A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study

A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study
Low grade gliomas (LGGs) are the most common type of brain tumor in children with excellent overall survival. Still, patients with incomplete resection and treatment/tumor progression can be affected with significant morbidity. MAP kinase pathway overexpression was commonly encountered (BRAF V600E mutation and BRAF:KIAA1549 fusion are the most commonly described). Selumetinib is an oral MEK inhibitor (downstream from BRAF in MAPK pathway), which has shown efficacy in xenografts and adults (for pediatrics, see recent NEJM article). This is the phase 1 study for selumetinib in LGG to describe the toxicity profile, phase 2 dose recommendation and pharmacokinetics.
Patients between 3-21 years of age with pathologically proven LGG were included who have been treated with 1 or more previous regimens. Patients with optic pathway gliomas and prior BRAF or MEK inhibitors treatment were excluded.
Pharmacokinetics were measured after the first dose of selumetinib. Pathology specimens were tested for MAPK pathway activation using immunohistochemistry for ERK (downstream from BRAF). Where possible, FISH was done to look for BRAF fusion and PCR was done to look for BRAF mutation.
Thirty-eight patients were enrolled on the study. Most patients had pilocytic astrocytoma (n=22) and were previously treated with chemotherapy (n=20) or chemotherapy plus radiation (n=18). All patients with pathology evaluated (n=20) had evidence of MAPK activation with IHC positive for ERK. 25 mg/m2/dose were identified as the recommended dose for phase 2 with 3/24 patients experiencing DLTs (all were over 12 years of age, and rash, diarrhea and elevated CPK being the most common).
There were 5 PRs at the recommended dose level (3 with BRAF fusion or mutation, 1 with both - fusion and mutation - and 1 with tissue that could not be evaluated). Seventeen patients progressed (7 while on treatment, 10 after discontinuing selumetinib. Median follow up in patients who did NOT progress was 7.7 months.
PK values were consistent through different doses and age groups.
There is no standard for measuring response to LGG through different studies. Another limitation is that not all patients had tissue to characterize the method of activation of MAPK pathway. The authors only screened for the most common alterations. This may be important given that previous studies have demonstrated paradoxical activation of the MAPK pathway with progression seen in patients with BRAF fusion who are given a BRAF inhibitor (i.e. dabrafenib), however this did not seem to be the case in this trial.
Selumetinib is tolerable in children, and the RP2D is 25 mg/m2/dose. Some activity was seen although further studies are needed with stratification based on type of alteration and NF-1 status.