LTBK-04. PHASE 1 TRIAL OF WEE1 KINASE INHIBITOR ADAVOSERTIB (AZD1775) COMBINED WITH RADIATION THERAPY FOR CHILDREN WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA: A REPORT FROM THE CHILDREN’S ONCOLOGY GROUP PHASE 1 PILOT CONSORTIUM (ADVL1217)

Abstract OBJECTIVES Children with diffuse intrinsic pontine glioma (DIPG) continue to have dismal outcomes. AZD1775 is an orally available inhibitor of Wee1 kinase, a key G2-M checkpoint regulator that has been shown to cross the blood brain barrier and has demonstrated efficacy in preclinical studies of DIPG. METHODS AZD1775 was administered orally once daily to children with newly diagnosed DIPG, only on days of radiation therapy (30 fractions of 180cGy over 6 weeks). The protocol assessed 7 dose levels (DL) starting from 50 mg/m2/dose and escalated up to 200 mg/m2/dose, the maximal planned dose level. Dose escalation occurred first by the number of days on which AZD1775 was administered followed by an increase in daily dosing. The entire length of radiation therapy constituted the dose limiting toxicity (DLT) period. Correlative studies included pharmacokinetic (PK) analyses as well as determination of expression of p-CDC2, p-HH3 and γ-H2AX in peripheral blood mononuclear cells (PBMC). RESULTS As of July 31, 2018 a total of 45 subjects were enrolled. Overall, 7 subjects (1 at each dose level) were inevaluable for DLT assessment due insufficient drug exposure. Median age for enrolled patients was 6 years (range 3–21 years) and 53% were female. The combination of AZD1775 and radiation was well tolerated with predominantly grade 1 and 2 toxicities. Only two dose limiting toxicities have occurred to date (DL 4: Grade 3 ALT elevation; DL 7: Grade 4 neutropenia). PK analysis to date shows a median (range) T1/2 of 4.4 h (1.8–6.5 hours; N=34) and oral clearance of 41 L/h/m2 (18–118 L/h/m2; N=34). There was no evidence of significant accumulation. Analysis of p-CDC2, p-HH3, and γ-H2AX of the first 3 DLs showed no consistent changes in PBMCs. CONCLUSION The combination of Wee1 kinase inhibitor AZD1775 and focal radiation therapy is well tolerated in this ongoing trial.