2087 Background: Mutations in growth factor receptors signaling and in Rb pathway characterize MG pathogenesis. PHA-848125 (PHA) is a dual CDK/TRKA oral inhibitor, able to cross the blood brain barrier. It induces autophagy, is active as single agent in glioma models subcutaneously and intracranially implanted and produces a clear therapeutic gain in combination with temozolomide (TMZ) or TMZ + radiotherapy. Methods: Phase I part in adult patients (pts) (13 glioblastoma [GBM], 5 astrocytoma, 3 oligodendroglioma, 1 meningioma) with KPS ≥ 70, not taking enzyme-inducing antiepileptic drugs (EIAEDs), to determine the recommended dose for phase II (RP2D) and dose-limiting toxicity (DLT) of PHA, given orally once daily for 14 days in a 3-week cycle (cy). Cohorts of 3-6 pts received PHA at dose levels of 18 (5 pts), 36 (4 pts), 54 (8 pts) and 72 (5 pts) mg/m2/day. Results: 22 pts were treated for a total of 53 cys (median 3, range 1-6): side effects were dose- dependent and mainly on liver function, starting from 36 mg/m2, with bilirubin and transaminase elevations of grade (gr) 2-3, and becoming dose-limiting at 72 mg/m2. Other effects were gr 1-2 tremors, diarrhea, nausea and vomiting and mild hematologic toxicity (occasionally severe). Two DLTs occurred at 72 mg/m2: one gr 4 PLT decrease and one prolonged gr 3 ALT elevation. The RP2D was defined as 54 mg/m2 (8 pts, 21 cys), its toxicity consisting mainly in reversible tremors (2 pts, max gr 2) and in transaminase elevations (5 pts, max gr 3). Two pts remained on study for 6 cys. PK data indicate that exposure proportionally increased with dose, with Cmax at 2.5h (median) and half-life of 30-40 h. Day 14/day 1 AUC (0- 24h) ratio was around 3. At RP2D, day 14 AUC (0-24h) was 15.4 μ M·h (CV: 34%) and Cmax 0.86 μ M. Phase II part in recurrent GBM is ongoing (8 pts treated, 1 pt progression-free at 6 months). A 6-pt cohort treated with EIAEDs is also underway. Conclusions: PHA shows mild/moderate, reversible and manageable toxicity at the RP2D of 54 mg/m2. Transaminase elevation is dose limiting. Side effects are in line with the already known toxicity pattern, with a more pronounced effect on liver with this 14-day on/7-day off schedule. PK data are predictable and highly reproducible across studies. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Accelera, Nerviano Medical Sciences