CTNI-54. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA

Abstract BACKGROUND The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) pharmacodynamics (PD) combined inhibition recurrent HGG patients. METHODS Eligible patients had with (1) RB+, (2) CDKN2A/B deletion or amplification, (3) PTEN loss PIK3CA mutations. Six received five days ribociclib (400mg QD) plus everolimus (2.5mg underwent resection at 2, 8 24 hours following last dose. dose-escalation cohorts (n = 3 each) reached dose-level (600mg (70mg QW). Tumor tissue, CSF, plasma were collected. Total unbound drug concentrations determined using validated LC-MS/MS methods. PD effects compared matched archival tissue. A PK ‘trigger’ (i.e., concentration > 5-fold biochemical IC50) ( >30% decrease both pRB pS6) Gd-nonenhancing tissue set qualify for expansion. RESULTS WHO Grade III 2) IV 22) gliomas enrolled. No dose-limiting toxicities observed. Following presurgical drug, all demonstrated marked Gd-enhancement on preoperative MRI. In regions, median was 561 nM whereas no detected. Across dose-levels, 57% (13/23) 43% (10/23) tumors RB S6 phosphorylation decrease, respectively. CONCLUSION adult HGG, achieves pharmacologically-relevant tumor. Everolimus exhibits limited penetration into human Our supports further development ribociclib, but not everolimus, treatment