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Proffered Paper – CNS tumours

4361 - A Phase 0/2 Clinical Trial of a CDK4/6 Inhibitor in Aggressive Meningioma Patients

Date

27 Sep 2019

Session

Proffered Paper – CNS tumours

Topics

Tumour Site

Central Nervous System Malignancies

Presenters

Nader Sanai

Citation

Annals of Oncology (2019) 30 (suppl_5): v143-v158. 10.1093/annonc/mdz243

Authors

N. Sanai1, A. Tien1, J. Li2, X. Bao2, A. DeRogatis1, Y. Fujita1, C. Pennington-Krygier1, S. Kim3, S. Mehta1

Author affiliations

  • 1 Ivy Brain Tumor Center, Barrow Neurological Institute, 85013 - Phoenix/US
  • 2 Pharmacology Core, Karmanos Cancer Institute, 48201 - Detroit/US
  • 3 Oncology, Karmanos Cancer Institute, 48201 - Detroit/US

Resources

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Abstract 4361

Background

New approaches are urgently needed for aggressive meningiomas, which remain largely incurable. Forkhead Box M1 (FOXM1) has been identified as a master transcription factor in aggressive meningiomas and Cyclin D-dependent Kinases (CDK) are positive regulators of cell-cycle entry, promoting tumorigenesis through FOXM1 activation. We evaluated the tumor pharmacokinetics (PK), tumor pharmacodynamics (PD), and preliminary clinical response of ribociclib, a selective CDK4/6-inhibitor, in aggressive meningioma patients.

Methods

Eight aggressive WHO Grade II/III meningioma patients with intact RB expression were enrolled and administered oral ribociclib daily (900mg) for 5 days prior to tumor resection. Plasma, tumor, and cerebrospinal fluid (CSF) samples were collected at 2, 8, or 24 h after the last dose. Total and unbound drug concentrations were determined using a validated LC-MS/MS method. PD effects, including RB and FoxM1 phosphorylation, were compared to matched archival tissue. Patients with PK and PD responses in tumor tissue, defined as unbound ribociclib concentration > 5-fold in vitro IC50 (0.04 µM) and >20% decrease in pRB levels, respectively, were enrolled into an exploratory phase 2 cohort.

Results

The median CSF concentration of ribociclib was 0.25 µM. In tumor tissue, the median unbound ribociclib concentration was 1.36 µM and the median unbound tumor-to-plasma ratio was 5.34. Suppression of G1-to-S phase was inferred in tumors with declining FoxM1 phosphorylation (50%), RB phosphorylation (38%), and cellular proliferation (75%). Four patients demonstrated concurrent PK and PD responses and were graduated to continuous ribociclib therapy. At one year, two of these patients (one Grade II and one Grade III) demonstrate partial responses per RANO criteria.

Conclusions

Ribociclib achieves pharmacologically-active concentrations in aggressive meningioma tissue. Target modulation was demonstrated by a decrease in FOXM1-mediated tumor proliferation. Further investigation of ribociclib as a therapeutic strategy for aggressive meningiomas is warranted.

Clinical trial identification

NCT02933736.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

The Ben and Catherine Ivy Foundation.

Disclosure

All authors have declared no conflicts of interest.

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