Phase-2 trial of palbociclib in adult patients with recurrent RB1-positive glioblastoma

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01227434.

Keywords: CDK4/6 inhibitor; Palbociclib; Recurrent glioblastoma; Retinoblastoma pathway.

Figure 1:. Progression free and overall survival.

(A) demonstrates progression free survival with median of 5.14 weeks (range 5 days – 142 weeks) and (B) overall survival with median of 15.4 weeks (range 2 – 274 weeks) for all evaluable patients

Figure 2:. Palbociclib exposure had no consistent effects on RB1 expression.

A and B are representative of immunohistochemical staining of RB1 expression for patient PD107 (A) at baseline (77%) and (B) after pre-surgical palbociclib (31%). (C) Quantification of RB1 expression for 5 patients who underwent resection demonstrating variable impact on protein expression. Median RB1 at baseline for all patients was 70.9% (range 2.6% – 97.8%)