A Study of Alisertib in Combination With Endocrine Therapy in Patients With HR-positive, HER2-negative Recurrent or Metastatic Breast Cancer

PUMA-ALI-1201 is a randomized, dose optimization, multicenter, Phase 2 study of alisertib administered in combination with endocrine therapy in participants with pathology-confirmed HR-positive/HER2-negative metastatic breast cancer (MBC) following progression on or after at least two prior lines of endocrine therapy in the recurrent or metastatic setting. This study is intended to evaluate the optimal alisertib dose administered in combination with the selected endocrine therapy. The study is also planned to evaluate the efficacy, safety, and pharmacokinetics of alisertib in combination with endocrine and to identify the biomarker-defined subgroup(s) that may benefit most from combined alisertib and endocrine therapy. Participants randomized prior to Amendment 4 are randomized 1:1:1 to Arm 1, Arm 2 or Arm 3. Participants randomized under Amendment 4 will be randomized 1:1 to Arm 1 or Arm 2.

Inclusion Criteria: * Aged ≥18 years at signing of informed consent. * Pathology-confirmed diagnosis of breast cancer with evidence of recurrent or metastatic disease not amenable to curative therapy. * Progression on or after treatment with at least two prior lines of endocrine therapy in the recurrent or metastatic setting. a. If metastatic disease recurrence occurs during or within six months of discontinuing adjuvant endocrine therapy, then that endocrine therapy will count as one line of prior therapy. * Participants must have received a CDK4/6i in combination with endocrine therapy in the recurrent or metastatic setting. * HR-positive and HER2-negative 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. Exclusion Criteria: * Treatment with chemotherapy in the recurrent or metastatic setting, including antibody drug conjugates with a chemotherapeutic payload. * Prior treatment with an Aurora Kinase A (AURKA) specific-targeted or pan-Aurora-targeted agent, including alisertib, in any setting. Note: There are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.