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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 发起方
- MapKure, LLC
- 入组人数
- 109
- 试验地点
- 18
- 主要终点
- Phase 1a: Number of Participants and Severity Experiencing Adverse Events (AEs)
研究概览
简要总结
This Phase 1a/1b study evaluated the safety, pharmacokinetics, and preliminary antitumor activity of the investigational oral RAF dimer inhibitor BGB-3245 (brimarafenib) in participants with advanced or refractory solid tumors. Dose escalation evaluated safety/tolerability and informed dose selection. Dose expansion evaluated activity in molecularly defined tumor subsets
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants had histologically confirmed advanced or metastatic solid tumors and experienced disease progression during or after systemic anticancer therapies that previously demonstrated clinical benefit (improved survival) in a representative population, or were unable to receive standard therapy. In addition, participants had to meet the eligibility criteria for the corresponding phase of the study:
- •Phase 1a: Participants had a known mutation status and tumors harboring an oncogenic mutation of the BRAF gene. The mutations of primary interest were BRAF Class II mutations, Class III mutations, or BRAF fusions. In addition, participants with tumors harboring mutations of the neuroblastoma RAS viral oncogene homolog (NRAS) gene or the Kirsten rat sarcoma virus oncogene homolog (KRAS) gene were eligible for Phase 1a. For participants with KRAS mutations, tumor types of colorectal cancer (CRC) and pancreatic cancer were excluded.
- •Phase 1b: Participants had a known mutation status and met one of the following criteria according to the group in which they were enrolled:
- •Group 1: Participants with tumor types other than CRC that harbored BRAF V600 mutations and who had been treated and progressed on prior BRAF and/or mitogen-activated protein kinase (MEK) inhibition.
- •Group 2: Participants with advanced solid tumors harboring a BRAF Class II mutation or a BRAF fusion mutation.
- •Group 2 BRAF Fusion Expansion: Participants with advanced solid tumors harboring a BRAF fusion mutation.
- •Participants provided archival tumor tissue or agreed to a fresh tumor biopsy for mutation and biomarker analysis. Fresh tumor biopsies were strongly recommended.
- •Participants had radiologically measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
- •Participants had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤
- •Participants demonstrated adequate organ function and had not received blood transfusions within 14 days prior to the first dose of study drug.
排除标准
- •Participants were receiving cancer therapy (chemotherapy or other systemic anticancer therapies, immunotherapy, radiation therapy, or surgery) at the time of Cycle 1 Day
- •Participants who had received prior systemic anticancer treatment within the following time frames were excluded:
- •Systemic chemotherapy within 4 weeks, or 6 weeks for nitrosourea or mitomycin, prior to Cycle 1 Day
- •Biologic therapy (e.g., monoclonal antibodies), continuous or intermittent small-molecule therapies, or any other investigational agents within a period of five times the half-life of the agent or ≤4 weeks (whichever was shorter) prior to Cycle 1 Day
- •Participants with severe or uncontrolled systemic disease.
- •Participants with clinically significant cardiac disease within 6 months of signing the informed consent form (ICF).
- •Participants with central nervous system (CNS) metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression.
- •Participants with any unstable, preexisting major medical condition, including known human immunodeficiency virus (HIV) infection, or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- •Participants who received systemic anticancer therapy within 2 weeks or five half-lives before the first dose.
- •Participants who underwent a major surgical procedure or significant traumatic injury within 4 weeks prior to the first dose, or who anticipated the need for major surgery while on study.
- •Note: Additional protocol-defined inclusion or exclusion criteria may have applied.
研究组 & 干预措施
Phase 1a: Brimarafenib 5 mg
Participants received brimarafenib 5 mg orally on Day 1 and then daily from Day 4 onwards. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1a: Brimarafenib 10 mg
Participants received brimarafenib 10 mg orally on Day 1 and then daily from Day 4 onwards. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1b: Group 1 (Brimarafenib 25 mg)
Participants with solid tumors harboring B-Raf Proto-Oncogene, Serine/Threonine Kinase (BRAF) V600 mutations (excluding colorectal cancer [CRC]) who had progressed on prior BRAF and/or MEK (mitogen-activated protein kinase) inhibition were randomized to receive 25 mg of brimarafenib once daily. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1a: Brimarafenib 60 mg
Participants received brimarafenib 60 mg orally on Day 1 and then daily from Day 4 onwards. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1b: Group 1 (Brimarafenib 40 mg Non-Randomized)
Participants with solid tumors harboring BRAF V600 mutations (excluding CRC) enrolled under Protocol Version 4.0 were treated with 40 mg of brimarafenib once daily without randomization. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1b: Group 1 (Brimarafenib 40 mg Randomized)
Participants with solid tumors harboring BRAF V600 mutations (excluding CRC) who had progressed on prior BRAF and/or MEK inhibition were randomized to receive 40 mg of brimarafenib once daily. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1a: Brimarafenib 40 mg
Participants received brimarafenib 40 mg orally on Day 1 and then daily from Day 4 onwards. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1a: Brimarafenib 25 mg
Participants received brimarafenib 25 mg orally on Day 1 and then daily from Day 4 onwards. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1b: Group 2 (Brimarafenib 40 mg)
Participants with advanced solid tumors harboring BRAF Class II mutations or a BRAF fusion mutation were treated with 40 mg of brimarafenib once daily. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
Phase 1a: Brimarafenib 15 mg
Participants received brimarafenib 15 mg orally on Day 1 and then daily from Day 4 onwards. Participants continued treatment until disease progression, unacceptable toxicity, or study completion.
干预措施: Brimarafenib (Drug)
结局指标
主要结局
Phase 1a: Number of Participants and Severity Experiencing Adverse Events (AEs)
时间窗: Up to 30 days after the last dose of study drug
Phase 1a: Number of Participants and Severity Experiencing Serious Adverse Events (SAEs)
时间窗: 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
时间窗: 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
时间窗: From Cycle 1 Day to the end of Cycle 1 (Cycle 1 is 30 days)
The MTD is defined as the highest dose evaluated for which the estimated toxicity rate is closest to the target toxicity rate of 33%.
Phase 1b: Recommended Phase 2 dose (RP2D) of BGB-3245
时间窗: From Cycle 1 Day to the end of Cycle 1 (Cycle 1 is 30 days)
The highest dose evaluated for which the estimated toxicity rate is closest to the target toxicity rate of 33%
Phase 1b: Objective Response Rate (ORR) as assessed by the investigator
时间窗: Up to 24 months
ORR is defined as the percentage of participants with partial or complete response, as assessed by the investigator
Phase 1b: Further review of the ORR
时间窗: Up to 24 months
ORR is defined as the percentage of participants with partial or complete response in up to 15 participants with tumors harboring BRAF fusion mutations
Phase 1a: Number of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
时间窗: From first dose up to 30 days after the last dose of study treatment. Maximum treatment duration was 47 months.
SAEs were defined as adverse events that resulted in death, were life-threatening, required or prolonged hospitalization, caused significant disability, or were considered important medical events.
Phase 1a: Maximum Tolerated Dose (MTD) of Brimarafenib
时间窗: From first dose through the end of Cycle 1 (approximately 30 days)
The MTD was determined by the Safety Monitoring Committee (SMC) based on the occurrence of dose-limiting toxicities (DLTs), overall safety, and tolerability. The MTD reflects the dose associated with an acceptable level of toxicity (30%).
Phase 1b: Recommended Phase 2 Dose (RP2D) Confirmation
时间窗: From first dose of study drug through last dose (maximum treatment duration in Phase 1b was 25 months)
The optimal RP2D was to be determined based on safety, tolerability, efficacy, and pharmacokinetic (PK) data obtained from participants treated with the two dose levels tested in Phase 1b (25 mg and 40 mg). The RP2D could not be determined since the study was terminated early.
Phase 1b: Objective Response Rate (ORR)
时间窗: From first dose until disease progression or death, Maximum treatment duration was 25 months.
ORR was defined as the percentage of participants who achieved a best overall response of complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST v1.1)
次要结局
- Phase 1a: Apparent Volume of Distribution (Vz/F) of BGB-3245(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: Progression Free Survival (PFS)(Up to 24 months)
- Phase 1a: Drug Clearance (CL/F) of BGB-3245(60 minutes predose up to 72 hours postdose)
- Phase 1b: Duration of Stable Disease (DSD) as Assessed by the Investigator(Up to 24 months)
- 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: Plasma Concentration of BGB-3245(Within 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: 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: Number of Participants Experiencing Serious Adverse Events (SAEs)(Up to 30 days after the last dose of study drug)
- Phase 1a: Duration of Stable Disease (DSD)(Up to 24 months)
- Phase 1b: Clinical Benefit Rate (CBR) 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: 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 1b: Duration of Response (DOR) as Assessed by the Investigator(Up to 24 months)
- Phase 1b: Number of Participants Experiencing Adverse Events (AEs)(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)
- Phase 1a: Best Overall Response (BOR) as Assessed by the Investigator(Up to 24 months)
- 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: Steady State Maximum Observed Plasma Concentration (Cmax, ss) of BGB-3245(60 minutes predose up to 72 hours postdose)
- Phase 1b: Disease-Control Rate (DCR) as Assessed by the Investigator(Up to 24 months)
- Phase 1b: Overall Survival(Up to 36 months)
- Phase 1a: ORR(From first dose until disease progression or death, Maximum treatment duration was 47 months.)
- Duration of Response (DOR)(From first dose until disease progression or death, Maximum treatment duration was 47 months in Phase 1a and 25 months in Phase 1b.)
- Clinical Benefit Rate (CBR)(From first dose until disease progression or death, Maximum treatment duration was 47 months.)
- Progression-free Survival (PFS)(From first dose until disease progression or death, Maximum treatment duration was 47 months Phase 1a and 25 months in Phase 1b.)
- Duration of Stable Disease (DSD)(From first dose until disease progression or death, Maximum treatment duration was 47 months Phase 1a and 25 months in Phase 1b.)
- Phase 1b: Disease Control Rate (DCR)(From first dose until death, maximum treatment duration was 25 months.)
- Phase 1b: Overall Survival (OS)(From first dose until death, assessed maximum treatment duration was 25 months.)
- Phase 1a: Trough Plasma Concentration (Ctrough) of Brimarafenib(Predose on Cycle 1 Day 15; Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1. Each cycle was 28 days.)
- Phase 1a: Area Under the Concentration-time Curve From Dosing to Time of Last Quantifiable Concentration (AUClast) of Brimarafenib(Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, and 8 hours postdose); Cycle 1 Days 2, 3, 4, 8, and 15; Cycle 2 Day 1 (predose and 1, 2, 3, 4, 6, and 8 hours postdose))
- Phase 1a: Area Under the Concentration-time Curve From Dosing Time to Time Tau (Tau=24 Hours) of Brimarafenib(Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, 8, and 24 hours postdose))
- Phase 1a: Area Under the Concentration-time Curve From Dosing Extrapolated to Infinity (AUC0-inf) of Brimarafenib(Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours postdose))
- Phase 1a: Maximum Observed Plasma Concentration (Cmax) of Brimarafenib(Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours postdose); Cycle 2 Day 1 (predose and 1, 2, 3, 4, 6, and 8 hours postdose))
- Phase 1a: Time to Maximum Observed Plasma Concentration (Tmax) of Brimarafenib(Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, a 8, 24, 48, and 72 hours postdose); Cycle 2 Day 1 (predose and 1, 2, 3, 4, 6, and 8 hours postdose))
- Phase 1a: Elimination Half-Life (t½) of Brimarafenib(Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours postdose))
- Phase 1a: Apparent Oral Clearance (CL/F) of Brimarafenib(Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours postdose))
- Phase 1a: Apparent Oral Volume of Distribution (Vz/F) of Brimarafenib(Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours postdose))
- Phase 1b: Plasma Concentrations for Brimarafenib(C1D1 (predose, 1, 3h postdose); C1D3, D8, D22 (±2d; predose, 2-4h postdose on D22); C2D1 (predose, 1, 3h); C3, 4, 6, 8, 10, 12 D1 and every 3rd cycle (predose); and at treatment discontinuation (2-4h).)
- Phase 1b: Number of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)(From first dose until 30 days after last dose of study treatment. Maximum treatment duration was 25 months.)