Evidence map›Paper›PMID 31399936›Full record

ArticleJournal of neuro-oncology2019

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 and 2 more

Registry-linked trialOpen access · greenAbstract readCase ReportsClinical Trial, Phase I
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuro-oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02345824 (Early-Phase Study to Assess Tumor Pharmacokinetics and Efficacy of the CDK4/6 Inhibitor Ribociclib), which is not on this map. Cited by 34 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
34citing papers in PubMed, 3 pooled it
4.4field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02345824 phase1unknown statusnot on this map

Early-Phase Study to Assess Tumor Pharmacokinetics and Efficacy of the CDK4/6 Inhibitor Ribociclib (LEE011) in Patients With Recurrent Glioblastoma or Anaplastic Glioma

TypeinterventionalSponsorUniversity of VirginiaRan2016 to 2020Enrolled3ConditionsGlioblastoma, GliomaArmsRibociclib
3 · Its place in the literature

Who cites it

34 citing papers in PubMed, 3 syntheses or guidelines pooled it, 50 citations in OpenAlex.

  1. Guideline
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  14. Synthesis and Preclinical Evaluation of NovelACS medicinal chemistry letters · 2024
    Article
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  20. Signaling pathways in brain tumors and therapeutic interventions.Signal transduction and targeted therapy · 2023
    Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 3 institutions in 1 country.

Todd W MillerDepartment of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine At Dartmouth, Lebanon, NH, USA.
Nicole A TraphagenDepartment of Molecular & Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine At Dartmouth, Lebanon, NH, USA.
Jing LiPharmacology Core, Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
Lionel D LewisSection of Clinical Pharmacology, Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine At Dartmouth, Lebanon, NH, USA.
Beatriz LopesDepartment of Pathology, Divisions of Neuropathology and Molecular Diagnostics, University of Virginia Health System, Charlottesville, VA, USA.
Ashok AsthagiriDepartment of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA.
Johanna LoombaDepartment of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA.
Jenny De JongDepartment of Neurological Surgery, University of Virginia Health System, Charlottesville, VA, USA.
David SchiffDepartment of Neurology, Division of Neuro-Oncology, University of Virginia Health System, P.O. Box 800432, Charlottesville, VA, 22908, USA.
Sohil H PatelDepartment of Radiology and Medical Imaging, Division of Neuroradiology, University of Virginia Health System, Charlottesville, VA, USA.
Benjamin W PurowDepartment of Neurology, Division of Neuro-Oncology, University of Virginia Health System, P.O. Box 800432, Charlottesville, VA, 22908, USA.
Camilo E FadulDepartment of Neurology, Division of Neuro-Oncology, University of Virginia Health System, P.O. Box 800432, Charlottesville, VA, 22908, USA. CEF3W@hscmail.mcc.virginia.edu.ORCID http://orcid.org/0000-0001-7459-7661
University of Virginia Health System · USDartmouth College · USWayne State University · US

Funding

Tumor Biology and Microenvironment (Program 1)P30CA022453 · NCI · WAYNE STATE UNIVERSITY · PI Julie Lynn Boerner · 1985 to 2026
$68.4M
NCI NIH HHS P30 CA022453Radiologic Society of North America RSCH1819
6 · The paper itself

Abstract

introductionWe 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).

methodsStudy 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.

resultsThree 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 IC

conclusionsThis 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.

Indexed as

AdultAged, 80 and overAminopyridinesBiomarkers, TumorCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Follow-Up StudiesGene Expression Regulation, NeoplasticGlioblastomaHumansMaleMiddle AgedNeoplasm Recurrence, LocalPrognosisPurinesSurvival RateAminopyridinesBiomarkers, TumorCDK4 protein, humanCDK6 protein, humanCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6PurinesribociclibCDK4CDK6GlioblastomaPharmacokinetics

Identifiers

PMID31399936
PMCPMC6863163
OpenAlexW2968318393

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.