Randomized Phase II Trial to Evaluate Alisertib Alone or Combined With Fulvestrant for Women With Advanced, Endocrine-Resistant Breast Cancer
Randomized Phase II Trial to Evaluate Alisertib Alone or Combined With Fulvestrant for Women With Advanced, Endocrine-Resistant Breast Cancer
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.
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
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:
Prior treatment
Disease that is measurable where:
No history of tumors involving spinal cord or heart
History of brain metastases as per the following criteria:
Fully recovered from acute, reversible effects of prior therapy regardless of interval since last treatment;
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:
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
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:
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