QOLP-34. DOSE FREQUENCY MODIFICATION OF TRAMETINIB TO MITIGATE SEVERE RASH AND IMPROVE QUALITY OF LIFE IN PEDIATRIC LOW-GRADE GLIOMA PATIENTS

Abstract

Abstract Circumscribed low-grade glioma is generally driven by MAP kinase pathway activation, and this discovery motivates use of the non-competitive MEK 1/2 inhibitor trametinib for children and adults with progressive disease. However, rash is a common dose-limiting toxicity with trametinib. Accordingly, we evaluated intermittent, 3-days-on, 1-day-off dosing in an effort to reduce the incidence and severity of rash. Seven patients with MAP-kinase activated low grade glioma were treated with trametinib (6 pilocytic astrocytoma (PA), one desmoplastic infantile ganglioglioma with V600E). Patients initiated treatment at 0.025mg/kg/day up to the maximum adult dosing of 2mg. Three teenage patients with PA were treated with the maximum daily adult dose of 2mg. All three developed a painful, grade 3 acneiform rash within 3 weeks, requiring trametinib hold and treated with topical cleansers and oral antibiotics. One patient discontinued treatment, and two restarted trametinib at a reduced dose (1.5mg) administered 3-days-on and 1-day-off. With this modified dosing, patients experienced no more than grade 1 rash. Two younger patients initiated trametinib with daily dosing, and both developed grade 1 eczematous rash within 3 weeks, progressing to grade 2 in one patient. The rash resolved without recurrence after dose frequency modification to 3-days-on, 1-day-off at the same overall dose. Two younger patients initiated trametinib with 3-days-on, 1-day-off dosing and have not developed a rash. All of the younger patients are currently continuing on therapy with no progression to date. However, both teenage patients developed progressive disease by 11 months into therapy. In conclusion, acneiform rash appears to preferentially impact teenage or young adult patients but can be mitigated with modified dose frequency 3 days on, 1 day off. However, continued assessment is needed to evaluate the effect of dosing frequency modification on treatment response.