A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors

Mark Andrew Dickson, Dana E. Rathkopf, Richard D. Carvajal, Steven Grant, John D. Roberts, Joel M. Reid, Matthew M. Ames, Renee M. McGovern, Robert A. Lefkowitz, Mithat Gonen, Lauren M. Cane, Heather J. Dials, Gary K. Schwartz

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28 Scopus citations

Abstract

Purpose: Vorinostat (V) at levels >2.5 μM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis. Experimental Design One week before combination treatment, V alone was given daily for 3d (cycle-1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied. Results 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m 2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m 2 over 30 min and 30 mg/m 2 over 4 h. V C max at the 800 mg dose was 4.8 μM (± 2.8). V C max ≥2.5 μM was achieved in 86% of patients at the MTD. F increased the C max of V by 27% (95% CI 11%-43%). F C max of ≥2 μM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m). Conclusions Intermittent high dose oral V in combination with F is feasible and achieves target serum levels ≤2.5 μM. V concentrations higher than previously reported with oral dosing were achieved.

Original languageEnglish (US)
Pages (from-to)1004-1012
Number of pages9
JournalInvestigational New Drugs
Volume29
Issue number5
DOIs
StatePublished - Oct 1 2011

Keywords

  • CDKs and CDK inhibitors
  • Combination chemotherapy
  • Histone deacetylase inhibitors
  • Pharmacokinetics
  • Phase I trials

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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  • Cite this

    Dickson, M. A., Rathkopf, D. E., Carvajal, R. D., Grant, S., Roberts, J. D., Reid, J. M., Ames, M. M., McGovern, R. M., Lefkowitz, R. A., Gonen, M., Cane, L. M., Dials, H. J., & Schwartz, G. K. (2011). A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors. Investigational New Drugs, 29(5), 1004-1012. https://doi.org/10.1007/s10637-010-9447-x