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

  • Clinical Trial Report
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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.

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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.

Author information

Authors and Affiliations

  1. Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    Prithviraj Bose, Edward B. Perkins, Connie Honeycut, Martha D. Wellons, John D. Roberts & Steven Grant

  2. Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA

    Prithviraj Bose, Edward B. Perkins, John D. Roberts & Steven Grant

  3. Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA, USA

    Steven Grant

  4. Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, VA, USA

    Steven Grant

  5. The Institute for Molecular Medicine, Virginia Commonwealth University, Richmond, VA, USA

    Steven Grant

  6. Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece

    Emmanouil Kontopodis

  7. The Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Emmanouil Kontopodis, Jan H. Beumer & Merrill J. Egorin

  8. The Molecular Therapeutics/Melanoma Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    Jan H. Beumer

  9. The Department of Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy, Pittsburgh, PA, USA

    Jan H. Beumer

  10. Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Merrill J. Egorin

  11. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Merrill J. Egorin

  12. Molecular Pharmacology Section and Clinical Pharmacology Program, Medical Oncology Branch, Center for Cancer Research, National Cancer Institute/National Institutes of Health, Bethesda, MD, USA

    W. Douglas Figg Sr.

  13. Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA

    Tammy Stefan, James W. Jacobberger & Brenda W. Cooper

  14. Division of Hematologic Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Judith E. Karp

  15. Department of Regional Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA

    Omer N. Koc

  16. Division of Hematology–Oncology, University of Pennsylvania, Philadelphia, PA, USA

    Selina M. Luger

  17. Stanford University Medical Center, Stanford, CA, USA

    A. Dimitrios Colevas

  18. Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, Tokyo, Japan

    Chiyo K. Imamura

  19. Virginia Commonwealth University, P.O. Box 980035, 401 College St, Richmond, VA, 23298-0230, USA

    Steven Grant

Authors
  1. Prithviraj Bose
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  2. Edward B. Perkins
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  3. Connie Honeycut
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Corresponding author

Correspondence to Steven Grant.

Additional information

Merrill J. Egorin—Deceased.

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Bose, P., Perkins, E.B., Honeycut, C. et al. Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies. Cancer Chemother Pharmacol 69, 1657–1667 (2012). https://doi.org/10.1007/s00280-012-1839-5

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  • DOI: https://doi.org/10.1007/s00280-012-1839-5

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