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

Mariko D. DeWire*, Christine Fuller, Olivia Campagne, Tong Lin, Haitao Pan, Tina Young Poussaint, Patricia A. Baxter, Eugene I. Hwang, Andrew Bukowinski, Kathleen Dorris, Lindsey Hoffman, Angela J. Waanders, Matthias A. Karajannis, Clinton F. Stewart, Arzu Onar-Thomas, Maryam Fouladi, Ira J. Dunkel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose: Genomic aberrations in cell cycle and PI3K pathways are commonly observed in pediatric brain tumors. This study determined the MTD/recommended phase II dose (RP2D) of ribociclib and everolimus and characterized single-agent ribociclib concentrations in plasma and tumor in children undergoing resection. Patients and Methods: Patients were 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 preoperatively followed by enrollment on the phase I study. Pharmacokinetics were analyzed for both cohorts. Results: Sixteen patients were enrolled on the phase I study (median age, 10.3 years; range, 3.9–20.4) and 6 patients in the surgical cohort (median age, 11.4 years; range: 7.2–17.1). Thirteen patients were enrolled at dose level 1 without dose-limiting toxicities (DLT). Two of the 3 patients at dose level 2 experienced DLTs (grade 3 hypertension and grade 4 alanine aminotransferase). The most common grade 3/4 toxicities were lymphopenia, neutropenia, and leukopenia. The RP2D of ribociclib and everolimus was 120 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 cerebrospinal fluid (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 pharmacokinetic properties similar to those in adults. Potential therapeutic ribociclib concentrations could be achieved in CSF and tumor tissue, although interpatient variability was observed.

Original languageEnglish (US)
Pages (from-to)2442-2451
Number of pages10
JournalClinical Cancer Research
Volume27
Issue number9
DOIs
StatePublished - May 1 2021
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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