Study Investigating BGB-24714 as Monotherapy and With Combination Therapies in Participants With Solid Tumors

Study Overview
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Brief Summary
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This study aims to understand how safe and well-tolerated a drug called BGB-24714 is when used alone, or in combination with chemotherapy or radiation therapy, for people with advanced or spreading solid tumors. The main objective is to identify the highest tolerable dose or the highest administered dose of BGB-24714. Additionally, the study aims to identify the most suitable doses for further investigation in larger groups of participants.

Official Title
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A Phase 1 Study Investigating the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Preliminary Antitumor Activity of Second Mitochondrial-derived Activator of Caspases Mimetic BGB-24714 as Monotherapy and With Combination Therapies in Patients With Solid Tumors

Conditions
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Solid Tumor, Adult

Intervention / Treatment
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* Drug: BGB-24714
* Drug: Paclitaxel
* Drug: Carboplatin


Participation Criteria
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Eligibility Criteria
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Key Eligibility Criteria : Participants must sign a written informed consent form (ICF); and agree to comply with study requirement Phase 1a (Dose Escalation): Part A, A-CN, and B: Participants with histologically or cytologically confirmed unresectable locally advanced or metastatic solid tumor previously treated with standard systemic therapy or for whom treatment is not available or not tolerated Note: Only participants in mainland China will be eligible for Part A-CN. Part C: Participant has histologically or cytologically confirmed, locally advanced, unresectable Stage III Non-small cell lung cancer (NSCLC) suitable for definitive chemoradiotherapy (CRT) Part D: Participant with locally advanced, histologically confirmed esophageal squamous cell carcinoma (ESCC) suitable for definitive CRT Participants must be able to provide an archived formalin-fixed paraffin embedded (FFPE) tumor tissue sample. If archival tissue is not available, fresh tumor biopsy is mandatory for Part A, A-CN and B. Part A, A-CN, B: ≥ 1 measurable lesion per Response evaluation criteria in solid tumors (RECIST) v1.1 Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1 Key Exclusion Criteria: Active 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 Any condition that required systemic treatment with either corticosteroids or other immunosuppressive medication ≤ 14 days before the first dose of study drug(s). Clinically significant infection requiring systemic therapy ≤ 14 days before the first dose of study drug(s). Prior exposure to agents with second mitochondria-derived activator of caspases (SMAC) mimetics, or other Inhibitors of apoptosis proteins (IAPs) antagonists. 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1a: Dose Escalation Part A<br>Participants will receive escalating doses of BGB-24714 as monotherapy | Drug: BGB-24714<br>* administered orally<br>|
| Experimental: Phase 1a: Dose Escalation Part B<br>Participants will receive increasing dose levels of BGB-24714 in combination with chemotherapy | Drug: BGB-24714<br>* administered orally<br>Drug: Paclitaxel<br>* administered intravenously<br>|
| Experimental: Phase 1a: Dose Escalation Part C<br>Participants will receive increasing dose levels of BGB-24714 in combination with chemoradiation | Drug: BGB-24714<br>* administered orally<br>Drug: Paclitaxel<br>* administered intravenously<br>Drug: Carboplatin<br>* administered intravenously<br>|
| Experimental: Phase 1a: Dose Escalation Part D<br>Participants will receive increasing dose levels of BGB-24714 in combination with chemoradiation | Drug: BGB-24714<br>* administered orally<br>Drug: Paclitaxel<br>* administered intravenously<br>Drug: Carboplatin<br>* administered intravenously<br>|
| Experimental: Phase 1a: Dose Escalation Part A-CN<br>Participants will receive escalating doses of BGB-24714 as monotherapy in mainland China | Drug: BGB-24714<br>* administered orally<br>|
| Experimental: Phase 1a: Dose Escalation Part E<br>Participants will receive increasing dose levels of BGB-24714 in combination with chemoradiation in mainland China | Drug: BGB-24714<br>* administered orally<br>Drug: Paclitaxel<br>* administered intravenously<br>Drug: Carboplatin<br>* administered intravenously<br>|
| Experimental: Phase 1b: Dose Expansion<br>Participants will receive the recommended phase 2 dose (RP2D) of BGB-24714 monotherapy or in combination with chemotherapy, or with a combination of chemotherapy and radiation therapy, as determined from Phase 1a | Drug: BGB-24714<br>* administered orally<br>Drug: Paclitaxel<br>* administered intravenously<br>Drug: Carboplatin<br>* administered intravenously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Number of participants with adverse events (AEs) | Number of participants with treatment-emergent adverse events (TEAEs), serious adverse events (SAEs ), and experiencing AEs meeting protocol defined Dose-Limiting Toxicity (DLT) criteria. | approximately 6 months | 
| Dose Escalation: Maximum tolerated dose (MTD) of BGB-24714 as monotherapy, in combination with chemotherapy, and in combination with concurrent chemoradiotherapy (cCRT) |  | approximately 6 months | 
| Dose Escalation: Recommended Doses for Expansion (RDFE) of BGB-24714 as monotherapy, in combination with chemotherapy, and in combination with concurrent chemoradiotherapy (cCRT) | Recommended dose based upon the MTD, as well as the long-term tolerability, pharmacokinetics, efficacy, and any other relevant data as available | approximately 6 months | 
| Dose Expansion: Objective response rate (ORR) | ORR is defined as the percentage of participants with partial or complete response, as determined by the investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | approximately 2 Years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation: Objective response rate (ORR) | ORR is defined as the percentage of participants with partial or complete response, as determined by the investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | approximately 2 Years | 
| Dose Expansion: Progression-free Survival (PFS) | PFS is defined as the time from the date of the first dose of study drug to the date of first documentation of disease progression as determined by the investigator using RECIST v1.1 or death, whichever occurs first | approximately 2 Years | 
| Dose Expansion: Number of participants with adverse events | Number of participants with AEs and SAEs | approximately 2 Years | 
| Duration of Response (DOR) | DOR is defined as the time from the date that response criteria are first met to the date that progressive disease is objectively documented or death, whichever comes first as determined by the investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | approximately 2 Years | 
| Disease Control Rate (DCR) | DCR is defined as the percentage of participants whose best overall response is complete response, partial response, or stable disease, as determined by the investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) | approximately 2 Years | 
| Plasma concentration of BGB-24714 |  | approximately 2 Years | 
| Plasma Concentrations of BGB-24714 metabolite |  | approximately 2 Years | 
| Maximum Observed Plasma Concentration (Cmax) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 
| Time to Maximum Plasma Concentration (Tmax) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 
| Terminal Half-life (t1/2) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 
| Area Under the Plasma Concentration Time Curve from Time 0 to the Last Quantifiable Concentration (AUC0-last) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 
| Area Under The Plasma Concentration Time Curve From Time 0 To Infinity (AUC0-inf) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 
| Apparent Clearance (CL/F) of BGB-24714 |  | Up to 48 hours postdose | 
| Apparent Volume Of Distribution (Vz/F) of BGB-24714 |  | Up to 48 hours postdose | 
| Concentration at steady state (Cmax,ss) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 
| Time to Maximum Plasma Concentration at steady state (Tmax,ss) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 
| Area Under the Plasma Concentration Time Curve from Time 0 to the Last Quantifiable Concentration at Steady State (AUClast,ss) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 
| rough Concentration At Steady State (Ctrough,ss) of BGB-24714 and its metabolite |  | Up to 48 hours postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumors, Advanced Solid Tumors, Metastatic Solid Tumors