BGB-43395 Alone or as Part of Combination Therapies in Participants With Breast Cancer and Other Advanced Solid Tumors

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1a/1b Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of the CDK4 Inhibitor BGB-43395, Alone or as Part of Combination Therapies in Patients With Metastatic HR+/HER2- Breast Cancer and Other Advanced Solid Tumors

Conditions
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Advanced Solid Tumor, Advanced Breast Cancer, Metastatic Breast Cancer, Hormone-receptor-positive Breast Cancer, Hormone Receptor Positive Breast Carcinoma, Hormone Receptor Positive Malignant Neoplasm of Breast, HER2-negative Breast Cancer, Hormone Receptor Positive HER-2 Negative Breast Cancer, Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: BGB-43395
* Drug: Fulvestrant
* Drug: Letrozole


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1a (Dose Escalation): Participants with histologically or cytologically confirmed advanced, metastatic, or unresectable solid tumors associated with dependency on CDK4, including HR+ breast cancer, non-small cell lung cancer, and others. Phase 1a: Received prior therapy for their condition (if available) and should be refractory to or intolerant of standard-of-care therapies. Phase 1b (Dose Expansion): Selected tumor cohorts will include HR+/HER2- breast cancer and additional tumor types. Phase 1b: Participants with HR+/HER2- breast cancer enrolled in regions where CDK4/6 inhibitors are approved and available must have received at least one line of therapy for advanced disease including endocrine therapy and a CDK4/6 inhibitor. Participants can have received up to 2 lines of prior cytotoxic chemotherapy for advanced disease. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1. Female participants with metastatic HR+/HER2- breast cancer must be postmenopausal or receiving ovarian function suppression treatment. Adequate organ function. Exclusion Criteria: Prior therapy selectively targeting CDK4 (prior CDK4/6 inhibitor therapy is permitted and required in local regions where it is approved and available). Known leptomeningeal disease or uncontrolled, untreated brain metastasis. Any malignancy ≤ 3 years before the first dose of study drug(s) except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated with curative intent (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast). Uncontrolled diabetes. Infection requiring systemic antibacterial, antifungal, or antiviral therapy ≤ 28 days before the first dose of study drug(s), or symptomatic COVID-19 infection. History of hepatitis B or active hepatitis C infection. Prior allogeneic stem cell transplantation, or organ transplantation. Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>Phase 1a: Sequential cohorts of increasing dose levels of BGB-43395 will be evaluated as monotherapy and in combination with either fulvestrant or letrozole. | Drug: BGB-43395<br>* Planned doses administered orally.<br>Drug: Fulvestrant<br>* Standard dose administered via intramuscular injection.<br>* Other names: Faslodex®;Drug: Letrozole<br>* Standard dose administered orally as a tablet.<br>* Other names: Femara®;|
| Experimental: Dose Expansion<br>Phase 1b: The recommended dose for expansion (RFDE) for BGB-43395 (in combination with fulvestrant) from Phase 1a will be evaluated in HR+ breast cancer and selected tumor cohorts. | Drug: BGB-43395<br>* Planned doses administered orally.<br>Drug: Fulvestrant<br>* Standard dose administered via intramuscular injection.<br>* Other names: Faslodex®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of participants with AEs and SAEs, including findings from physical examinations, electrocardiograms (ECGs), laboratory assessments, and that meet protocol-defined dose-limiting toxicity criteria. | Up to approximately 3 years | 
| Phase 1a: Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) of BGB-43395 | MTD is defined as the highest dose evaluated for which estimated toxicity rate is the closest to the target toxicity rate of 30%. MAD is defined as the highest dose administered if MTD is not reached. | Up to approximately 3 years | 
| Phase 1a: Recommended Dose for Expansion (RDFE) of BGB-43395 | RDFE of BGB-43395 alone or in combination with fulvestrant or letrozole will be determined based upon the MTD or MAD. | Up to approximately 3 years | 
| Phase 1b: Objective Response Rate (ORR) | ORR is defined as the percentage of participants who have confirmed complete response (CR) or partial response (PR) assessed by the investigator using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Up to approximately 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: ORR | ORR is defined as the percentage of participants who have confirmed CR or PR assessed by the investigator using RECIST v1.1. | Up to approximately 3 years | 
| Phase 1a and 1b: Duration of Response (DOR) | DOR is defined as the time from the first determination of an overall response per RECIST v1.1 until the first documentation of disease progression or death, whichever occurs first as assessed by the investigator. | Up to approximately 3 years | 
| Phase 1a and 1b: Time to Response (TTR) | TTR is defined as the time from the date of the first dose of study drugs to the date of the first determination of objective response by the investigator using RECIST v1.1. | Up to approximately 3 years | 
| Phase 1a and 1b: Disease Control Rate (DCR) | DCR is defined as the percentage of participants with best overall response of CR, PR, or stable disease assessed by the investigator using RECIST v1.1. | Up to approximately 3 years | 
| Phase 1a and 1b: Clinical Benefit Rate (CBR) | CBR is defined as the percentage of participants with best overall response of confirmed CR, PR, or stable disease lasting ≥ 24 weeks. | Up to approximately 3 years | 
| Phase 1b: Progression-Free Survival (PFS) | PFS is defined as the time from the date of the first dose of study drug(s) to the date of the first documentation of progressive disease assessed by the investigator using RECIST v1.1 or death, whichever occurs first. | Up to approximately 3 years | 
| Phase 1b: Number of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) | Number of participants with AEs and SAEs, including findings from physical examinations, electrocardiograms (ECGs), and laboratory assessments. | Up to approximately 3 years | 
| Phase 1a: Observed Plasma Maximum Concentration (Cmax) of BGB-43395 and its metabolite |  | From Cycle 1 Day 1 up to Cycle 7 Day 1 (each cycle is 28 days) | 
| Phase 1a: Observed Plasma Trough Concentration (Ctrough) of BGB-43395 and its metabolite |  | From Cycle 1 Day 1 up to Cycle 7 Day 1 (each cycle is 28 days) | 
| Phase 1a: Area under the concentration-time curve (AUC) of BGB-43395 and its metabolite |  | From Cycle 1 Day 1 up to Cycle 7 Day 1 (each cycle is 28 days) | 
| Phase 1a: Half-life (t1/2) of BGB-43395 and its metabolite |  | From Cycle 1 Day 1 up to Cycle 7 Day 1 (each cycle is 28 days) | 
| Phase 1b: Plasma concentrations of BGB-43395 and its metabolite |  | From Cycle 1 Day 1 up to Cycle 5 Day 1 (each cycle is 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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breast cancer, advanced solid tumor, advanced breast cancer, hormone receptor positive breast cancer, HER2-negative breast cancer, Hormone Receptor Positive HER-2 Negative Breast Cancer, BGB-43395, non-small cell lung cancer