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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
96
Georgetown University Medical Center
Washington D.C., District of Columbia, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
University of Michigan
Ann Arbor, Michigan, United States
Mayo Clinic
Rochester, Minnesota, United States
Montefiore Medical Center
The Bronx, New York, United States
Duke University Medical Center
Durham, North Carolina, United States
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Vanderbilt Breast Center at One Hundred Oaks
Nashville, Tennessee, United States
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
Time frame: Up to 4.5 years
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).
Time frame: 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.
Time frame: 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.
Time frame: Baseline to 28 days
Clinical Benefit Rate (CBR) During Initial Treatment Defined as Percentage 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.
Time frame: 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.
Time frame: Up to about 5 years
Incidence of Grade 4 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.
Time frame: Up to 30 days after last administration of study drug
Overall Survival
Will be estimated using the Kaplan-Meier method.
Time frame: Up to 5 years
Progression-free Survival
Will be estimated using the Kaplan-Meier method.
Time frame: 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
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