ATNT-12: PHASE I, TWO-STAGE, OPEN-LABEL, DOSE-ESCALATION STUDY OF BUPARLISIB (BKM120) IN COMBINATION WITH ADJUVANT TEMOZOLOMIDE (TMZ) AND WITH CONCOMITANT RADIATION THERAPY (RT) AND TMZ IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA (GBM)

BACKGROUND: Phase I, two-stage study of buparlisib combined with standard-of-care (RT + TMZ followed by adjuvant TMZ) in newly diagnosed GBM. METHODS: Stage I evaluated buparlisib with adjuvant TMZ in 28-day treatment cycles after prior RT + TMZ treatment. Stage II evaluated buparlisib with concomitant RT + TMZ and then adjuvant TMZ. In the concomitant phase, buparlisib was administered at two schedules: 60mg/40mg/QD or 40mg D1–5/Q7, in combination with RT (2.5 Gy/day) + TMZ 75mg/m²/day over 42 days. In the adjuvant phase, buparlisib was administered at 80mg/QD during Cycle 1 with TMZ 150mg/m² D1–D5/Q28 (A1), and at 60mg/80mg/QD during Cycles 2–12 with TMZ 200mg/m² on D1–D5/Q28 (A2). Dose-escalation was guided by a Bayesian logistic regression model with overdose control principle. Primary study objectives were to identify buparlisib dose-limiting toxicities (DLTs) and to determine the recommended Phase II dose (RP2D). RESULTS: Adjuvant: Of 16 patients treated, six developed DLTs, including three DLTs in A1: Grade(G) 3-hyperglycemia, G3-anxiety, G3-intermittent confusion (1 patient each) at 80mg/QD; and three in A2: G2-hyperglycemia (1 patient) at 60mg/QD, G4-platelet count decrease and G4-thrombocytopenia (1 patient each) at 80mg/QD. Concomitant: Of 22 patients treated, seven developed DLTs: G4-thrombocytopenia (2 patients) at 60mg/QD, G4-lipase elevation (2 patients) and G2-thrombocytopenia (1 patient) at 40mg/QD, G3-decreased mood (1 patient) and G4-decreased platelet count (1 patient) at 40mg D1–5/Q7. Twenty-three patients (60.5%) experienced study-drug-related G3/4 adverse events (AEs) including hyperglycemia, neutropenia, thrombocytopenia (13.2% each), and lipase increase (10.5%). Twenty-nine patients discontinued treatment due to AEs (44.7%), disease progression (26.3%), and withdrawal of consent (5.3%). CONCLUSION: RP2D of buparlisib for the adjuvant phase in combination with TMZ was defined as 80mg/QD. RP2D of buparlisib plus RT + TMZ was not determined due to challenging safety at all doses/schedules. Exposure of buparlisib with RT + TMZ was slightly lower than that of single-agent buparlisib. Anti-tumor activity is under evaluation and will be reported.