347 Efficacy of Dasatinib in Targeting Diffuse Intrinsic Pontine Glioma (DIPG) Specific Pathway Activation in Vitro

70% of pediatric DIPG and 50% of HGG patients, suggesting that inhibition of this pathway may be of clinical benefit. Crenolanib is a highly selective and potent antagonist of the PDGF pathway with in vitro IC50 of 35and 185-fold lower than observed with Dasatanib and Imatinib, respectively. Methods: We are conducting a Phase I study using rolling-6 design of crenolanib during and after local RT in children with DIPG, and in recurrent/progressive HGG. We are presently accruing patients to the second dose level (130mg/m) in ND-DIPG receiving concurrent RT (Stratum A), and to the fourth dose level (220mg/m) for the recurrent/ progressive HGG (Stratum B). The dose-limiting toxicity (DLT) evaluation period was comprised by the first 8 weeks of therapy (Stratum A) and the first 4 weeks of therapy (Stratum B). Serum pharmacokinetic studies were performed on all patients on days 1 and 28 of course 1, and for select patients on day 28 of cycles 3 and 5 both on and off dexamethasone therapy. Pharmacodynamic and mutational analyses of peripheral blood mononuclear cells and tumor tissue are ongoing. Tumor autopsy studies are also being conducted to attempt to establish cell lines from a subset of patients that will be used for investigation of mechanisms of drug resistance and pharmacodynamic modulation of PDGF pathway. Results: Thirty-three patients have been enrolled on study (Stratum A: n = 12 at 100mg/m2, n = 6 at 130mg/m2; Stratum B: n = 3 at 100, n = 6 at 130 and n = 4 at 170, n = 2 at 220mg/m2), with anticipated accrual of 54 patients. One patient in Stratum A experienced neutropenia (Grade 4) and no DLTs have yet been observed in Stratum B. The most common Grade 3 toxicity seen in a subset of patients is leucopenia that resolves with drug interruption. Mild (Grade 2) elevation in liver enzymes was observed in fewer than 15% of patients. The maximum tolerated dose (MTD) has not yet been reached in either cohort and we have exceeded the adult MTD of 340mg/day in Stratum B patients. On day 1, median crenolanib AUC0−∞ values for 100mg/m dosage were 7997 nM*hr (2971−16,207) for Stratum A and Stratum B combined, which is comparable to adult Phase I data. We have successfully established cell lines from autopsy tissue at intervals of >36 hours post mortem. Conclusions: While the MTD has not yet been reached in this ‘first in pediatrics’ study, the PK and current preliminary toxicity data indicate that crenolanib is well tolerated in children (age 21 years) at doses approaching (Stratum A) and exceeding (Stratum B) the established MTD from Phase I trial in adults (200mg/day). The spectrum of toxicities observed in children differs from those observed in adults.