Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma. J Neurooncol 2019 Sep;144(3):563-572
Date
08/11/2019Pubmed ID
31399936Pubmed Central ID
PMC6863163DOI
10.1007/s11060-019-03258-0Scopus ID
2-s2.0-85070279150 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
INTRODUCTION: We conducted a phase Ib study (NCT02345824) to determine whether ribociclib, an inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6), penetrates tumor tissue and modulates downstream signaling pathways including retinoblastoma protein (Rb) in patients with recurrent glioblastoma (GBM).
METHODS: Study participants received ribociclib (600 mg QD) for 8-21 days before surgical resection of their recurrent GBM. Total and unbound concentrations of ribociclib were measured in samples of tumor tissue, plasma, and cerebrospinal fluid (CSF). We analyzed tumor specimens obtained from the first (initial/pre-study) and second (recurrent/on-study) surgery by immunohistochemistry for Rb status and downstream signaling of CDK4/6 inhibition. Participants with Rb-positive recurrent tumors continued ribociclib treatment on a 21-day-on, 7-day-off schedule after surgery, and were monitored for toxicity and disease progression.
RESULTS: Three participants with recurrent Rb-positive GBM participated in this study. Mean unbound (pharmacologically active) ribociclib concentrations in plasma, CSF, MRI-enhancing, MRI-non-enhancing, and tumor core regions were 0.337 μM, 0.632 μM, 1.242 nmol/g, 0.484 nmol/g, and 1.526 nmol/g, respectively, which exceeded the in vitro IC50 (0.04 μM) for inhibition of CDK4/6 in cell-free assay. Modulation of pharmacodynamic markers of ribociclib CDK 4/6 inhibition in tumor tissues were inconsistent between study participants. No participants experienced serious adverse events, but all experienced early disease progression.
CONCLUSIONS: This study suggests that ribociclib penetrated recurrent GBM tissue at concentrations predicted to be therapeutically beneficial. Our study was unable to demonstrate tumor pharmacodynamic correlates of drug activity. Although well tolerated, ribociclib monotherapy seemed ineffective for the treatment of recurrent GBM.
Author List
Miller TW, Traphagen NA, Li J, Lewis LD, Lopes B, Asthagiri A, Loomba J, De Jong J, Schiff D, Patel SH, Purow BW, Fadul CEAuthor
Todd W. Miller PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged, 80 and over
Aminopyridines
Biomarkers, Tumor
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Glioblastoma
Humans
Male
Middle Aged
Neoplasm Recurrence, Local
Prognosis
Purines
Survival Rate
Tissue Distribution
