A Phase I Study of PLX8394 Plus Ritonavir in Children with Recurrent or Progressive BRAF Activated Gliomas

Principal Institutions: Children’s Hospital of Los Angeles in partnership with the Pediatric Brain Tumor Consortium (PBTC) – This trial launches the first combinatorial drug agent trial for children with BRAF mutations. The majority of LGG have abnormal signaling through the mitogen-activated protein kinase (MAPK) pathway, usually due to activation of BRAF. The most common activating BRAF alteration in LGG is a tandem duplication that results in BRAF-KIAA1549 fusion, which is seen in 70-84% of pilocytic astrocytomas, the most common  subtype of pediatric LGG. The BRAFV600e point mutation is another activating alteration seen in 10% of pilocytic astrocytomas and up to 66% of pleomorphic xanthroastrocytomas.  LGG with BRAF activation have shown responses to newer agents targeting members of the MAPK pathway. PBTC recently presented preliminary results of a multi-institutional phase II study of selumetinib, a MEK I/II inhibitor, in children with recurrent/refractory LGG. Thirty-two percent of those with BRAF activated tumors achieved a partial response (PR) with a 2-year progression free survival (PFS) of 66+/-11% (29% of tumors with a BRAFV600e mutation and 33% of those with a BRAF-KIAA1549 fusion achieved a PR). These results support the development of additional targeted agents for the treatment of BRAF activated LGG.

The use of first-generation BRAF inhibitors such as dabrafenib and vemurafenib in the treatment of BRAFV600e mutated malignancies including gliomas has shown striking tumor regression and prolonged progression-free survival (PFS) and overall survival (OS). While the experience in pediatrics remains limited, there is concern for development of resistance to these medications similar to that observed in adult melanoma patients.

PLX8394 is a next-generation, orally available, small-molecule inhibitor of mutated BRAF. Xenograft models show that PLX8394 has similar efficacy in inducing regression of BRAFV600e mutated tumors compared to vemurafenib [Figure 1] and has been demonstrated to overcome resistance when tested in relevant vemurafenib-resistant cell lines. Combining this with drugs such as low-dose ritonavir and cobicistat act as potent inhibitors of CYP3A, the body’s major drug-metabolizing enzyme, and are used as a PK enhancers or boosting agents to increase the systemic levels of co-administered agents metabolized by this enzyme system Inhibition of CYP3A-mediated metabolism of PLX8394 by a boosting agent may increase the systemic exposure of PLX8394, potentially increasing its effectiveness on BRAF activated tumors.