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Tumor pharmacokinetics and pharmacodynamics of the CDK4/6 inhibitor ribociclib in patients with recurrent glioblastoma

  • Todd W. Miller
  • Nicole A. Traphagen
  • Jing Li
  • Lionel D. Lewis
  • Beatriz Lopes
  • Ashok Asthagiri
  • Johanna Loomba
  • Jenny De Jong
  • David Schiff
  • Sohil H. Patel
  • Benjamin W. Purow
  • Camilo E. FadulEmail author
Clinical Study

Abstract

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.

Keywords

Glioblastoma CDK4 CDK6 Pharmacokinetics 

Notes

Funding

Supported by Novartis Pharmaceuticals, which provided research grant funding and drug for the study, and the Norris Cotton Cancer Center, which provided funding to TWM. SHP has grant support from the Radiologic Society of North America, Research Scholar Grant (Grant No. RSCH1819).

Compliance with ethical standards

Conflict of interest

The University of Virginia (CEF) received research funding from Novartis Pharmaceuticals to conduct this clinical study. All other authors declare that they have no conflicts of interest.

Ethical approval

This study (NCT02345824) was approved by the local Institutional Review Board for Health Sciences Research (IRB approval #18729), was conducted in accordance with Good Clinical Practice, and was monitored by the Data Safety and Monitoring Committee of the University of Virginia Cancer Center. The FDA (IND #125168) approved the IND application for this study. Informed consent was obtained from all individual participants included in the study, prior to performing any study related procedures. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Supplementary material

11060_2019_3258_MOESM1_ESM.docx (269 kb)
Supplementary file1 (DOCX 269 kb)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Todd W. Miller
    • 1
  • Nicole A. Traphagen
    • 1
  • Jing Li
    • 2
  • Lionel D. Lewis
    • 3
  • Beatriz Lopes
    • 4
  • Ashok Asthagiri
    • 5
  • Johanna Loomba
    • 5
  • Jenny De Jong
    • 5
  • David Schiff
    • 6
  • Sohil H. Patel
    • 7
  • Benjamin W. Purow
    • 6
  • Camilo E. Fadul
    • 6
    Email author
  1. 1.Department of Molecular & Systems Biology, Norris Cotton Cancer CenterGeisel School of Medicine At DartmouthLebanonUSA
  2. 2.Pharmacology Core, Karmanos Cancer InstituteWayne State UniversityDetroitUSA
  3. 3.Section of Clinical Pharmacology, Department of Medicine, Norris Cotton Cancer CenterGeisel School of Medicine At DartmouthLebanonUSA
  4. 4.Department of Pathology, Divisions of Neuropathology and Molecular DiagnosticsUniversity of Virginia Health SystemCharlottesvilleUSA
  5. 5.Department of Neurological SurgeryUniversity of Virginia Health SystemCharlottesvilleUSA
  6. 6.Department of Neurology, Division of Neuro-OncologyUniversity of Virginia Health SystemCharlottesvilleUSA
  7. 7.Department of Radiology and Medical Imaging, Division of NeuroradiologyUniversity of Virginia Health SystemCharlottesvilleUSA

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