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

Phase 1TerminatedNCT04249843

MapKure, LLC109 enrolled

Overview

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

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

109

Conditions

Solid Tumor B-Raf Mutation-Related Tumors

Interventions

BrimarafenibDRUG

administered orally (PO) once daily at doses specified in the description of each arm

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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 exclusion criteria may have applied.

Locations (9)

Cedars Sinai Medical Center

Beverly Hills, California, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Outcomes

Primary Outcomes

Phase 1a: Number of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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.

Time frame: From first dose up to 30 days after the last dose of study treatment. Maximum treatment duration was 47 months.

Phase 1a: Maximum Tolerated Dose (MTD) of Brimarafenib

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%).

Time frame: From first dose through the end of Cycle 1 (approximately 30 days)

Phase 1b: Recommended Phase 2 Dose (RP2D) Confirmation

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.

Time frame: From first dose of study drug through last dose (maximum treatment duration in Phase 1b was 25 months)

Phase 1b: Objective Response Rate (ORR)

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)

Time frame: From first dose until disease progression or death, Maximum treatment duration was 25 months.

Secondary Outcomes

Phase 1a: ORR

Data from ClinicalTrials.gov

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Houston, Texas, United States

University of Virginia Comprehensive Cancer Centre

Charlottesville, Virginia, United States

Blacktown Hospital

Blacktown, New South Wales, Australia

The Kinghorn Cancer Centre, St Vincent Hospital Sydney

Sydney, New South Wales, Australia

One Clinical Research

Nedlands, Perth, Australia

Peter MacCallum Cancer Centre

Melbourne, Victoria, Australia

Time frame: From first dose until disease progression or death, Maximum treatment duration was 47 months.

Duration of Response (DOR)

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.

Time frame: 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)

CBR is defined as the percentage of participants with confirmed CR, PR, or durable stable disease (stable disease ≥ 24 weeks).

Time frame: From first dose until disease progression or death, Maximum treatment duration was 47 months.

Progression-free Survival (PFS)

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.

Time frame: 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)

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.

Time frame: 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)

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.

Time frame: From first dose until death, maximum treatment duration was 25 months.

Phase 1b: Overall Survival (OS)

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.

Time frame: From first dose until death, assessed maximum treatment duration was 25 months.

Phase 1a: Trough Plasma Concentration (Ctrough) of Brimarafenib

Ctrough is the observed concentration at predose.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: Cycle 1 Day 1 (predose and 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours postdose)

Phase 1b: Plasma Concentrations for Brimarafenib

Time frame: 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)

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.

Time frame: From first dose until 30 days after last dose of study treatment. Maximum treatment duration was 25 months.