B-Raf Mutation-Related Tumors, Solid Tumor
Conditions
Keywords
BGB3245, BRAF inhibitor, BRAF, KRAS, NRAS, Mitogen Activated Protein Kinase (MAPK) Pathway, BRAF fusion, BRAF Class II
Brief summary
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
Interventions
DRUGBrimarafenib
administered orally (PO) once daily at doses specified in the description of each arm
Sponsors
MapKure, LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria 1. 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: 1. 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. 2. 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. 2. Participants provided archival tumor tissue or agreed to a fresh tumor biopsy for mutation and biomarker analysis. Fresh tumor biopsies were strongly recommended. 3. Participants had radiologically measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). 4. Participants had an Eastern Cooperative Oncology Group (ECOG) performance status of ≤1. 5. Participants demonstrated adequate organ function and had not received blood transfusions within 14 days prior to the first dose of study drug. Key
Exclusion criteria
1. Participants were receiving cancer therapy (chemotherapy or other systemic anticancer therapies, immunotherapy, radiation therapy, or surgery) at the time of Cycle 1 Day 1. 2. Participants who had received prior systemic anticancer treatment within the following time frames were excluded: 1. Systemic chemotherapy within 4 weeks, or 6 weeks for nitrosourea or mitomycin, prior to Cycle 1 Day 1. 2. 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 1. 3. Participants with severe or uncontrolled systemic disease. 4. Participants with clinically significant cardiac disease within 6 months of signing the informed consent form (ICF). 5. Participants with central nervous system (CNS) metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. 6. 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. 7. Participants who received systemic anticancer therapy within 2 weeks or five half-lives before the first dose. 8. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a: Maximum Tolerated Dose (MTD) of Brimarafenib | 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 | 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 1a: Number of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | 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 1b: Objective Response Rate (ORR) | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | PFS was defined as the time from randomization to the date of first documented disease progression per RECIST v1.1 or death from any cause, whichever occurred first. Median PFS was estimated using the Kaplan-Meier method. |
| 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. | DSD is defined as the time interval, in the absence of either confirmed CR or PR, between the date of the first administration of study drug and the first documented disease progression per RECIST v1.1 or death due to any cause, whichever occurred first. |
| Phase 1b: Disease Control Rate (DCR) | From first dose until death, maximum treatment duration was 25 months. | DCR is defined as the percentage of participants with a best overall response of CR, PR, or SD per RECIST v1.1 criteria. DCR reflects the percentage of participants whose disease did not progress during the study, including those with confirmed responses and those with durable SD. |
| Phase 1b: Overall Survival (OS) | From first dose until death, assessed maximum treatment duration was 25 months. | OS was defined as the time from randomization to the date of death from any cause. Median OS was estimated using the Kaplan-Meier method. |
| 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. | Ctrough is the observed concentration at predose. |
| 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. | SAEs were defined as events that resulted in death, were life-threatening, required or prolonged hospitalization, caused significant disability, or were considered important medical events. |
| Phase 1a: ORR | From first dose until disease progression or death, Maximum treatment duration was 47 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) |
| 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. | DOR was defined as the time from the date that a confirmed response (CR or PR) was first observed per RECIST 1.1 to the date of first documented disease progression or death, whichever occurred first. Median DOR was estimated using the Kaplan-Meier method. |
| Clinical Benefit Rate (CBR) | From first dose until disease progression or death, Maximum treatment duration was 47 months. | CBR is defined as the percentage of participants with confirmed CR, PR, or durable stable disease (stable disease ≥ 24 weeks). |
Countries
Australia, United States
Participant flow
Recruitment details
Participants were enrolled at 9 study sites in the United States and Australia. The study consisted of a dose escalation part (Phase 1a) and a dose expansion part (Phase 1b). The Phase 1b part of the study closed early, before all planned participants were enrolled."
Pre-assignment details
Participants in Phase 1a were enrolled sequentially in cohorts of increasing doses of brimarafenib. In Phase 1b, participants in Group 1 who enrolled under Protocol Amendment 6 or 7 (from 17 Apr 2023) were randomized equally to receive 25 mg or 40 mg brimarafenib; participants enrolled prior to Protocol Amendment 6 were assigned to receive 40 mg brimarafenib in a non-randomized fashion. In Phase 1b Group 2, participants were assigned to receive 40 mg brimarafenib.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 58.9 years STANDARD_DEVIATION 13.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 7 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants |
| Race/Ethnicity, Customized Multiple | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Not Reported/Unknown | 1 Participants |
| Race/Ethnicity, Customized White | 90 Participants |
| Region of Enrollment Australia | 41 participants |
| Region of Enrollment United States | 68 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 6 Participants |
| The Eastern Cooperative Oncology Group (ECOG) Performance Status 0 (fully Active) | 53 Participants |
| The Eastern Cooperative Oncology Group (ECOG) Performance Status 1 (Limited strenuous activity; light work possible) | 51 Participants |
| The Eastern Cooperative Oncology Group (ECOG) Performance Status Missing | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 4 | 5 / 12 | 2 / 7 | 2 / 7 | 3 / 8 | 2 / 4 | 3 / 13 | 5 / 14 | 1 / 6 | 19 / 34 |
| other Total, other adverse events | 4 / 4 | 12 / 12 | 7 / 7 | 7 / 7 | 8 / 8 | 4 / 4 | 12 / 13 | 14 / 14 | 6 / 6 | 34 / 34 |
| serious Total, serious adverse events | 2 / 4 | 8 / 12 | 5 / 7 | 3 / 7 | 5 / 8 | 4 / 4 | 8 / 13 | 6 / 14 | 4 / 6 | 30 / 34 |
Outcome results
None listed