A Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of BGB-21447 (a Bcl-2 Inhibitor) Combinations for Patients With HR+/HER2- Metastatic Breast Cancer
Overview
- Phase
- Phase 1
- Intervention
- BGB-21447
- Conditions
- Hormone-receptor-positive Breast Cancer
- Sponsor
- BeOne Medicines
- Enrollment
- 120
- Locations
- 16
- Primary Endpoint
- Part 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
- Status
- Recruiting
- Last Updated
- 5 months ago
Overview
Brief Summary
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.
Detailed Description
This new study will check how safe and helpful a potential anticancer drug called BGB-21447 (Bcl-2i) is. This drug will be tested in combination with fulvestrant, with or without BGB-43395 (CDK4i), in adults with metastatic breast cancer. HR+/HER2- tumors account for approximately 70% of all breast cancers and are responsible for most breast cancer-related deaths. While CDK4/6 inhibitors combined with endocrine therapy have improved outcomes for patients with HR+/HER2- metastatic breast cancer, patients eventually develop progressive disease on these therapies and require new treatments. BGB-21447 is an oral drug that is highly potent and selectively stops a protein called B-cell lymphoma-2 (Bcl-2). Bcl-2 proteins are often overexpressed in some cancers (like HR+ breast cancer) by keeping the cancer cells from dying. Disrupting this pathway is believed to lead to cell death. BGB-43395 is an oral drug that selectively stops a protein called cyclin-dependent kinase 4 (CDK4). CDK4 is a type of protein that regulates cell growth and division in your body. Fulvestrant is a treatment that blocks estrogen receptors and reduces estrogen production. Fulvestrant has been approved to treat hormone receptor positive metastatic breast cancer to help stop the cancer cells from growing. This combination might be a good way to fight cancer, aiming to give patients the best possible treatment. The study is designed to see if this combination is safe and works well.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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 ≤
- •Adequate organ function.
- •Female participants of childbearing potential and nonsterile male participants with female partners of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study and for 7 days after the last dose of BGB-21447, 6 months after the last dose of BGB-43395, and 2 years after the last dose of fulvestrant.
- •Food effect substudy only: Participants who are able and willing to fast overnight (≥ 10 hours) and consume a high-fat meal.
Exclusion Criteria
- •Prior Bcl-2 inhibitor exposure. For triplet combination cohorts only: Prior therapy selectively targeting CDK
- •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.
- •History of hepatitis B or active Hepatitis C infection
- •China Only: Untreated chronic hepatitis B or chronic hepatitis B virus (HBV) carriers with HBV DNA \> 500 IU/ml (or \> 2500 copies/ml) at screening.
- •Note: Other protocol defined Inclusion/Exclusion criteria may apply.
Arms & Interventions
Part 1A: BGB-21447 + Fulvestrant
Sequential cohorts of increasing dose levels of BGB-21447 will be evaluated in combination with fulvestrant.
Intervention: BGB-21447
Part 1A: BGB-21447 + Fulvestrant
Sequential cohorts of increasing dose levels of BGB-21447 will be evaluated in combination with fulvestrant.
Intervention: Fulvestrant
Part 1B: BGB-21447 + BGB-43395 + Fulvestrant
Sequential cohorts of increasing dose levels of BGB-21447 will be evaluated in combination with fulvestrant and BGB-43395.
Intervention: BGB-21447
Part 1B: BGB-21447 + BGB-43395 + Fulvestrant
Sequential cohorts of increasing dose levels of BGB-21447 will be evaluated in combination with fulvestrant and BGB-43395.
Intervention: Fulvestrant
Part 1B: BGB-21447 + BGB-43395 + Fulvestrant
Sequential cohorts of increasing dose levels of BGB-21447 will be evaluated in combination with fulvestrant and BGB-43395.
Intervention: BGB-43395
BGB-21447 + Fulvestrant Food Effect Substudy
Participants will receive BGB-21447 at the recommended dose with a high-fat meal and under a fasted state in combination with fulvestrant.
Intervention: BGB-21447
BGB-21447 + Fulvestrant Food Effect Substudy
Participants will receive BGB-21447 at the recommended dose with a high-fat meal and under a fasted state in combination with fulvestrant.
Intervention: Fulvestrant
Part 2: Dose Expansion, BGB-21447 + Fulvestrant
Participants will receive BGB-21447 at the recommended dose(s) for expansion determined in Part 1A in combination with fulvestrant.
Intervention: BGB-21447
Part 2: Dose Expansion, BGB-21447 + Fulvestrant
Participants will receive BGB-21447 at the recommended dose(s) for expansion determined in Part 1A in combination with fulvestrant.
Intervention: Fulvestrant
Outcomes
Primary Outcomes
Part 1: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time Frame: From the first dose of study drug(s) to 30 days after the last dose; up to approximately 6 months
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
Time Frame: From first dose of the study drug(s) to 30 days after the last dose or initiation of a new anticancer therapy, whichever occurs first, up to approximately 6 to 9 months
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)
Time Frame: Approximately 12 months
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.
Secondary Outcomes
- Part 1: ORR(Approximately 12 months)
- Parts 1 and 2: Duration of Response (DOR)(Approximately 12 months)
- Part 1:Time to Response (TTR)(Approximately 12 months)
- Part 2: Disease Control Rate (DCR)(Approximately 12 months)
- Part 2: Clinical Benefit Rate (CBR)(Approximately 12 months)
- Part 2: Progression-Free Survival (PFS)(Approximately 12 months)
- Part 2: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)(From the first dose of study drug(s) to 30 days after the last dose; up to approximately 6 months)
- Maximum observed plasma concentration (Cmax) of BGB-21447 and BGB-43395(Up to approximately 2 months)
- Time to reach maximum observed plasma concentration (Tmax) of BGB-21447 and BGB-43395(Up to approximately 2 months)
- Area under the concentration-time curve (AUC) of BGB-21447 and BGB-43395(Up to approximately 2 months)
- Apparent terminal elimination half-life (t1/2) of BGB-21447 and BGB-43395(Up to approximately 2 months)
- Food Effect Substudy: AUC of BGB-21447 under fasted and fed state(Up to approximately 2 months)
- Food Effect Substudy: Cmax of BGB-21447 under fasted and fed state(Up to approximately 2 months)