Abstract
BACKGROUND
Vemurafenib is an orally available, selective ATP-competitive inhibitor of BRAF-V600E kinase, approved in adult metastatic melanoma patients with the V600E mutation. This study was designed to determine the recommended phase 2 dose (RP2D) in patients < 18yrs with BRAF-V600E mutant brain tumors.
METHODS
Vemurafenib was given orally, beginning at the adult dose equivalent of 550 mg/m2, twice daily. Toxicity, pharmacokinetics, and response were assessed. Doses of 420 mg/m2 and 550 mg/m2 were assessed by a 3 + 3 design in a dose de-escalation study.
RESULTS
Enrollment for phase 1 completed at 19 patients, 9 male, median age 9 years (range 4–17), with pilocytic astrocytoma (n=10), and ganglioglioma (n=5) the most common histologies. Grade 3/4 adverse events judged related to vemurafenib included secondary keratoacanthoma (n=1); rash (n=16); hyponatremia (n=1), hepatic enzyme elevations (n=4) and fever (n=5). We initially found dose limiting toxicities (DLT’s) of rash (2 of 3 patients at 550 mg/m2; and 2 of 3 patients at 420 mg/m2). As these rashes resolved shortly after holding drug with appropriate supportive care, we subsequently amended the study to exclude resolving rash as a DLT. Under the new DLT definitions, no further DLT’s were found. Duration on treatment ranged from 2 to 31 months (ongoing); 12 patients remain on treatment. The RP2D for patients < 18 yrs is 550 mg/m2 twice daily. Investigator-assessed best radiographic responses included 1 complete response, 2 partial responses, and 15 stable disease (source data verification ongoing).
CONCLUSIONS
The RP2D of vemurafenib for children < 18 yrs was determined to be 550 mg/m2 twice daily. The drug was well tolerated with manageable toxicity. The proportion of patients with responses and stable disease warrant continued evaluation of vemurafenib in patients with BRAF V600 mutated gliomas. The phase 2 component of the study is underway (NCT01748149).