Clinical trial NCT06756932: BGB-21447 (Bcl-2 Inhibitor) Combinations for Adults With Hormone-Receptor Positive (HR+)/Human Epidermal Growth Factor Receptor 2 Negative (HER2-) Metastatic Breast Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Hormone-receptor-positive Breast Cancer
HER2-negative Breast Cancer
Metastatic Breast Cancer
Keywords: BGB-21447
BGB-43395
metastatic breast cancer
Bcl-2i
CDK4i
Lead sponsor: BeiGene
Sponsor class: INDUSTRY
First posted: 2025-01-03
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is 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. By disrupting this pathway, antitumor effects can be achieved.

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. CDK4 inhibition is believed to have antitumor effects.

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.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed HR+/HER2- metastatic breast cancer. Participants must have received ≥ 2 prior lines of treatment for 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 90 days after the last dose of BGB-21447, 3 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.
* 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).
* 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.

Primary outcomes:
measure: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From the first dose of study drug(s) to 30 days after the last dose; up to approximately 6 months
measure: Recommended Dose for Expansion (RDFE) of BGB-21447 in combination with fulvestrant and in combination with fulvestrant and BGB-43395
timeFrame: Approximately 6 to 9 months
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Approximately 12 months
measure: Duration of Response (DOR)
timeFrame: Approximately 12 months
measure: Time to Response (TTR)
timeFrame: Approximately 12 months
measure: Maximum observed plasma concentration (Cmax) of BGB-21447, BGB-43395, and BGB-43395 metabolite
timeFrame: Up to approximately 2 months
measure: Time to reach maximum observed plasma concentration (Tmax) of BGB-21447, BGB-43395, and BGB-43395 metabolite
timeFrame: Up to approximately 2 months
measure: Area under the concentration-time curve (AUC) of BGB-21447, BGB-43395, and BGB-43395 metabolite
timeFrame: Up to approximately 2 months
measure: Apparent terminal elimination half-life (t1/2) of BGB-21447, BGB-43395, and BGB-43395 metabolite
timeFrame: Up to approximately 2 months
measure: Food Effect Substudy: AUC of BGB-21447 under fasted and fed state
timeFrame: Up to approximately 2 months
measure: Food Effect Substudy: Cmax of BGB-21447 under fasted and fed state
timeFrame: Up to approximately 2 months
Other outcomes:
Locations:
city: Newport Beach
country: United States
facility: Hoag Memorial Presbyterian
state: California
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Houston
country: United States
facility: Md Anderson Cancer Center
state: Texas
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center
state: Washington
city: Darlinghurst
country: Australia
facility: Saint Vincents Hospital Sydney
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Private Hospital
state: Queensland
city: Melbourne
country: Australia
facility: Peter Maccallum Cancer Centre
state: Victoria
city: St Albans
country: Australia
facility: Western Health Sunshine Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Linear Clinical Research
state: Western Australia
city: Guangzhou
country: China
facility: Sun Yat Sen Memorial Hospital, Sun Yat Sen University (South)
state: Guangdong
city: Zhengzhou
country: China
facility: The First Affiliated Hospital of Zhengzhou University
state: Henan
city: Nanchang
country: China
facility: The First Affiliated Hospital of Nanchang University Branch Donghu
state: Jiangxi
city: Shanghai
country: China
facility: Fudan University Shanghai Cancer Centerpudong
state: Shanghai
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital
state: Tianjin
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University School of Medicine
state: Zhejiang
Study officials:
affiliation: BeiGene
name: Study Director
role: STUDY_DIRECTOR
References: