INTRODUCTION: Alterations in the CDK4/6-RB signaling pathway are common causes 
of cell cycle dysregulation in many cancers, including glioblastoma. Palbociclib 
is an oral inhibitor of CDK4/6, which leads to phosphorylation of RB1 and 
cell-cycle arrest. We conducted a two-arm study evaluating efficacy and tissue 
pharmacokinetics/pharmacodynamics of palbociclib in patients with recurrent 
glioblastoma.
METHODS: Eligibility criteria included confirmation of RB1 proficiency by IHC; 
≤ 3 relapses; KPS ≥ 60; no limit on prior treatments. Arm 1 received palbociclib 
for 7 days prior to indicated resection followed by adjuvant palbociclib. Arm 2 
received palbociclib without resection. Primary objective was PFS6; secondary 
included toxicity, OS, and ORR. Exploratory aims included biomarker assessment 
and pharmacokinetic/pharmacodynamic effects in surgical patients.
RESULTS: Total of 22 patients were enrolled; 6 on Arm 1 and 16 on Arm 2. Trial 
was stopped early secondary to lack of efficacy, with 95% of evaluable patients 
progressing within 6 months. Median PFS was 5.14 weeks (range 5 days-142 weeks) 
and median OS was 15.4 weeks (range 2-274 weeks). Two patients (10%) had related 
grade ≥ 3 AEs. In Arm 1, 5 patients had tissue concentrations of palbociclib 
felt to be sufficient for biological effect and paired samples available for RB1 
IHC. There were no consistent changes in RB1 expression or cell proliferation in 
the paired tissue.
CONCLUSION: In this trial, despite adequate tissue PK, palbociclib monotherapy 
was not an effective treatment for recurrent glioblastoma. However, these were 
heavily pretreated patients and targeting the CDK4/6 pathway may still deserve 
further exploration.