A Phase 0 Trial of Ribociclib in Recurrent Glioblastoma Patients Incorporating a Tumor Pharmacodynamic- and Pharmacokinetic-Guided Expansion Cohort

Clin Cancer Res. 2019 Oct 1;25(19):5777-5786. doi: 10.1158/1078-0432.CCR-19-0133. Epub 2019 Jul 8.


Purpose: CDK4/6-dependent cell-cycle regulation is disrupted in most glioblastomas. This study assesses the central nervous system (CNS) pharmacokinetics and tumor pharmacodynamics of ribociclib, a highly selective CDK4/6 inhibitor, in patients with recurrent glioblastoma.

Patients and methods: Patients with recurrent glioblastoma with intact retinoblastoma protein (RB) expression and CDKN2A deletion or CDK4/6 amplification were treated with ribociclib daily (900 mg) for 5 days before tumor resection. Blood, tumor, and cerebrospinal fluid (CSF) samples were collected, and total and unbound ribociclib concentrations were determined. Pharmacodynamic effects, assessed by RB and FOXM1 phosphorylation, were compared with matched archival tissue. Patients with positive pharmacokinetic and pharmacodynamic effects were enrolled into the expansion cohort for preliminary assessment of progression-free survival (PFS).

Results: Twelve patients were enrolled. The mean unbound ribociclib concentrations in CSF, nonenhancing, and enhancing tumor regions were 0.374 μmol/L, 0.560, and 2.152 μmol/kg, respectively, which were more than 5-fold the in vitro IC50 for inhibition of CDK4/6 (0.04 μmol/L). G1-to-S phase suppression was inferred by decreases in phosphorylation of RB (P < 0.01) and cellular proliferation (P < 0.05). Six of 12 patients were enrolled into the pharmacokinetic/pharmacodynamic-guided expansion cohort and demonstrated a median PFS of 9.7 weeks. Examination of recurrent tumors following monotherapy indicated upregulation of the PI3K/mTOR pathway.

Conclusions: Ribociclib exhibited good CNS penetration, and target modulation was indicated by inhibition of RB phosphorylation and tumor proliferation. Ribociclib monotherapy showed limited clinical efficacy in patients with recurrent glioblastoma. Combination therapy with CDK4/6 and PI3K/mTOR inhibitors may be explored for treating recurrent glioblastoma.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aminopyridines / pharmacokinetics
  • Aminopyridines / pharmacology
  • Aminopyridines / therapeutic use*
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Cell Proliferation
  • Cohort Studies
  • Female
  • Glioblastoma / drug therapy*
  • Glioblastoma / metabolism
  • Glioblastoma / pathology
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / metabolism
  • Neoplasm Recurrence, Local / pathology
  • Phosphorylation
  • Progression-Free Survival
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Purines / pharmacokinetics
  • Purines / pharmacology
  • Purines / therapeutic use*
  • Retinoblastoma Binding Proteins / metabolism
  • Tissue Distribution
  • Ubiquitin-Protein Ligases / metabolism
  • Young Adult


  • Aminopyridines
  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • Purines
  • RB1 protein, human
  • Retinoblastoma Binding Proteins
  • Ubiquitin-Protein Ligases
  • ribociclib