Alisertib With or Without Fulvestrant in Treating Patients With Locally Advanced or Metastatic, Endocrine-Resistant Breast Cancer
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|ClinicalTrials.gov Identifier: NCT02860000|
Recruitment Status : Recruiting
First Posted : August 9, 2016
Last Update Posted : April 18, 2019
|Condition or disease||Intervention/treatment||Phase|
|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||Drug: Alisertib Drug: Fulvestrant Other: Laboratory Biomarker Analysis||Phase 2|
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.
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.
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 (Clinical Trial)|
|Estimated Enrollment :||96 participants|
|Intervention Model:||Crossover Assignment|
|Masking:||None (Open Label)|
|Official Title:||Randomized Phase II Trial to Evaluate Alisertib Alone or Combined With Fulvestrant for Women With Advanced, Endocrine-Resistant Breast Cancer|
|Actual Study Start Date :||July 6, 2017|
|Estimated Primary Completion Date :||December 15, 2021|
|Estimated Study Completion Date :||December 15, 2021|
Experimental: Arm I (alisertib)
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.
Other: Laboratory Biomarker Analysis
Experimental: Arm II (alisertib, fulvestrant)
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.
Other: Laboratory Biomarker Analysis
- 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 [ Time Frame: Up to 5 years ]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
- Biomarkers and ER alpha expression assessed using tumor tissue [ Time Frame: Up to 4 weeks ]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).
- Change in blood biomarker levels [ Time Frame: Baseline to 28 days ]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.
- Change in tumor biomarker levels [ Time Frame: Baseline to 28 days ]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.
- Clinical benefit rate (CBR) during initial treatment defined as proportion of patients who completed 6 courses of treatment without documentation of disease progression [ Time Frame: At 24 weeks ]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.
- 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 [ Time Frame: Up to 5 years ]Will be estimated using the Kaplan-Meier method.
- Incidence of adverse events graded by Common Terminology Criteria-Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: Up to 30 days after last administration of study drug ]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.
- Overall survival [ Time Frame: Up to 5 years ]Will be estimated using the Kaplan-Meier method.
- Progression-free survival [ 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 ]Will be estimated using the Kaplan-Meier method.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02860000
|United States, District of Columbia|
|Georgetown University Medical Center||Recruiting|
|Washington, District of Columbia, United States, 20007|
|Contact: Antonella Noviella, R.N 202-444-3932 firstname.lastname@example.org|
|Principal Investigator: Claudine Isaacs, M.D.|
|United States, Massachusetts|
|Dana-Farber Cancer Institute||Recruiting|
|Boston, Massachusetts, United States, 02215|
|Contact: Research Nurse Office, R.N 617-632-3478 DFCIBOCResearchNurses@partners.org|
|Principal Investigator: Eric Mayer, M.D.|
|United States, Michigan|
|University of Michigan||Recruiting|
|Ann Arbor, Michigan, United States, 48109|
|Contact: Robert Bridges, B.A 734-936-6936 email@example.com|
|Principal Investigator: Aki Morikawa, M.D.|
|United States, Minnesota|
|Rochester, Minnesota, United States, 55905|
|Contact: Clinical Trials Referral Office 855-776-0015|
|Principal Investigator: Tufia C. Haddad, M.D.|
|United States, New York|
|Montefiore Medical Center||Recruiting|
|Bronx, New York, United States, 10461|
|Contact: Sun Young Oh, MD 718-405-8505|
|Principal Investigator: Sun Young Oh, MD|
|United States, North Carolina|
|Duke University Medical Center||Recruiting|
|Durham, North Carolina, United States, 27710|
|Contact: Heather Sperling, MSN, RN 919-660-1278 Heather.firstname.lastname@example.org|
|Principal Investigator: P. Kelly Marcom, MD|
|United States, Pennsylvania|
|Hospital of the University of Pennsylvania||Recruiting|
|Philadelphia, Pennsylvania, United States, 19104|
|Contact: Dan Glasscott 215-615-2231 Dan.email@example.com|
|Principal Investigator: Amy Clark, M.D.|
|United States, Tennessee|
|Vanderbilt Breast Center at One Hundred Oaks||Recruiting|
|Nashville, Tennessee, United States, 37204|
|Contact: Vanderbilt Ingram Cancer Center Eligibility Office 800-811-8480 firstname.lastname@example.org|
|Principal Investigator: Ingrid Mayer, M.D., MSCI|
|Principal Investigator:||Tufia Haddad||Mayo Clinic|