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Investigational New Drugs

, Volume 33, Issue 2, pp 371–379 | Cite as

A phase I and pharmacodynamic study of the histone deacetylase inhibitor belinostat plus azacitidine in advanced myeloid neoplasia

  • Olatoyosi OdenikeEmail author
  • Anna Halpern
  • Lucy A. Godley
  • Jozef Madzo
  • Theodore Karrison
  • Margaret Green
  • Noreen Fulton
  • Ryan J. Mattison
  • Karen. W. L. Yee
  • Meghan Bennett
  • Gregory Koval
  • Gregory Malnassy
  • Richard A. Larson
  • Mark J. Ratain
  • Wendy Stock
PHASE I STUDIES

Summary

Background We hypothesized that targeting two mechanisms of epigenetic silencing would be additive or synergistic with regard to expression of specific target genes. The primary objective of the study was to establish the maximum tolerated dose (MTD) of belinostat in combination with a fixed dose of azacitidine (AZA). Methods In Part A of the study, patients received a fixed dose of AZA, with escalating doses of belinostat given on the same days 1–5, in a 28 day cycle. Part B was designed to evaluate the relative contribution of belinostat to the combination based on analysis of pharmacodynamic markers, and incorporated a design in which patients were randomized during cycle 1 to AZA alone, or the combination, at the maximally tolerated dose of belinostat. Results 56 patients with myeloid neoplasia were enrolled. Dose escalation was feasible in part A, up to 1000 mg/m2 dose level of belinostat. In Part B, 18 patients were assessable for quantitative analysis of specific target genes. At day 5 of therapy, MDR1 was significantly up-regulated in the belinostat/AZA arm compared with AZA alone arm (p = 0.0023). There were 18 responses among the 56 patients. Conclusions The combination of belinostat and AZA is feasible and associated with clinical activity. The recommended phase II dose is 1000 mg/m2 of belinostat plus 75 mg/m2 of AZA on days 1–5, every 28 days. Upregulation in MDR1 was observed in the combination arm at day 5 compared with the AZA alone arm, suggesting a relative biologic contribution of belinostat to the combination.

Keywords

Belinostat Azacitidine Myeloid neoplasm Histone deacetylase inhibitor DNA methyltransferase inhibitor MDR1 DNA hypomethylating agent 

Notes

Acknowledgments

This work was supported by: NCI (grant # U01-CA69852) in collaboration with Spectrum Pharmaceuticals.

Conflict of Interest

Olatoyosi Odenike received research funding from Curagen/Topotarget, and has served on advisory boards convened by Spectrum pharmaceuticals, Suneisis, Sanofi-Aventis, Incyte and Algeta pharmaceuticals.

Lucy A. Godley has received research support from Pharmion/Celgene.

Ryan J Mattison has served on advisory boards convened by Bristol Myers Squibb and Incyte pharmaceuticals.

Karen Yee has served as a consultant for Celgene.

Mark J. Ratain has served as a consultant for Onconova and Cyclacel.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Olatoyosi Odenike
    • 1
    • 2
    • 5
    Email author
  • Anna Halpern
    • 1
  • Lucy A. Godley
    • 1
    • 2
  • Jozef Madzo
    • 1
  • Theodore Karrison
    • 2
  • Margaret Green
    • 1
  • Noreen Fulton
    • 1
  • Ryan J. Mattison
    • 3
  • Karen. W. L. Yee
    • 4
  • Meghan Bennett
    • 1
  • Gregory Koval
    • 1
  • Gregory Malnassy
    • 1
  • Richard A. Larson
    • 1
    • 2
  • Mark J. Ratain
    • 1
    • 2
  • Wendy Stock
    • 1
    • 2
  1. 1.Department of MedicineThe University of ChicagoChicagoUSA
  2. 2.The University of Chicago Comprehensive Cancer CenterChicagoUSA
  3. 3.The University of Wisconsin and the Carbone Comprehensive Cancer CenterMadisonUSA
  4. 4.Princess Margaret HospitalTorontoUSA
  5. 5.Section of Hematology/OncologyThe University of ChicagoChicagoUSA

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