This is a dose escalation and dose expansion study to assess the safety and tolerability of BGB-21447 (a B-cell leukemia/lymphoma 2 inhibitor, Bcl-2i) in combination with fulvestrant, with or without BGB-43395 (cyclin-dependent kinase 4 inhibitor, CDK4i), in adults with HR+/HER2- metastatic breast cancer.
Histologically or cytologically confirmed HR+/HER2- metastatic breast cancer. Part 1A and 1B: Participants must have received ≥ 1 prior line(s) of treatment for advanced/metastatic disease, including prior endocrine therapy and CDK4/6 inhibitor in either the adjuvant or advanced/metastatic setting. Part 2: Participants must have received 1-3 prior line(s) of treatment for advanced/metastatic disease, including prior endocrine therapy and CDK4/6 inhibitor in either the adjuvant or advanced/metastatic setting.
Female participants will be required (either continue ongoing or initiate as soon as feasible) to have ovarian function suppression using gonadotropin-releasing hormone (GnRH) agonists (such as goserelin) or be postmenopausal.
Male participants may be required to use GnRH agonists when being treated with fulvestrant at the discretion of the investigator.
Participants must have a stable Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1.
Prior Bcl-2 inhibitor exposure. For triplet combination cohorts only: Prior therapy selectively targeting CDK4.
Known leptomeningeal disease or uncontrolled, untreated brain metastases.
Any malignancy ≤ 3 years before the first dose of study treatment(s) except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated with curative intent (eg, treated papillary thyroid carcinoma, resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast).
For Part 1B: Uncontrolled diabetes.
Sequential
BGB-21447
DrugAdministered orally.
Fulvestrant
DrugAdministered via intramuscular injection.
BGB-43395
DrugAdministered orally.
Part 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Number of participants with AEs and SAEs, including findings from physical examinations, electrocardiograms (ECGs), laboratory assessments, and AEs that meet protocol-defined dose-limiting toxicity criteria.
Part 1: Recommended Dose for Expansion (RDFE) of BGB-21447 in combination with fulvestrant and in combination with fulvestrant and BGB-43395
RDFE of BGB-21447 in combination with fulvestrant and in combination with fulvestrant and BGB-43395 will be determined based upon the maximum tolerated dose (MTD) or maximum administered dose (MAD).
Part 2: Objective Response Rate (ORR)
ORR is defined as the percentage of participants who had confirmed complete response (CR) or partial response (PR) as assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Part 1: ORR
ORR is defined as the percentage of participants who had confirmed CR or PR as assessed by the investigator per RECIST v1.1.
Parts 1 and 2: Duration of Response (DOR)
DOR is defined as the time from the first determination of an objective response until the first documentation of progression or death, whichever comes first, as assessed by the investigator per RECIST v1.1.
Part 1:Time to Response (TTR)
TTR is defined as the time from the date of the first dose of study drug to the date of the first CR or PR, as assessed by the investigator per RECIST v1.1.
Part 2: Disease Control Rate (DCR)
DCR is defined as the percentage of participants with best overall response of a CR, PR, and stable disease.
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