Alisertib With or Without Fulvestrant in Treating Patients With Locally Advanced or Metastatic, 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Stage IV Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Invasive Breast Carcinoma; Stage IIIC Breast Cancer; HER2/Neu Negative; Stage III Breast Cancer; Postmenopausal; Estrogen Receptor Status
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Alisertib; Drug: Fulvestrant

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.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
  • Tennessee
    • Nashville, Tennessee, United States, 37204
      • Vanderbilt Breast Center at One Hundred Oaks

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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; Correlative studies; Drug: Alisertib; Given PO; Other Names: MLN8237; Aurora A Kinase Inhibitor MLN8237; MLN-8237
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; Correlative studies; Drug: Alisertib; Given PO; Other Names: MLN8237; Aurora A Kinase Inhibitor MLN8237; MLN-8237; Drug: Fulvestrant; Given IM; Other Names: Faslodex; Faslodex(ICI 182,780); ICI 182,780; ICI 182780; ZD9238

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

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Tufia C. Haddad, M.D., Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2017
• Primary Completion (Actual): January 10, 2022
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: August 4, 2016
• First Submitted That Met QC Criteria: August 4, 2016
• First Posted (Estimated): August 9, 2016

Study Record Updates

• Last Update Posted (Estimated): January 18, 2024
• Last Update Submitted That Met QC Criteria: January 16, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Hormone Antagonists; Estrogen Antagonists; Estrogen Receptor Antagonists; Fulvestrant
• Other Study ID Numbers: MC1431 (Other Identifier: Mayo Clinic); P30CA015083 (U.S. NIH Grant/Contract); NCI-2016-01211 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); R01CA214893 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No