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

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, Judith E. Karp, Omer N. Koc, Brenda W. Cooper, Selina M. Luger, A. Dimitrios Colevas, John D. Roberts, Steven Grant

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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.

Original languageEnglish
Pages (from-to)1657-1667
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume69
Issue number6
DOIs
Publication statusPublished - 2012 Jun 1

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Keywords

  • Alvocidib
  • Bcr-Abl
  • CDK inhibitor
  • Cyclin-dependent kinase inhibitor
  • Flavopiridol
  • Imatinib
  • Tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Bose, P., Perkins, E. B., Honeycut, C., Wellons, M. D., Stefan, T., Jacobberger, J. W., Kontopodis, E., Beumer, J. H., Egorin, M. J., Imamura, C. K., Figg, W. D., Karp, J. E., Koc, O. N., Cooper, B. W., Luger, S. M., Colevas, A. D., Roberts, J. D., & Grant, S. (2012). Phase i trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl + hematological malignancies. Cancer Chemotherapy and Pharmacology, 69(6), 1657-1667. https://doi.org/10.1007/s00280-012-1839-5