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