HER2-negative Breast Cancer, Hormone-receptor-positive Breast Cancer, Metastatic Breast Cancer
Conditions
Keywords
BGB-21447, BGB-43395, metastatic breast cancer, Bcl-2i, CDK4i
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.
Interventions
Sponsors
BeOne Medicines
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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 ≤ 1. * 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 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. * 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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: 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 | 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 | 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) | 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
| Measure | Time frame | Description |
|---|---|---|
| Part 1: ORR | Approximately 12 months | 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) | Approximately 12 months | 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) | Approximately 12 months | 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) | Approximately 12 months | DCR is defined as the percentage of participants with best overall response of a CR, PR, and stable disease. |
| Part 2: Clinical Benefit Rate (CBR) | Approximately 12 months | CBR is defined as the percentage of participants who achieve CR, PR, or durable stable disease (stable disease ≥ 24 weeks). |
| Part 2: Progression-Free Survival (PFS) | Approximately 12 months | PFS is defined as the time from the date of the first dose of study drug to the date of the first documentation of progressive disease as assessed by the investigator, or death, whichever occurs first. The progressive disease assessment is based on RECIST v1.1. |
| 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 | Number of participants with AEs and SAEs, including findings from physical examinations, electrocardiograms (ECGs), and laboratory assessments. |
| 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 | — |
Countries
Australia, China, United States
Contacts
CONTACTStudy Director
STUDY_DIRECTORStudy Director
BeOne Medicines
Outcome results
None listed