Evaluating how well and how safely Alisertib works with hormone therapy in treating patients with breast cancer that has come back or spread (hormone receptor positive, HER2 negative

Prior treatment

• Treatment with chemotherapy in the recurrent or metastatic setting.
• Unresolved Grade >1 toxicities from previous systemic anti-cancer therapy, defined as toxicities not yet improved to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0) Grade ≤1 or baseline, prior to randomization, except for any Grade alopecia and Grade 2 neuropathy or anemia
• Coagulopathy or any history of coagulopathy within the past 6 months, including history of deep vein thrombosis or pulmonary embolism. However, patients with the following conditions will be allowed to participate: a. Adequately treated catheter-related venous thrombosis occurring >28 days prior to randomization. b. If Investigator-selected endocrine therapy is tamoxifen, treatment with an anticoagulant, e.g., warfarin or heparin, for a thrombotic event occurring > 6 months prior to randomization, or for an otherwise stable and allowed medical conditions (e.g., well-controlled atrial fibrillation), provided dose and coagulation parameters (as defined by local standard of care) are stable for at least 28 days prior to randomization.
• Any use of a proton pump inhibitor (PPI) and H2 receptor antagonists within 5 days before randomization and during study conduct.
• Treatment with moderate to strong CYP3A4 inducers (e.g., phenytoin, rifampin) and inhibitors (e.g., ketoconazole) within 14 days prior to randomization and during study conduct.
• Known hypersensitivity to any component of the investigational product or compounds of similar chemical composition.
• Major surgery within 28 days before randomization (major according to the Investigator’s and/or Medical Monitor’s assessment).
• Prior treatment with an Aurora Kinase A (AURKA) specific-targeted or pan-Auroratargeted agent, including alisertib, in any setting.
• Known upcoming need for radiation therapy.
• Symptomatic or untreated central nervous system (CNS) metastases. Note: Patients with stable, treated brain metastases are eligible if there is no evidencprogression or hemorrhage and are asymptomatic for at least 14 days prior to randomization. Patients must be off steroids for at least 14 days prior to randomizatiPatients may remain on a stable dose of non-enzyme inducing anti-convulsants.

Other illness

• Intact uterus with a history of endometrial intraepithelial neoplasia (atypical endometrial hyperplasia or higher-grade lesion).
• Active, uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association [NYHA] functional classification of ≥2), unstable angina, myocardial infarction, or ventricular arrhythmia within 12 months of randomization.
• History of malignancy other than the one to be studied within the past 5 years with the exception of appropriately treated non-invasive malignancies (e.g., non-melanoma skin cancers, in situ carcinoma of the uterine cervix) or second primary breast cancer.
• Significant chronic GI disorder that can impair the absorption of orally administered drugs (e.g., Crohn’s disease, malabsorption, or NCI CTCAE v.5.0 Grade ≥2 diarrhea of any etiology at baseline).
• Patients with bone only disease presenting with only blastic bone lesions or only lytic/mixed lytic-blastic bone lesions that do not meet the definition of measurability according to RECIST v1.1
• Any condition that, in the Investigator’s and/or Medical Monitor’s judgment, makes the patient an unreliable trial subject (such as known dependence on alcohol, benzodiazepines, opioids), unlikely to complete the trial, and/or unable to comply with the protocol procedures.
• Any active infection requiring systemic treatment (antibacterial, antiviral, or antifungal) within 7 days of randomization.
• Presence of uncontrolled, symptomatic disease. Note: Visceral disease is defined as liver, lung, brain, kidney, or adrenal metastasis.

Lab values

• Mean resting corrected QTcF interval >0.480 seconds or known history of congenital QT-prolongation or Torsade de Pointes.
• Left ventricular ejection fraction (LVEF) <50% measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA).
• Immunocompromised patients, including: a. Known active Human Immunodeficiency Virus (HIV) infection as determined by HIV ribonucleic acid (RNA) viral load and CD4 count. b. Known active or uncontrolled hepatitis B or C infection as determined by positive hepatitis B tests (HBs and anti-HBc) or hepatitis C test (HCV antibody).

Other

• Unable or unwilling to swallow tablets whole.

• Provide written, informed consent to participate in the study and follow the study procedures.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Elapsed time from prior indication-based therapy to randomization: a. >14 days from any other prior endocrine therapy. b. ≥14 days from previous radiation therapy (28 days for brain lesions). c. >14 days or 5 half-life periods (whichever is shorter) from last dose of prior investigational anticancer drug therapy.
• Female patients must meet 1 of the following criteria: a. Documented bilateral surgical oophorectomy. b. Aged ≥60 years with amenorrhea ≥1 year since last menses. c. Aged <60 years with serum estradiol and follicle stimulating hormone (FSH) levels within the laboratory reference range for post-menopausal women. d. Pre- or peri-menopausal female patients are eligible if amenable to treatment with a luteinizing hormone-releasing hormone (LHRH) agonist. Patients are to have commenced concomitant treatment with LHRH agonist prior to randomization and must be willing to continue it for the duration of the study.
• Pre- and peri-menopausal female patients must have negative β-human chorionic gonadotropin (hCG) serum or urine pregnancy test prior to study entry, periodically for the duration of treatment, and at the EOT visit.
• Pre- or peri-menopausal female patients must agree and commit to the use of a highly effective method of contraception from the time of informed consent until 6 months after the last dose of alisertib, and must agree to comply with contraception methods after the last dose of fulvestrant and tamoxifen (if applicable) for the duration specified in the approved product label. If the highly effective method cannot be used, using 2 other effective methods at the same time is required. a. Highly effective methods: Intra-uterine devices. b. Other effective methods (barrier methods): Latex condom, diaphragm with spermicide, cervical cap, sponge.
• Male patients, even if surgically sterilized (i.e., status post-vasectomy), must agree and commit to using a highly effective method of contraception with their biologically female partner(s) of reproductive potential while on treatment and for 3 months after last dose of investigational product. If 1 of the highly effective methods cannot be used, patients must use 2 other effective methods at the same time. Male patients must refrain from donating sperm during the trial and for 3 months after last dose of investigational product. Male patients must receive concomitant treatment with gonadotropin releasing hormone (GnRH) analog. Patients are to have commenced concomitant treatment with GnRH analog prior to randomization and must be willing to continue it for the duration of the study. a. Highly effective methods: Intra-uterine devices, hormonal (birth control pills/oral contraceptives, injectable contraceptives, contraceptive patches, or contraceptive implants). b. Other effective methods (barrier methods): Latex condom, diaphragm with spermicide, cervical cap, sponge.
• Adequate major organ and hematologic function as defined by the screening parameters below:
• Aged ≥18 years at signing of informed consent.
• Willing to provide tumor tissue for biomarker assessment. Note: Tumor tissue from a pre-treatment biopsy or from after the last known disease progression is required. If the biopsy procedure presents an unacceptable safety concern for the patient as determined by the Investigator, or other exceptional reason upon agreement with the Sponsor, archival formalin-fixed paraffin-embedded (FFPE) tissue from the recurrent or metastatic tumor may be submitted.
• Pathology-confirmed diagnosis of adenocarcinoma of the breast with evidence of recurrent or metastatic disease not amenable to curative therapy.
• Progression on or after treatment with at least 2 prior lines of endocrine therapy in the recurrent or metastatic setting. a. If metastatic disease recurrence occurs during or within 6 months of discontinuing adjuvant endocrine therapy, then that endocrine therapy will count as one line of prior therapy.
• Patients must have received a CDK4/6i in combination with endocrine therapy in the recurrent or metastatic setting. a. If metastatic disease recurrence occurs during or within 6 months of discontinuing adjuvant CDK4/6i therapy in combination with endocrine, then the adjuvant CDK4/6i will count as the required CDK4/6i.
• HR+ and HER2- tumor status reported per local laboratory testing. HR and HER2 testing must be performed consistent with current American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society of Medical Oncology (ESMO) guidelines: a. HR+ disease defined as ≥1% estrogen receptor (ER) positive and/or progesterone receptor (PgR) positive cells. b. HER2- tumor with an immunohistochemistry (IHC) result of 0 or 1+ for cellular membrane protein expression or 2+ with a negative in-situ hybridization result.
• At least one measurable target lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Note: Lytic bone lesions or mixed lytic-blastic bone lesions with identifiable soft tissue components that can be evaluated by cross sectional imaging techniques, such as CT or MRI, can be considered as measurable lesions if the soft tissue component meets the definition of measurability according to RECIST v1.1.
• Must be an appropriate candidate for Investigator-selected endocrine therapy and treatment naïve to Investigator-selected endocrine therapy in the recurrent or metastatic setting. Note: The Investigator may select an endocrine therapy the patient received in the adjuvant setting if the patient did not have a recurrence while receiving the selected endocrine therapy.