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Cancer Chemotherapy and Pharmacology
Published in: Cancer Chemotherapy and Pharmacology 6/2012

01-06-2012 | Clinical Trial Report

Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies

Authors: Prithviraj Bose, Edward B. Perkins, Connie Honeycut, Martha D. Wellons, Tammy Stefan, James W. Jacobberger, Emmanouil Kontopodis, Jan H. Beumer, Merrill J. Egorin, Chiyo K. Imamura, W. Douglas Figg Sr., Judith E. Karp, Omer N. Koc, Brenda W. Cooper, Selina M. Luger, A. Dimitrios Colevas, John D. Roberts, Steven Grant

Published in: Cancer Chemotherapy and Pharmacology | Issue 6/2012

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Abstract

Purpose

Imatinib is an inhibitor of the Bcr-Abl tyrosine kinase; however, resistance is common. Flavopiridol, a cyclin-dependent kinase (CDK) inhibitor, down-regulates short-lived anti-apoptotic proteins via inhibition of transcription. In preclinical studies, flavopiridol synergizes with imatinib to induce apoptosis. We investigated this novel combination regimen in patients with Bcr-Abl+ malignancies.

Methods

In a phase I dose-escalation study, imatinib was administered orally daily, and flavopiridol by 1 h intravenous infusion weekly for 3 weeks every 4 weeks. Adults with chronic myelogenous leukemia or Philadelphia chromosome-positive acute leukemia were eligible. Patients were divided into two strata based on peripheral blood and bone marrow blast counts. The primary objective was to identify the recommended phase II doses for the combination. Correlative pharmacokinetic and pharmacodynamic studies were also performed.

Results

A total of 21 patients received study treatment. Four dose levels were evaluated before the study was closed following the approval of the second-generation Bcr-Abl tyrosine kinase inhibitors (TKIs). Five patients responded, including four sustained responses. Four patients had stable disease. All but one responder, and all patients with stable disease had previously been treated with imatinib. One patient had a complete response sustained for 30 months. Changes in expression of phospho-Bcr/Abl, -Stat5, and Mcl-1 were monitored. No major pharmacokinetic interaction was observed.

Conclusions

This is the first study to evaluate the combination of a CDK inhibitor and a TKI in humans. The combination of flavopiridol and imatinib is tolerable and produces encouraging responses, including in some patients with imatinib-resistant disease.
Appendix
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Metadata
Title
Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies
Authors
Prithviraj Bose
Edward B. Perkins
Connie Honeycut
Martha D. Wellons
Tammy Stefan
James W. Jacobberger
Emmanouil Kontopodis
Jan H. Beumer
Merrill J. Egorin
Chiyo K. Imamura
W. Douglas Figg Sr.
Judith E. Karp
Omer N. Koc
Brenda W. Cooper
Selina M. Luger
A. Dimitrios Colevas
John D. Roberts
Steven Grant
Publication date
01-06-2012
Publisher
Springer-Verlag
Published in
Cancer Chemotherapy and Pharmacology / Issue 6/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI
https://doi.org/10.1007/s00280-012-1839-5

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