The Ivy Brain Tumor Center at the Barrow Neurological Institute recently completed a Phase 0 clinical trial of the breast cancer drug ribociclib (Kisqali) for the treatment of recurrent glioblastoma. The Ivy recently received $50 million to combat brain cancer. This new drug cocktail represents one of the potential weapons in humankind’s war against this killer disease.
The study assessed the central nervous system (CNS) pharmacokinetics and tumor pharmacodynamics of ribociiclib, a highly selective CDK4/6-inhibitor, in patients with recurrent glioblastoma.
The study team design included recurrent glioblastoma patients with intact retinoblastoma protein (RB) expression and CDKN2A deletion or CDK4/6 amplification, which were treated with ribociclib daily (900 mg) for 5 days total and unbound ribociclib concentrations were determined. Pharmacodynamic effects, assessed by RB and FOXM1 phosphorylation, were compared to matched archival tissue. Patients with positive pharmacokinetic and pharmacodynamic effects were enrolled in the expansion cohort for preliminary assessment of progression-free survival (PFS).
Twelve patients were enrolled. The mean unbound ribociclib concentrations in CSF, non-enhancing, and enhancing tumor regions were 0.374 µM, 0.560, and 2.152 µmol/kg, respectively, which were > 5-fold the in vitro IC50 for inhibition of CDK4/6 (0.04 µM). 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 in 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.
Principal Investigator Comments
Dr. Nader Sanai commented “Glioblastoma presents singular, complex challenges as compared to other types of cancer.” He continued, “You are not dealing with a single entity, but rather a collection of genetic variants that differ from patient to patient. This Phase 0 clinical trial used a precision medicine approach to uncover which subtypes of glioblastoma may respond to ribociclib and how our patients’ tumors developed resistance to the new therapy.”
What is Ribociclib?
Ribociclib (trade name Kisqali) is an inhibitor of cyclin D1/CDK4 and CDK6 and is used for the treatment of certain kinds of breast cancer. It is also being studied as a treatment for other drug-resistant cancers. It was developed by Novartis and Astex Pharmaceuticals.
Dr. Nader Sanai, Director of the Ivy Brain Tumor CenterSource: American Association for Cancer Research