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

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

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

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.