BGB-43395 Combinations for Breast Cancer

Recruiting at 73 trial locations

Overseen By Study Director

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: BeiGene

Must be taking: Endocrine therapy

Must not be taking: Systemic antibacterials

Disqualifiers: Uncontrolled diabetes, Brain metastases, others

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

Compensation: Varies

Number of Visits: Unknown

79 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a dose escalation and dose expansion study to compare how well BGB-43395, a cyclin-dependent kinase 4 (CDK4) inhibitor, works as monotherapy or in combination with either fulvestrant or letrozole in participants with hormone receptor positive (HR+) and human epidermal growth factor 2 negative (HER2-) breast cancer (BC) and other advanced solid tumors. The main purpose of this study is to explore the recommended dosing for BGB-43395.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, prior therapy with CDK4/6 inhibitors is required in some regions, and certain infections or conditions may exclude you from participation.

What data supports the effectiveness of the drug BGB-43395 Combinations for Breast Cancer?

The research highlights that combining hormonal therapies with new biological agents can improve treatment for certain types of breast cancer, especially those with hormone receptor positivity. Although some combinations have not been successful, ongoing studies are exploring how to tailor treatments to individual patients for better outcomes. ^{1 2 3 4 5}

What makes the drug BGB-43395 unique for breast cancer treatment?

The drug BGB-43395 is unique because it is being tested in combination with other therapies to target triple-negative breast cancer (TNBC), a subtype that lacks targeted treatment options and often develops resistance to standard therapies like chemotherapy. This approach aims to improve outcomes by using novel mechanisms of action, potentially offering new hope for patients with this aggressive form of breast cancer. ^{3 6 7 8 9}

Research Team

Study Director

Principal Investigator

BeiGene

Eligibility Criteria

This trial is for adults with advanced solid tumors, like HR+ breast cancer or non-small cell lung cancer, that rely on CDK4. Participants must have tried standard treatments without success and be in good physical condition (ECOG ≤ 1). Women with metastatic HR+/HER2- breast cancer should be postmenopausal or suppressing ovarian function.

Inclusion Criteria

I have tried and not responded to or couldn't tolerate standard treatments.

I have HR+/HER2- breast cancer and have been treated with endocrine therapy and a CDK4/6 inhibitor.

I am a woman with advanced HR+/HER2- breast cancer and am either postmenopausal or receiving treatment to suppress ovarian function.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Sequential cohorts of increasing dose levels of BGB-43395 are evaluated as monotherapy and in combination with either fulvestrant or letrozole to assess for safety and tolerability

Up to approximately 60 months

Dose Expansion

The recommended dose for expansion (RFDE) for BGB-43395 in combination with fulvestrant or letrozole is evaluated in HR+ breast cancer and selected tumor-specific cohorts

Up to approximately 60 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

Treatment Details

Interventions

• BGB-43395
• Fulvestrant
• Letrozole

Trial Overview The study tests BGB-43395 alone or combined with fulvestrant or letrozole in patients with certain cancers. It aims to find the best dose of BGB-43395 by gradually increasing amounts and observing effects in different groups of participants.

Participant Groups

Group I: Dose Expansion Experimental Treatment 3 Interventions

Phase 1b: The recommended dose for expansion (RFDE) for BGB-43395 (in combination with fulvestrant or letrozole) from Phase 1a will be evaluated in HR+ breast cancer and selected tumor-specific cohorts.

Group II: Dose Escalation Experimental Treatment 3 Interventions

Phase 1a: Sequential cohorts of increasing dose levels of BGB-43395 will be evaluated as monotherapy and in combination with either fulvestrant or letrozole to assess for safety and tolerability.

Who Is Running the Clinical Trial?

BeiGene

Lead Sponsor

Trials

216

Recruited

32,500+

Findings from Research

Recent advancements in understanding how breast cancer develops resistance to hormone therapies have led to new clinical trials that combine hormonal treatments with biological agents to improve outcomes for patients with ER+ breast cancer.

Despite promising results in laboratory studies, many of these combination therapies have not performed as well in clinical trials, highlighting the need for ongoing research to identify which patients will benefit most from these tailored treatment approaches.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical trials update: endocrine and biological therapy combinations in the treatment of breast cancer. Leary, AF., Sirohi, B., Johnston, SR.[2021]

Triple positive breast cancers (TPBC), which express both HER-2 and hormone receptors, show unique biological characteristics that affect treatment efficacy, particularly leading to decreased effectiveness of hormonal therapies compared to HER-2-negative patients.

The study highlights the potential for improved outcomes in TPBC through tailored treatment strategies, including combinations of anti-HER-2 agents with hormonal therapy and other targeted therapies, as well as the importance of distinguishing between HER-2-positive subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic significance of hormone receptor positivity in patients with HER-2 positive breast cancer. Kolarova, I., Vanasek, J., Odrazka, K., et al.[2020]

Oncolytic adenoviruses (OAds) represent a promising new therapeutic strategy for treating triple-negative breast cancer (TNBC), which is particularly aggressive and often resistant to standard treatments. Preclinical studies have shown that OAds can selectively target and destroy cancer cells while sparing normal cells, enhancing the potential for improved patient outcomes.

Combining OAds with existing treatments, such as PARP inhibitors like Olaparib and immune checkpoint antibodies, has demonstrated enhanced anti-tumor effects, suggesting that these combinations could lead to more effective therapies for women with TNBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting Triple Negative Breast Cancer With Oncolytic Adenoviruses. Green-Tripp, G., Nattress, C., Halldén, G.[2022]

In a study of 332 ductal breast cancer patients, the phosphorylation of the androgen receptor at ser515 (AR-515) combined with pERK1/2 was linked to improved cancer-specific survival and better tumor characteristics in estrogen receptor-positive (ER+) tumors.

Conversely, in triple negative breast cancer (TNBC) patients, AR-515 phosphorylation was associated with poorer cancer-specific survival, suggesting it may play a role in inflammation regulation and could serve as a prognostic marker and therapeutic target for TNBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phosphorylation of androgen receptors at serine 515 is a potential prognostic marker for triple negative breast cancer. Roseweir, AK., McCall, P., Scott, A., et al.[2018]

CD8-positive tumors in triple-negative breast cancer (TNBC) patients are more likely to benefit from immunotherapy, and targeting angiogenesis can enhance the effectiveness of checkpoint inhibitors.

In a phase II trial involving 48 patients, a combination of famitinib, camrelizumab, and chemotherapy achieved an impressive objective response rate of 81.3% and a median progression-free survival of 13.6 months, with no treatment-related deaths reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial. Wu, SY., Xu, Y., Chen, L., et al.[2022]

Metastatic breast cancer, particularly in HER2-positive and triple-negative subtypes, poses a significant risk of brain metastases, which are a leading cause of mortality in these patients.

Recent advancements in treatment options for brain metastases, including targeted therapies, immunotherapies, and improved radiation techniques, show promise in improving outcomes for patients with breast cancer brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging treatment strategies for breast cancer brain metastasis: from translational therapeutics to real-world experience. Ren, D., Cheng, H., Wang, X., et al.[2020]

This study identified a promising combination therapy for basal-like triple-negative breast cancer (TNBC) using KPT-330, an XPO1 inhibitor, and GSK2126458, a PI3K/mTOR inhibitor, which significantly reduced tumor burden in mouse models compared to single-agent treatments.

XPO1 was found to be overexpressed in basal-like TNBC cell lines and patient samples, correlating with increased tumor proliferation and metastasis, suggesting that targeting XPO1 could be a key strategy in treating this aggressive cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer. Rashid, NS., Hairr, NS., Murray, G., et al.[2021]

Triple-negative breast cancer (TNBC) is a challenging subtype of breast cancer that does not respond to hormonal or anti-HER2 therapies, making chemotherapy the standard treatment despite its limited effectiveness.

Recent advancements in treatment options, such as immune checkpoint inhibitors for PD-L1+ tumors and PARP inhibitors for BRCA-mutated tumors, show promise, but responses are limited and often lead to resistance, highlighting the need for ongoing research into new therapies and combination strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triple‑negative breast cancer therapy: Current and future perspectives (Review). Won, KA., Spruck, C.[2021]

Triple-negative breast cancer (TNBC) currently lacks targeted therapy options, relying primarily on chemotherapy, which is generally more effective for TNBC than for other breast cancer subtypes.

Recent research highlights the potential for targeted therapies in TNBC, driven by the subtype's genetic heterogeneity, suggesting that combinatorial treatments could improve outcomes for the 80% of patients who do not achieve a complete response to chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triple-negative breast cancer and the potential for targeted therapy. Jhan, JR., Andrechek, ER.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Clinical trials update: endocrine and biological therapy combinations in the treatment of breast cancer. [2021]

2. Czech Republic pubmed.ncbi.nlm.nih.gov

Therapeutic significance of hormone receptor positivity in patients with HER-2 positive breast cancer. [2020]

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

Targeting Triple Negative Breast Cancer With Oncolytic Adenoviruses. [2022]

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

Phosphorylation of androgen receptors at serine 515 is a potential prognostic marker for triple negative breast cancer. [2018]

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

Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Emerging treatment strategies for breast cancer brain metastasis: from translational therapeutics to real-world experience. [2020]

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

Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer. [2021]

8. Greece pubmed.ncbi.nlm.nih.gov

Triple‑negative breast cancer therapy: Current and future perspectives (Review). [2021]

9. England pubmed.ncbi.nlm.nih.gov

Triple-negative breast cancer and the potential for targeted therapy. [2018]