The cyclin-dependent kinase (CDK) 4/6 inhibitors have demonstrated marked survival advantage for women with breast cancer, and now, a body of research is examining the effect of these powerful small molecules in glioblastoma.
A phase 0 study of ribociclib in patients with recurrent glioblastoma, conducted at the Barrow Neurological Institute, Phoenix, Arizona, is helping unlock important principles about the treatment and pharmacokinetics of CDK 4/6 inhibitors in these deadly brain tumors.1
Central to the disease pathology of glioblastoma is dysregulation of CDK 4/6, and homozygous mutation of retinoblastoma tumor suppressor (RB). The advent of CDK 4/6 inhibitor therapy in preclinical glioblastoma studies has shown a decrease in phosphorylation of RB, leading to arrested growth in the G1 phase of the cell cycle, ultimately resulting in halted cellular growth.2
Nadar Sanai, MD, director of the Ivy Brain Tumor Center at Barrow Neurologic Institute and lead author of the study, commented on the path to discovery leading up to this study: “The CDK 4/6 inhibitors had compelling early data in breast cancer and based on the drug and mechanism of action, it became obvious that these agents were relevant to targets for the treatment of glioblastoma.”
This pharmacokinetics trial for grade IV recurrent glioblastoma included an expansion therapeutic cohort for patients who showed tumor response. Eligible subjects were identified via genomic screening to uncover the presence of variants, including RB-positive cells and amplification of CDK4 or CDK6. Pharmacokinetic analyses were completed across all relevant sample mediums; concentrations of ribociclib were tested in plasma, cerebrospinal fluid (CSF), and tumor tissue.
A phase 0 design is a unique approach to clinical trials in brain tumors. “This study is an example of a tissue-based trial design … [for central nervous system tumors there] are 2 major obstacles of the blood-brain barrier and the limitation of reliable and accurate animal modeling,” stated Dr Sanai. This type of phase 0 study allows us to humanize the model and see effects on tissue modulation. That helps highlight the most effective strategies in progress to late-phase studies and randomized clinical trials.”