Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 6, pp 1657–1667

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

Authors

  • Prithviraj Bose
    • Massey Cancer CenterVirginia Commonwealth University
    • Department of Internal MedicineVirginia Commonwealth University
  • Edward B. Perkins
    • Massey Cancer CenterVirginia Commonwealth University
    • Department of Internal MedicineVirginia Commonwealth University
  • Connie Honeycut
    • Massey Cancer CenterVirginia Commonwealth University
  • Martha D. Wellons
    • Massey Cancer CenterVirginia Commonwealth University
  • Tammy Stefan
    • Case Comprehensive Cancer CenterCase Western Reserve University
  • James W. Jacobberger
    • Case Comprehensive Cancer CenterCase Western Reserve University
  • Emmanouil Kontopodis
    • Department of Medical OncologyUniversity Hospital of Heraklion
    • The Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer Institute
  • Jan H. Beumer
    • The Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer Institute
    • The Molecular Therapeutics/Melanoma ProgramUniversity of Pittsburgh Cancer Institute
    • The Department of Pharmaceutical SciencesUniversity of Pittsburgh School of Pharmacy
  • Merrill J. Egorin
    • The Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer Institute
    • Department of MedicineUniversity of Pittsburgh School of Medicine
    • Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of Medicine
  • Chiyo K. Imamura
    • Department of Clinical Pharmacokinetics and Pharmacodynamics, School of MedicineKeio University
  • W. Douglas FiggSr.
    • Molecular Pharmacology Section and Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer ResearchNational Cancer Institute/National Institutes of Health
  • Judith E. Karp
    • Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University
  • Omer N. Koc
    • Department of Regional OncologyCleveland Clinic Taussig Cancer Institute
  • Brenda W. Cooper
    • Case Comprehensive Cancer CenterCase Western Reserve University
  • Selina M. Luger
    • Division of Hematology–OncologyUniversity of Pennsylvania
  • A. Dimitrios Colevas
    • Stanford University Medical Center
  • John D. Roberts
    • Massey Cancer CenterVirginia Commonwealth University
    • Department of Internal MedicineVirginia Commonwealth University
    • Massey Cancer CenterVirginia Commonwealth University
    • Department of Internal MedicineVirginia Commonwealth University
    • Department of Microbiology and ImmunologyVirginia Commonwealth University
    • Department of Biochemistry and Molecular BiologyVirginia Commonwealth University
    • The Institute for Molecular MedicineVirginia Commonwealth University
    • Virginia Commonwealth University
Clinical Trial Report

DOI: 10.1007/s00280-012-1839-5

Cite this article as:
Bose, P., Perkins, E.B., Honeycut, C. et al. Cancer Chemother Pharmacol (2012) 69: 1657. doi:10.1007/s00280-012-1839-5

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.

Keywords

ImatinibFlavopiridolCyclin-dependent kinase inhibitorCDK inhibitorBcr-AblTyrosine kinase inhibitorAlvocidib

Supplementary material

280_2012_1839_MOESM1_ESM.doc (1.2 mb)
Supplementary material 1 (DOC 1261 kb)

Copyright information

© Springer-Verlag 2012