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

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well alisertib with or without fulvestrant works in treating patients with endocrine-resistant breast cancer that has spread to other places in the body. Alisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Hormone therapy using fulvestrant may fight breast cancer by blocking the use of estrogen by the tumor cells or reducing the amount of estrogen made by the body. Giving alisertib with or without fulvestrant may be better in treating patients with breast cancer.

Detailed Description
-----------------
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.

Official Title
-----------------
Randomized Phase II Trial to Evaluate Alisertib Alone or Combined With Fulvestrant for Women With Advanced, Endocrine-Resistant Breast Cancer

Conditions
-----------------
Estrogen Receptor Status, HER2/Neu Negative, Invasive Breast Carcinoma, Postmenopausal, Stage III Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer

Intervention / Treatment
-----------------
* Drug: Alisertib
* Drug: Fulvestrant
* Other: Laboratory Biomarker Analysis


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (alisertib)<br>Patients 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. Patients with disease progression, may cross-over to Arm II. | Drug: Alisertib<br>* Given PO<br>* Other names: MLN8237;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|
| Experimental: Arm II (alisertib, fulvestrant)<br>Patients receive fulvestrant 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. | Drug: Alisertib<br>* Given PO<br>* Other names: MLN8237;Drug: Fulvestrant<br>* Given IM<br>* Other names: ZD9238;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor response rate defined as 100% times the number of patients who meet the criteria for complete response (CR) or partial response (PR) using RECIST criteria version 1.1 | For arm I, tumor response rate is defined as 100% times the number of patients who meet the criteria for CR or PR on 2 consecutive evaluations approximately 8 weeks apart during treatment with alisertib monotherapy divided by the number of patients who started alisertib monotherapy. For arm II, tumor response rate is defined as 100% times the number of patients who meet the criteria for CR or PR on 2 consecutive evaluations approximately 8 weeks apart during treatment with combination of alisertib and fulvestrant divided by the number of patients who started treatment with the combination of a | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biomarkers and ER alpha expression assessed using tumor tissue | Spearman rank correlation coefficient will be used to examine the association between ER alpha expression and the biomarkers: CD44, CD24, total and phosphorylated expression of AURKA, SMAD5, and SOX2. A two sample test of the difference in proportions will be used to examine whether weak or no phosphorylated expression of AURKA, SMAD5, and SOX2 after one cycle of alisertib is associated with clinical benefit (CR + PR + stable disease on treatment for at least 6 months). | Up to 4 weeks | 
| Change in blood biomarker levels | Percent change in CTC expression of aurora A kinase, ER, and phospho- SOX2 expression from pre-treatment levels will be determined for each patient. Bland-Altman plots and weighted kappa statistics will be used to examine the concordance between the percent change in aurora A kinase, ER, and phospho-SOX2 expression from pre-treatment levels in CTC and in tumor tissue. | Baseline to 28 days | 
| Change in tumor biomarker levels | Spearman rank correlation coefficient will be used to examine the association of maximum percentage of tumor shrinkage during treatment with the percent change after 1 cycle of treatment in aurora A Kinase (AAK) expressing cells, as well as percent changes after 1 cycle of treatment in tissue ER alpha, SMAD5, SOX2 expression and phosphorylation. | Baseline to 28 days | 
| Clinical benefit rate (CBR) during initial treatment defined as proportion of patients who completed 6 courses of treatment without documentation of disease progression | For initial treatment in each arm, the CBR at 24 weeks will be defined as the proportion of patients who completed 6 cycles of treatment without documentation of disease progression. A 90% confidence interval for the CBR will be constructed using the Duffy-Santner approach to take into account the sequential nature of the study design. | At 24 weeks | 
| Duration of response defined as time from randomization to disease progression among those patients whose disease meets the RECIST criteria for CR or PR on 2 consecutive evaluations approximately 8 weeks apart during initial treatment | Will be estimated using the Kaplan-Meier method. | Up to 5 years | 
| Incidence of adverse events graded by Common Terminology Criteria-Criteria for Adverse Events (CTCAE) version 4.0 | The CTCAE version 4.0 will be used to grade and assign attribution to each adverse event reported during initial treatment and crossover treatment separately. | Up to 30 days after last administration of study drug | 
| Overall survival | Will be estimated using the Kaplan-Meier method. | Up to 5 years | 
| Progression-free survival | Will be estimated using the Kaplan-Meier method. | Time from randomization to the first of these disease events: local/regional or distant breast recurrence, DCIS or invasive breast disease in contralateral breast, non-breast second primary, or death due to any cause, assessed up to 5 years |