BGB-21447 Combinations for Breast Cancer

Recruiting at 16 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: BeiGene

Must be taking: GnRH agonists

Must not be taking: Bcl-2 inhibitors

Disqualifiers: Leptomeningeal disease, Brain metastases, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 6 to 9 months

92 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you must not have had prior exposure to Bcl-2 inhibitors, and you may need to continue or start ovarian function suppression if you are a female participant.

What data supports the effectiveness of the drug BGB-21447 for breast cancer?

The research on similar drugs like alpelisib (BYL-719) shows that it can be effective in treating certain types of breast cancer, especially when combined with other treatments. Alpelisib has been approved for use with fulvestrant in hormone receptor-positive breast cancer, suggesting that drugs targeting similar pathways may also be effective. ^{1 2 3 4 5}

Is BGB-21447 safe for use in humans?

The safety of buparlisib (BGB-21447) has been evaluated in combination with other treatments for breast cancer, showing it is generally tolerable, but specific side effects or safety concerns are not detailed in the provided studies. ^{1 4 6 7 8}

What is the purpose of this trial?

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.

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

Adults with HR+/HER2- metastatic breast cancer who've had at least two prior treatments, including endocrine therapy and CDK4/6 inhibitors. Women must manage ovarian function suppression; men may need GnRH agonists. Participants should be relatively healthy (ECOG ≤ 1) and willing to use effective birth control during the study.

Inclusion Criteria

My breast cancer is HR+/HER2- and I've had at least 2 treatments for it, including hormone therapy and a CDK4/6 inhibitor.

I am a woman with breast cancer and will start or continue ovarian suppression.

I am a male willing to use hormone therapy if treated with certain breast cancer drugs.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive BGB-21447 in combination with fulvestrant, with or without BGB-43395, to assess safety and tolerability

6 to 9 months

Regular visits for dose escalation and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Long-term follow-up

Participants are monitored for long-term outcomes such as Objective Response Rate and Duration of Response

Approximately 12 months

Treatment Details

Interventions

• BGB-21447
• BGB-43395

Trial Overview The trial is testing BGB-21447, a drug aimed at blocking a protein that helps cancer cells survive, combined with fulvestrant. It's also looking at adding another drug, BGB-43395, which inhibits enzymes involved in cell division. The goal is to see if these combinations are safe for patients.

Participant Groups

Group I: Part B: BGB-21447 + BGB-43395 + Fulvestrant Experimental Treatment 3 Interventions

Sequential cohorts of increasing dose levels of BGB-21447 will be evaluated in combination with fulvestrant and BGB-43395.

Group II: Part A: BGB-21447 + Fulvestrant Experimental Treatment 2 Interventions

Sequential cohorts of increasing dose levels of BGB-21447 will be evaluated in combination with fulvestrant.

Group III: BGB-21447 Food Effect Substudy Experimental Treatment 1 Intervention

Participants will receive BGB-21447 at the recommended dose with a high-fat meal and under a fasted state.

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

The study established the recommended phase 2 doses (RP2D) for alpelisib (350 mg) and buparlisib (100 mg) when combined with tamoxifen and goserelin in premenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, showing that both combinations were well-tolerated.

Patients treated with alpelisib experienced a longer progression-free survival of 25.2 months compared to 20.6 months for those on buparlisib, suggesting that alpelisib may be a more effective option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer. Lu, YS., Lee, KS., Chao, TY., et al.[2021]

Basal-like triple-negative breast cancer (TNBC) often has an overactive PI3K pathway, making it a target for treatment with BYL-719, a PIK3CA inhibitor that shows promise in combination therapies due to its low drug-drug interaction risk.

In studies using patient-derived xenograft models, BYL-719 was found to work synergistically with 20 different compounds, effectively reducing tumor growth, suggesting that these combinations could be beneficial for treating cancers with PIK3CA mutations or overactive PI3K pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovering Synergistic Compounds with BYL-719 in PI3K Overactivated Basal-like PDXs. Boyd, DC., Zboril, EK., Olex, AL., et al.[2023]

CB-103 demonstrated significant anti-tumor activity when combined with fulvestrant in endocrine-resistant ER+ breast cancer models, effectively reducing tumor volume in ESR1-mutant xenografts.

In triple-negative breast cancer (TNBC) models, CB-103 combined with paclitaxel significantly delayed tumor growth and inhibited cancer stem cell formation, suggesting its potential as a treatment option alongside standard chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer. Vigolo, M., Urech, C., Lamy, S., et al.[2023]

The combination of buparlisib and letrozole was found to be safe for patients with metastatic ER-positive breast cancer, with a maximum-tolerated dose of 100 mg/day and manageable side effects like hyperglycemia and fatigue.

In this phase Ib study involving 51 patients, the treatment showed a clinical benefit rate of 31%, indicating some patients experienced significant disease control, regardless of their PIK3CA mutation status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. Mayer, IA., Abramson, VG., Isakoff, SJ., et al.[2021]

The BYLieve trial demonstrated that alpelisib combined with fulvestrant significantly improves progression-free survival (PFS) in patients with hormone receptor-positive, HER2-negative, PIK3CA-mutated advanced breast cancer, showing a median PFS of 7.3 months compared to 3.7 months in a matched real-world cohort.

This study is the first to compare the efficacy of alpelisib with fulvestrant against standard treatments in a real-world setting, confirming that the combination therapy is more effective than standard care after prior treatment with CDK4/6 inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer. Turner, S., Chia, S., Kanakamedala, H., et al.[2022]

The rise in breast cancer brain metastases (BCBMs) is linked to improved systemic control of HER2+ breast cancer, highlighting the need for effective treatments that can cross the blood-brain barrier (BBB).

Preclinical studies suggest that inhibitors targeting the PI3K/AKT/mTOR signaling pathway, such as buparlisib and everolimus, may effectively treat BCBMs by penetrating the BBB and down-regulating cancer signaling, and are currently being tested in combination with trastuzumab in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer. Peddi, PF., Hurvitz, SA.[2023]

In the MONALEESA-2 study involving 213 US patients with hormone receptor-positive, HER2-negative advanced breast cancer, ribociclib combined with letrozole significantly improved progression-free survival (PFS) to 27.6 months compared to 15.0 months with letrozole alone, indicating its efficacy as a first-line treatment.

The most common side effects of ribociclib included neutropenia (72%), nausea (69%), and fatigue (60%), highlighting the importance of monitoring for these adverse events during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study. Yardley, DA., Hart, L., Favret, A., et al.[2020]

The combination of everolimus, letrozole, and trastuzumab was found to be safe and showed promising anticancer activity in a study of 32 patients with treatment-refractory hormone receptor-positive, HER2-positive advanced cancers.

Partial responses were observed in five breast cancer patients, indicating potential effectiveness, while specific adverse events like hyperglycemia and mucositis were noted, helping to establish a recommended dose for future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors. Ballhausen, A., Wheler, JJ., Karp, DD., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

A Phase Ib Study of Alpelisib or Buparlisib Combined with Tamoxifen Plus Goserelin in Premenopausal Women with HR-Positive HER2-Negative Advanced Breast Cancer. [2021]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Discovering Synergistic Compounds with BYL-719 in PI3K Overactivated Basal-like PDXs. [2023]

3. Switzerland pubmed.ncbi.nlm.nih.gov

The Efficacy of CB-103, a First-in-Class Transcriptional Notch Inhibitor, in Preclinical Models of Breast Cancer. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Ribociclib With Letrozole in US Patients Enrolled in the MONALEESA-2 Study. [2020]

8. United States pubmed.ncbi.nlm.nih.gov

Phase I Study of Everolimus, Letrozole, and Trastuzumab in Patients with Hormone Receptor-positive Metastatic Breast Cancer or Other Solid Tumors. [2022]