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

Overview

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

• Drug BGB-21447
  Administered orally.
• Drug Fulvestrant
  Administered via intramuscular injection.
• Drug BGB-43395
  Administered orally.

Primary outcome measures

• 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]
• 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]
• Part 2: Objective Response Rate (ORR) [Time frame: Approximately 12 months]

Secondary outcome measures (12)

• Part 1: ORR [Time frame: Approximately 12 months]
• Parts 1 and 2: Duration of Response (DOR) [Time frame: Approximately 12 months]
• Part 1:Time to Response (TTR) [Time frame: Approximately 12 months]
• Part 2: Disease Control Rate (DCR) [Time frame: Approximately 12 months]
• Part 2: Clinical Benefit Rate (CBR) [Time frame: Approximately 12 months]
• Part 2: Progression-Free Survival (PFS) [Time frame: Approximately 12 months]
• Part 2: 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]
• Maximum observed plasma concentration (Cmax) of BGB-21447 and BGB-43395 [Time frame: Up to approximately 2 months]
• Time to reach maximum observed plasma concentration (Tmax) of BGB-21447 and BGB-43395 [Time frame: Up to approximately 2 months]
• Area under the concentration-time curve (AUC) of BGB-21447 and BGB-43395 [Time frame: Up to approximately 2 months]
• Apparent terminal elimination half-life (t1/2) of BGB-21447 and BGB-43395 [Time frame: Up to approximately 2 months]
• Food Effect Substudy: AUC of BGB-21447 under fasted and fed state [Time frame: Up to approximately 2 months]

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 ≤ 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/Exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

Australia · 6 centers

• Saint Vincents Hospital Sydney — Darlinghurst
• Calvary Mater Newcastle — Waratah
• Sunshine Coast University Private Hospital — Birtinya
• Peter Maccallum Cancer Centre — Melbourne
• Western Health Sunshine Hospital — St Albans
• Linear Clinical Research — Nedlands

China · 5 centers

• Sun Yat Sen Memorial Hospital, Sun Yat Sen University (South) — Guangzhou
• The First Affiliated Hospital of Zhengzhou University — Zhengzhou
• Fudan University Shanghai Cancer Centerpudong — Shanghai
• Tianjin Medical University Cancer Institute and Hospital — Tianjin
• Sir Run Run Shaw Hospital, Zhejiang University School of Medicine — Hangzhou

United States · 3 centers

• University of Iowa Hospitals and Clinics — Iowa City
• Md Anderson Cancer Center — Houston
• Fred Hutchinson Cancer Research Center — Seattle

Identifiers

NCT: NCT06756932 · BGB-21447-102 · CTR20250114

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)
• NMPA/CDE CTR20250114 (chinadrugtrials.org.cn platform)

View this study on ClinicalTrials.gov ↗