endocrine resistant, advanced estrogen receptor positive breast cancer.

SECONDARY OBJECTIVES:

I. To evaluate the safety profile of each treatment regimen. II. To assess the impact on
median progression-free survival with the addition of fulvestrant to alisertib.

III. To obtain estimated tumor response rate and the median progression-free survival time
during alisertib and fulvestrant treatment in the cohort of patients who progress during
alisertib monotherapy, and crossover to receive the combination of alisertib and fulvestrant.

TERTIARY OBJECTIVES:

I. To assess the changes in aurora A kinase, SMAD5 and SOX2 expression and phosphorylation in
tumor tissue after first cycle of assigned treatment.

II. To assess the changes in estrogen receptor (ER) expression and function in tumor tissue
after the first cycle of assigned treatment.

III. To generate patient derived xenografts (PDX) from tumors collected at baseline and
progression of disease (PD) in order to identify mechanisms associated with both de novo and
acquired alisertib resistance.

IV. After the first cycle of treatment, to assess changes in aurora A kinase, phosphorylated
(p)~SOX2 and ER expression on circulating tumor cells (CTCs), and to assess concordance
between change in expression with tumor tissue and CTCs.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive alisertib orally (PO) twice daily (BID) on days 1-3, 8-10, and 15-17.
Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients with disease progression, may cross-over to Arm II.

ARM II: Patients receive fulvestrant intramuscularly (IM) over 1-2 minutes on days 1 and 15
of course 1 and on day 1 of all subsequent courses. Patients also receive alisertib PO BID on
days 1-3, 8-10, and 15-17. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 5
years.

Inclusion Criteria:

- PRE-REGISTRATION ELIGIBILITY

- Post-menopausal defined as

- Age >= 60 and amenorrhea > 12 consecutive months, OR

- Age < 60 and amenorrhea > 12 consecutive months without another cause and
documented follicle stimulating hormone (FSH) level of > 35 mIU/mL, OR

- Previous bilateral oophorectomy

- Histologic proof of metastatic or locally advanced, unresectable breast cancer

- History of ER positive (+) (>= 10% of cells positive on hematoxylin and eosin stain
[H&E]), HER2 negative (−) breast cancer disease, either as a

- History of primary, operable ER+/HER2− invasive breast cancer OR

- History of de novo metastatic breast cancer that is ER+/HER2−

- Note: HER2− (negative) disease defined as one of the following:

- HER2 immunohistochemistry (IHC) expression of 0, 1+ and in-situ
hybridization (ISH) non-amplified

- HER2 IHC expression of 0, 1+ and ISH not done

- HER2 IHC expression of 2+ and ISH non-amplified

- IHC not done and ISH non-amplified

- Prior treatment

- No more than two prior chemotherapy regimens in the metastatic setting

- Prior treatment with fulvestrant in the metastatic setting is required, except
for patients with a history of ER-negative metastatic breast cancer

- Unlimited prior endocrine therapy regimens in the metastatic setting are allowed

- No prior treatment with an aurora Kinase inhibitor (either an aurora A or
pan-aurora kinase inhibitor)

- Disease that is measurable where:

- A non-nodal lesion is considered measurable if its longest diameter can be
accurately measured as >= 2.0 cm with chest x-ray, or as >= 1.0 cm with computed
tomography (CT) scan, CT component of a positron emission tomography (PET)/CT, or
magnetic resonance imaging (MRI)

- A malignant lymph node is considered measurable if its short axis is >= 1.5 cm
when assessed by CT scan (CT scan slice thickness recommended to be no greater
than 5 mm); Note: tumor lesions in a previously irradiated area are not
considered measurable disease; Note: disease that is measurable by physical
examination only is not eligible

- No history of tumors involving spinal cord or heart

- History of brain metastases as per the following criteria:

- Patients with a history of resected brain metastases are eligible only if they
are asymptomatic and have stable MRI scans for 3 consecutive months, including <
28 days prior to pre-registration

- Patients who receive stereotactic radiosurgery or whole brain radiation for brain
metastases are eligible only if they are asymptomatic and have stable MRI scans
for 3 consecutive months, including < 28 days prior to pre-registration

- Fully recovered from acute, reversible effects of prior therapy regardless of interval
since last treatment;

- EXCEPTION: neuropathies - if grade 2 neuropathies have been stable for at least 3
months since completion of prior treatment patient is eligible

- Eastern Cooperative Oncology Group (ECOG) performance status: 0, 1, 2

- Not receiving administration of proton pump inhibitor, H2 antagonist, or pancreatic
enzymes

- Willing to limit daily alcohol intake to the following: one 12-oz glass of beer, one
6-oz glass of wine, or one 1.5-oz portion of 80-proof alcohol

- No uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Uncontrolled symptomatic cardiac arrhythmia

- Uncontrolled hypertension (defined as blood pressure > 160/90)

- No 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

- No other active second malignancy other than non-melanoma skin cancers and in situ
cervical cancers within 5 years of registration

- NOTE: A second malignancy is not considered active if all treatment for that
malignancy is completed and the patient has been disease-free for at least 5
years prior to registration

- Ability to provide written informed consent

- Willing to return to enrolling institution for follow-up during the active treatment;
event monitoring following completion of therapy may occur outside the enrolling
institution

- No history of myocardial infarction =< 6 months prior to pre-registration or New York
Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities

- No prior allogeneic bone marrow or organ transplantation

- No known clinical finding or suspicion of human immunodeficiency virus (HIV)
infection, hepatitis B, or hepatitis C

- No co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into this
study or interfere significantly with the proper assessment of safety and toxicity of
the prescribed regimens

- Able to swallow oral medication

- No known gastrointestinal (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

- No visceral crisis: Visceral crisis is not the mere presence of visceral metastases,
but implies severe organ dysfunction as assessed by symptoms and signs, laboratory
studies, and rapid progression of disease

- No requirement for constant administration of proton pump inhibitor, H2 antagonist, or
pancreatic enzymes

- Willing to undergo a biopsy of a metastatic site of breast disease for central
laboratory determination of ER and correlative research purposes

- REGISTRATION ELIGIBILITY CRITERIA

- =< 28 days post pre-registration

- Central ER determination on pre-registration biopsy completed

- Absolute neutrophil count (ANC) >= 1500/mm^3

- Platelet count >= 100,000/mm^3

- Hemoglobin >= 9.0 g/dL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- Alanine transaminase (ALT) =< 3 x ULN (=< 5 x ULN for patients with liver involvement)

- Calculated creatinine clearance must be >= 45 ml/min using the Cockcroft-Gault formula

- Willing to provide blood and tissue for correlative research purposes

Exclusion Criteria:

- REGISTRATION EXCLUSION CRITERIA

- Any of the following therapies prior to registration:

- Chemotherapy =< 21 days

- Immunotherapy =< 21 days

- Biologic therapy =< 21 days

- Hormonal therapy =< 14 days

- Monoclonal antibodies =< 14 days

- Radiation therapy =< 14 days

- Administration of myeloid growth factors or platelet transfusion =< 14 days prior to
registration

- Systemic infection requiring intravenous (IV) antibiotic therapy =< 14 days prior to
registration

- 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 =< 14 days prior to registration

- Receipt of corticosteroids =< 7 days prior to registration, unless patient has been
taking a continuous dose of no more than 15 mg/day of prednisone for at least 30 days
prior to registration