Cancer Chemotherapy and Pharmacology

, Volume 69, Issue 6, pp 1657–1667 | Cite as

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

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

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

Notes

Acknowledgments

The authors would like to acknowledge Mary Beth Tombes, R. N., M. N. for assistance in preparing the manuscript tables, Lora Kramer for the Western blot figure, Sookyung Woo and Shawn Spencer for the manuscript and supplemental sections on flavopiridol pharmacokinetics and Brian J. Druker, Director, Knight Cancer Institute, Oregon Health and Science University, for performing correlative studies on characterization of mechanisms of resistance to imatinib in patients previously treated with imatinib. This work was supported by the following NIH grants: R01 CA93738-05, CA 100866, and R21 CA106139, NCI Cooperative Agreement U01 CA70095, Massey Cancer Center Support Grant P30 CA016059, General Clinical Research Center Grant M01 RR00065, Leukemia and Lymphoma Society of America award 6181-10, Multiple Myeloma Research Foundation, Myeloma SPORE award 1P50CA142509, and Lymphoma SPORE award 1P50CA130805. EK was supported by a scholarship from the Hellenic Society of Medical Oncology. JHB and MJE were supported by grant P30-CA47904 from the National Cancer Institute. MJE was the recipient of an American Society of Clinical Oncology Cancer Foundation Translational Research Professorship.

Conflict of interest

JHB discloses having received research support from Novartis. None of the other authors have any conflicts of interest relevant to this article to disclose.

Supplementary material

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

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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

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