BGB-43395 Combinations for Breast Cancer
Recruiting in Palo Alto (17 mi)
+65 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: BeiGene
Must be taking: Endocrine therapy
Must not be taking: Systemic antibacterials
Disqualifiers: Uncontrolled diabetes, Brain metastases, others
No Placebo Group
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.12345
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.36789
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.
See 4 more
Trial 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 (CDK4 Inhibitor)
- Fulvestrant (Hormone Therapy)
- Letrozole (Hormone Therapy)
Trial OverviewThe 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
2Treatment groups
Experimental Treatment
Group I: Dose ExpansionExperimental Treatment3 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 EscalationExperimental Treatment3 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
James Cancer Hospital and Solove Research InstituteColumbus, OH
Next DallasIrving, TX
Washington University School of MedicineSaint Louis, MO
Florida Cancer Specialists and Research InstituteLake Mary, FL
More Trial Locations
Loading ...
Who Is Running the Clinical Trial?
BeiGeneLead Sponsor
References
Clinical trials update: endocrine and biological therapy combinations in the treatment of breast cancer. [2021]A greater understanding of the biological mechanisms responsible for de novo and acquired endocrine resistance has led to the rational design of clinical trials exploring the benefit of combining hormonal therapies with novel biological agents in an effort to enhance the efficacy of ER+ breast cancer treatment. These studies are increasingly including parallel biological analyses to elucidate the molecular characteristics of those tumors that are most likely to respond to specific targeted/endocrine combinations in an effort to develop a tailored approach to the management of individual patients. Unfortunately despite encouraging preclinical data, some of these combinations have yielded disappointing results in the clinical setting. This article will review the results of clinical trials of endocrine/biological combinations conducted in early and advanced breast cancer as well as provide an update on ongoing studies.
Therapeutic significance of hormone receptor positivity in patients with HER-2 positive breast cancer. [2020]Breast cancer with high expression of human epidermal growth factor receptor (HER)-2 represents a biologically and clinically heterogeneous group of neoplastic disorders. Importantly, hormone receptor expression has an effect on biological properties and affects the selection of therapies. On the basis of molecular genetics, four principal subtypes, including luminal A, luminal B, HER2-enriched (HER-2-E), and basal-like can be distinguished. Breast tumors characterized by HER-2 positivity and simultaneous expression of hormone receptors, triple positive breast cancers (TPBC) are of increasing interest owing to the unique biological characteristics associated with complex interactions between HER-2 and hormone receptor signaling pathways. Interactions between hormone receptors and HER-2 explain the decreased efficacy of hormonal therapy in comparison with HER-2-negative patients. The expression of estrogen receptors in HER-2 positive tumors may also be associated with resistance to anti-HER-2 treatment. Multiple available therapeutic options, including hormonal therapy, anti-HER-2 agents and cytotoxic drugs explain favorable prognosis of TPBC. Escalation and de-escalation therapeutic strategies that could result in lower toxicities are being investigated as well as combinations of anti-HER-2 agents with hormonal therapy, immunotherapy, cyclin dependent kinase 4/6 and phosphatidyl inositol-3-kinase inhibitors. Distinction between subtypes of HER-2-positive breast cancer and treatment diversification may result in improved outcomes in TPBC. A response to neoadjuvant therapy may serve in the tailoring of therapy management.
Targeting Triple Negative Breast Cancer With Oncolytic Adenoviruses. [2022]Breast cancer (BC) is the most common cancer globally, accounting for 685,000 deaths in 2020. Triple-negative breast cancers (TNBC) lack oestrogen (ER) and progesterone (PR) hormone receptor expression and HER2 overexpression. TNBC represent 10-15% of all BC with high incidence in women under 50-years old that have BRCA mutations, and have a dismal prognosis. African American and Hispanic women are at higher risk partly due to the common occurrence of BRCA mutations. The standard treatment for TNBC includes surgery, radiotherapy, and chemotherapy although, resistance to all standard-of-care therapies eventually develops. It is crucial to identify and develop more efficacious therapeutics with different mechanisms of action to improve on survival in these women. Recent findings with oncolytic adenoviruses (OAds) may generate a new strategy to improve on the outcomes for women afflicted by TNBC and other types of BC. OAds are genetically engineered to selectively lyse, eliminate and recruit the host antitumour immune responses, leaving normal cells unharmed. The most common modifications are deletions in the early gene products including the E1B55 KDa protein, specific regions of the E1A protein, or insertion of tumour-specific promoters. Clinical trials using OAds for various adenocarcinomas have not yet been sufficiently evaluated in BC patients. Preclinical studies demonstrated efficacy in BC cell lines, including TNBC cells, with promising novel adenoviral mutants. Here we review the results reported for the most promising OAds in preclinical studies and clinical trials administered alone and in combination with current standard of care or with novel therapeutics. Combinations of OAds with small molecule drugs targeting the epidermal growth factor receptor (EGFR), androgen receptor (AR), and DNA damage repair by the novel PARP inhibitors are currently under investigation with reported enhanced efficacy. The combination of the PARP-inhibitor Olaparib with OAds showed an impressive anti-tumour effect. The most promising findings to date are with OAds in combination with antibodies towards the immune checkpoints or expression of cytokines from the viral backbone. Although safety and efficacy have been demonstrated in numerous clinical trials and preclinical studies with cancer-selective OAds, further developments are needed to eliminate metastatic lesions, increase immune activation and intratumoural viral spread. We discuss shortcomings of the OAds and potential solutions for improving on patient outcomes.
Phosphorylation of androgen receptors at serine 515 is a potential prognostic marker for triple negative breast cancer. [2018]1.7 million cases of breast cancer are diagnosed every year with 522,000 deaths. Molecular classifications of breast cancer have resulted in improved treatments. However, treatments for triple negative breast cancer (TNBC) are lacking. Analysis of molecular targets for TNBC is a priority. One potential candidate is androgen receptor (AR) phosphorylation. This study assessed the role of AR phosphorylation at ser81/ser515 and their two upstream effectors, cyclin-dependent kinase 1 (pCDK1) and extracellular-regulated kinase 1/2 (pERK1/2) in 332 ductal breast cancer patients by immunohistochemistry.pERK1/2 combined with AR-515 associated with improved cancer-specific survival (CSS, p = 0.038), decreased size (p = 0.001), invasive grade (p
Combined angiogenesis and PD-1 inhibition for immunomodulatory TNBC: concept exploration and biomarker analysis in the FUTURE-C-Plus trial. [2022]Immune checkpoint inhibitors had a great effect in triple-negative breast cancer (TNBC); however, they benefited only a subset of patients, underscoring the need to co-target alternative pathways and select optimal patients. Herein, we investigated patient subpopulations more likely to benefit from immunotherapy and inform more effective combination regimens for TNBC patients.
Emerging treatment strategies for breast cancer brain metastasis: from translational therapeutics to real-world experience. [2020]Systemic therapies for primary breast cancer have made great progress over the past two decades. However, oncologists confront an insidious and particularly difficult problem: in those patients with metastatic breast cancer, up to 50% of human epidermal growth factor 2 (HER2)-positive and 25-40% of triple-negative subtypes, brain metastases (BM) kill most of them. Fortunately, standard- of-care treatments for BM have improved rapidly, with a decline in whole brain radiation therapy and use of fractionated stereotactic radiosurgery as well as targeted therapies and immunotherapies. Meanwhile, advances in fundamental understanding of the basic biological processes of breast cancer BM (BCBM) have led to many novel experimental therapeutic strategies. In this review, we describe the most recent clinical treatment options and emerging experimental therapeutic strategies that have the potential to combat BCBM.
Identification of nuclear export inhibitor-based combination therapies in preclinical models of triple-negative breast cancer. [2021]An estimated 284,000 Americans will be diagnosed with breast cancer in 2021. Of these individuals, 15-20% have basal-like triple-negative breast cancer (TNBC), which is known to be highly metastatic. Chemotherapy is standard of care for TNBC patients, but chemoresistance is a common clinical problem. There is currently a lack of alternative, targeted treatment strategies for TNBC; this study sought to identify novel therapeutic combinations to treat basal-like TNBCs. For these studies, four human basal-like TNBC cell lines were utilized to determine the cytotoxicity profile of 1363 clinically-used drugs. Ten promising therapeutic candidates were identified, and synergism studies were performed in vitro. Two drug combinations that included KPT-330, an XPO1 inhibitor, were synergistic in all four cell lines. In vivo testing of four basal-like patient-derived xenografts (PDX) identified one combination, KPT-330 and GSK2126458 (a PI3K/mTOR inhibitor), that decreased tumor burden in mice significantly more than monotherapy with either single agent. Bulk and single-cell RNA-sequencing, immunohistochemistry, and analysis of published genomic datasets found that XPO1 was abundantly expressed in human basal-like TNBC cell lines, PDXs, and patient tumor samples. Within basal-like PDXs, XPO1 overexpression was associated with increased proliferation at the cellular level. Within patient datasets, XPO1 overexpression was correlated with greater rates of metastasis in patients with basal-like tumors. These studies identify a promising potential new combination therapy for patients with basal-like breast cancer.
Triple‑negative breast cancer therapy: Current and future perspectives (Review). [2021]Triple‑negative breast cancer (TNBC) accounts for 10‑15% of all breast cancer cases. TNBCs lack estrogen and progesterone receptors and express low levels of HER2, and therefore do not respond to hormonal or anti‑HER2 therapies. TNBC is a particularly aggressive form of breast cancer that generally displays poorer prognosis compared to other breast cancer subtypes. TNBC is chemotherapy sensitive, and this treatment remains the standard of care despite its limited benefit. Recent advances with novel agents have been made for specific subgroups with PD‑L1+ tumors or germline Brca‑mutated tumors. However, only a fraction of these patients responds to immune checkpoint or PARP inhibitors and even those who do respond often develop resistance and relapse. Various new agents and combination strategies have been explored to further understand molecular and immunological aspects of TNBC. In this review, we discuss clinical trials in the management of TNBC as well as perspectives for potential future treatments.
Triple-negative breast cancer and the potential for targeted therapy. [2018]Breast cancer is composed of several well-recognized subtypes including estrogen receptor, progesterone receptor and HER2 triple-negative breast cancer (TNBC). Without available targeted therapy options, standard of care for TNBC remains chemotherapy. It is of interest to note that TNBC tumors generally have better responses to chemotherapy compared with other subtypes. However, patients without complete response account for approximately 80% of TNBC. Mounting evidence suggests significant heterogeneity within the TNBC subtype, and studies have focused on genetic targets with high rates of altered expression. Recent studies suggest clear possibilities for benefits from targeted therapy in TNBC. In this review, we summarize studies of targeted therapy, including within mouse models, and discuss their applications in the development of combinatorial treatments to treat TNBC.