Study of Plixorafenib in Cancers with BRAF Gene Mutations

In cancer, the body’s cells grow and divide uncontrollably. This is caused, among other things, by changes in specific sections of the genome (gene mutations) that normally control cell growth and division. The BRAF gene contains the blueprint for a protein that transmits information in the so-called MAPK signaling pathway. This signaling pathway is involved in regulating cell division and cell growth. If the BRAF gene is altered, the BRAF protein can remain permanently active and stimulate the cell to multiply uncontrollably. BRAF alterations have been described in various solid tumors—cancers that form a solid mass of tissue—as well as in tumors of the central nervous system (CNS, brain, and spinal cord), which include low-grade (LGG) and high-grade gliomas (HGG). Depending on the type of tumor, treatment options may include surgery, radiation therapy, and chemotherapy, among others. Plixorafenib (also known as FORE8394) is a novel anticancer drug administered as a tablet. It acts as a so-called selective BRAF inhibitor, which is designed to specifically block the mutated BRAF protein and thereby inhibit the signaling pathways responsible for tumor growth. Plixorafenib targets both the BRAF V600E mutation and BRAF fusions, another form of BRAF alteration. The goal of the Phase 2 study is to investigate the efficacy and safety of the BRAF inhibitor containing the active ingredient plixorafenib in patients with solid tumors harboring BRAF alterations (BRAF V600E mutation or BRAF fusion). To this end, patients will be assigned to four parallel study arms (subprotocols A through D). Assignment is not random but is based on tumor type and BRAF alteration. Study arm A includes advanced solid tumors and CNS tumors with a BRAF fusion; study arm B includes recurrent CNS tumors (relapse) with a BRAF V600E mutation; Study arm C includes advanced rare solid tumors outside the CNS with a BRAF V600E mutation, including anaplastic thyroid cancer, ovarian cancer, and bile duct cancer; and Study Arm D includes other advanced solid tumors with a BRAF V600E mutation that do not qualify for any of the other study arms. The study provides the same treatment with plixorafenib for all patients; there is no comparison group (uncontrolled). Plixorafenib is taken as a tablet. The study is open-label (unblinded), which means that both patients and study physicians know which medication is being administered. Treatment will continue until the disease progresses, the patient can no longer tolerate it, or another reason for discontinuation arises. Patients aged 8 years or older who weigh at least 25 kilograms and in whom a solid tumor or a CNS tumor has been confirmed by histopathological examination and a BRAF alteration (BRAF V600E mutation or BRAF fusion) has been confirmed. Depending on the study arm (A–D), another requirement is that available standard therapies have already been used, are not tolerated, or are not suitable. Patients who are already receiving certain targeted drugs that act on the same signaling pathway, among others, are ineligible to participate.