Study of Safety, Pharmacokinetics, and Antitumor Activity of BGB-3245 in Participants With Advanced or Refractory Tumors

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, and antitumor activity of BGB-3245 in participants with advanced or refractory solid tumors

Official Title
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A First-in-Human, Phase 1a/1b, Open Label, Dose-Escalation and Expansion Study to Investigate the Safety, Pharmacokinetics, and Antitumor Activity of the RAF Dimer Inhibitor BGB-3245 in Patients With Advanced or Refractory Tumors

Conditions
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Solid Tumor, B-Raf Mutation-Related Tumors

Intervention / Treatment
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* Drug: BGB-3245


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Participants with histologically confirmed advanced or metastatic solid tumor who had disease progression during or after systemic anticancer therapies that previously demonstrated clinical benefit (eg, improved survival) in a representative population, or are unable to receive standard therapy(ies). In addition, participants must meet the following eligibility criteria for the corresponding phase of the study: Phase 1a: participants with a known mutation status and tumor harboring an oncogenic mutation of the v-RAF murine sarcoma viral oncogene homolog B (BRAF) gene (the mutations of primary interest are the BRAF Class II mutation, Class III mutation or BRAF fusion). In addition, participants with tumors harboring the mutation of the neuroblastoma RAS viral oncogene homolog (NRAS) gene or the Kirsten rat sarcoma virus oncogene homolog (KRAS) are eligible for Part 1a. For participants with KRAS mutations, tumor types of colorectal cancer (CRC) and pancreatic cancer are excluded. Phase 1b: participants must have a known mutation status and meet one of the following criteria according to the group they are enrolled into: I. Group 1: participants with tumor types other than CRC that harbor BRAF V600 mutations who have been treated and progressed on prior BRAF and/or mitogen activated protein kinase (MEK) inhibition. a. Participants must have received the last dose of prior BRAF and/or MEK inhibitor therapy within 90 days of initiation of BGB-3245 study treatment (Cycle 1 Day 1) II. Group 2: participants with advanced solid tumors harboring a BRAF Class II mutation or a BRAF fusion mutation. Participants must provide archival tumor tissue or agree to a fresh tumor biopsy for mutation and biomarkers analysis (fresh tumor biopsies are strongly recommended) Participants must have radiologically measurable disease as defined by RECIST v1.1 Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 Adequate organ function and no transfusions within 14 days of first dose Key Exclusion Criteria : Participants receiving cancer therapy (chemotherapy or other systemic anticancer therapies, immunotherapy, radiation therapy, or surgery) at the time of Cycle 1 Day 1. All participants who have received prior systemic anticancer treatment within the following time frames will be excluded: Systemic chemotherapy within 4 weeks or 6 weeks for nitrosourea, mitomycin prior to Cycle 1 Day 1; and Biologic therapy (i.e., antibodies), continuous or intermittent small-molecule therapies, or any other investigational agents within a period of 5 times the half-life of the agent or ≤4 weeks (whichever is shorter) prior to Cycle 1 Day 1. Severe or uncontrolled systemic disease. Clinically significant cardiac disease within 6 months of signing the ICF CNS metastases, leptomeningeal carcinomatosis or untreated spinal cord compression. Inability to swallow oral medicines. Any unstable, preexisting major medical condition, including known human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Systemic anti-cancer therapy within 2 weeks or 5 half-lives before first dose. Major surgical procedure or significant traumatic injury within 4 weeks prior to the first dose or anticipates need for major surgery while on study. 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: Phase 1a: Dose Escalation<br>BGB-3245 administered orally (PO) | Drug: BGB-3245<br>* administered orally (PO)<br>|
| Experimental: Phase 1b, Group 1: Dose Expansion<br>BGB-3245 administered orally (PO) | Drug: BGB-3245<br>* administered orally (PO)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Number of Participants and Severity Experiencing Adverse Events (AEs) |  | Up to 30 days after the last dose of study drug | 
| Phase 1a: Number of Participants and Severity Experiencing Serious Adverse Events (SAEs) |  | Up to 30 days after the last dose of study drug | 
| Phase 1a: number of Participants Experiencing AEs meeting protocol defined Dose-Limiting Toxicity (DLT) criteria |  | From Cycle 1 Day to the end of Cycle 1 (Cycle 1 is 30 days) | 
| Phase 1a: Maximum Tolerated Dose (MTD) of BGB-3245, and the recommended Phase 2 Dose (RP2D) for BGB-3245 | The MTD is defined as the highest dose evaluated for which the estimated toxicity rate is closest to the target toxicity rate of 33%. | From Cycle 1 Day to the end of Cycle 1 (Cycle 1 is 30 days) | 
| Phase 1b: Recommended Phase 2 dose (RP2D) of BGB-3245 | The highest dose evaluated for which the estimated toxicity rate is closest to the target toxicity rate of 33% | From Cycle 1 Day to the end of Cycle 1 (Cycle 1 is 30 days) | 
| Phase 1b: Objective Response Rate (ORR) as assessed by the investigator |  | Up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1a: Overall Response Rate (ORR) as Assessed by the Investigator |  | Up to 24 months | 
| Phase 1a: Duration of Response (DOR) as Assessed by the Investigator |  | Up to 24 months | 
| Phase 1a: Clinical Benefit Rate (CBR) as Assessed by the Investigator |  | Up to 24 months | 
| Phase 1a: Best Overall Response (BOR) as Assessed by the Investigator |  | Up to 24 months | 
| Phase 1a: Duration of Stable Disease (DSD) |  | Up to 24 months | 
| Phase 1a: Progression Free Survival (PFS) |  | Up to 24 months | 
| Phase 1a: Plasma Concentration of BGB-3245 |  | Within 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Maximum Observed Plasma Concentration (Cmax) of BGB-3245 |  | Within 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Time to Maximum Plasma Concentration (Tmax) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Time Taken for Half the Initial Dose Administered To Be Eliminated From The Body (T1/2) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Area Under the Concentration-Time Curve of 0-infinity Days (AUC0-inf) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1a:Area Under the Concentration-Time Curve of 0-Last hour (AUC0-last) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Drug Clearance (CL/F) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Apparent Volume of Distribution (Vz/F) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Steady State Area Under the Concentration-Time Curve of 0- Last hour (AUCLast, ss) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Steady State Maximum Observed Plasma Concentration (Cmax, ss) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1a: Steady State Time to Maximum Plasma Concentration (Tmax, ss) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 
| Phase 1b: Progression-free survival (PFS) as Assessed by the Investigator |  | Up to 36 months | 
| Phase 1b: Duration of Response (DOR) as Assessed by the Investigator |  | Up to 24 months | 
| Phase 1b: Disease-Control Rate (DCR) as Assessed by the Investigator |  | Up to 24 months | 
| Phase 1b: Duration of Stable Disease (DSD) as Assessed by the Investigator |  | Up to 24 months | 
| Phase 1b: Clinical Benefit Rate (CBR) as Assessed by the Investigator |  | Up to 24 months | 
| Phase 1b: Overall Survival |  | Up to 36 months | 
| Phase 1b: Number of Participants Experiencing Adverse Events (AEs) |  | Up to 30 days after the last dose of study drug | 
| Phase 1b: Number of Participants Experiencing Serious Adverse Events (SAEs) |  | Up to 30 days after the last dose of study drug | 
| Phase 1b: Plasma Concentration of BGB-3245 |  | 60 minutes predose up to 3 hours postdose | 
| Phase 1b: Steady State Trough Observed Plasma Concentration (Ctrough, SS) of BGB-3245 |  | 60 minutes predose up to 72 hours postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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BGB3245, BRAF inhibitor, BRAF, KRAS, NRAS, Mitogen Activated Protein Kinase (MAPK) Pathway, BRAF fusion, BRAF Class II