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

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

Authors and Affiliations

  • Prithviraj Bose
    • 1
    • 2
  • Edward B. Perkins
    • 1
    • 2
  • Connie Honeycut
    • 1
  • Martha D. Wellons
    • 1
  • Tammy Stefan
    • 13
  • James W. Jacobberger
    • 13
  • Emmanouil Kontopodis
    • 6
    • 7
  • Jan H. Beumer
    • 7
    • 8
    • 9
  • Merrill J. Egorin
    • 7
    • 10
    • 11
  • Chiyo K. Imamura
    • 18
  • W. Douglas FiggSr.
    • 12
  • Judith E. Karp
    • 14
  • Omer N. Koc
    • 15
  • Brenda W. Cooper
    • 13
  • Selina M. Luger
    • 16
  • A. Dimitrios Colevas
    • 17
  • John D. Roberts
    • 1
    • 2
  • Steven Grant
    • 1
    • 2
    • 3
    • 4
    • 5
    • 19
  1. 1.Massey Cancer CenterVirginia Commonwealth UniversityRichmondUSA
  2. 2.Department of Internal MedicineVirginia Commonwealth UniversityRichmondUSA
  3. 3.Department of Microbiology and ImmunologyVirginia Commonwealth UniversityRichmondUSA
  4. 4.Department of Biochemistry and Molecular BiologyVirginia Commonwealth UniversityRichmondUSA
  5. 5.The Institute for Molecular MedicineVirginia Commonwealth UniversityRichmondUSA
  6. 6.Department of Medical OncologyUniversity Hospital of HeraklionHeraklionGreece
  7. 7.The Molecular Therapeutics/Drug Discovery ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  8. 8.The Molecular Therapeutics/Melanoma ProgramUniversity of Pittsburgh Cancer InstitutePittsburghUSA
  9. 9.The Department of Pharmaceutical SciencesUniversity of Pittsburgh School of PharmacyPittsburghUSA
  10. 10.Department of MedicineUniversity of Pittsburgh School of MedicinePittsburghUSA
  11. 11.Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA
  12. 12.Molecular Pharmacology Section and Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer ResearchNational Cancer Institute/National Institutes of HealthBethesdaUSA
  13. 13.Case Comprehensive Cancer CenterCase Western Reserve UniversityClevelandUSA
  14. 14.Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins UniversityBaltimoreUSA
  15. 15.Department of Regional OncologyCleveland Clinic Taussig Cancer InstituteClevelandUSA
  16. 16.Division of Hematology–OncologyUniversity of PennsylvaniaPhiladelphiaUSA
  17. 17.Stanford University Medical CenterStanfordUSA
  18. 18.Department of Clinical Pharmacokinetics and Pharmacodynamics, School of MedicineKeio UniversityTokyoJapan
  19. 19.Virginia Commonwealth UniversityRichmondUSA