A Phase I and Surgical Study of Ribociclib and Everolimus in Children with Recurrent or Refractory Malignant Brain Tumors: A Pediatric Brain Tumor Consortium Study

Abstract

Purpose: Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the maximum tolerated dose (MTD)/Recommended phase 2 Dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection. Experimental Design: Patients enrolled in the Phase I study according to a rolling 6-design and received ribociclib and everolimus daily for 21 and 28 days, respectively. Surgical patients received ribociclib at the pediatric RP2D (350 mg/m²) for 7-10 days pre-operatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts. Results: Sixteen patients enrolled on the phase I study (median age 10.3 years; range: 3.9-20.4) and 6 on the surgical cohort (median age 11.4 years; range: 7.2-17.1). Thirteen patients enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the three patients at dose level 2 experienced DLT (grade 3 hypertension and grade 4 ALT). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leucopenia. The RP2D of ribociclib and everolimus was 120 mg/m² and 1.2 mg/ m² for 21 and 28 days, respectively. Steady state everolimus exposures with ribociclib were 2.5-fold higher than everolimus administered alone. Ribociclib plasma, tumor concentrations and CSF samples were collected. The mean tumor-to-plasma ratio of ribociclib was 19.8 (range: 2.22- 53.4). Conclusions: Ribociclib and everolimus were well tolerated and demonstrated similar pharmacokinetic properties as in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.