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A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors

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Summary

Purpose: Based on the promising activity and tolerability of flavopiridol administered with a pharmacokinetically-derived dosing schedule in chronic lymphocytic leukemia (CLL), we conducted a phase I study using this schedule in patients with advanced solid tumors. Experimental Design: Flavopiridol was given IV as a 30-min loading dose followed by a 4-hr infusion weekly for 4 weeks repeated every 6 weeks. Dose-escalation was in cohorts of three patients using the standard 3+3 phase I study design. Blood samples were obtained for pharmacokinetic and pharmacodynamic studies. Results: Thirty-four eligible patients with advanced solid tumors received a total of 208 doses (median 7, range 1–24). Total doses ranged from 40 to 105 mg/m2. The primary dose limiting toxicity was cytokine release syndrome (CKRS). No antitumor responses were observed. The mean peak plasma concentration across all doses was 1.65 ± 0.86 μM. Area under the concentration-versus-time curve (\( {\hbox{AU}}{{\hbox{C}}_{0 - \infty }} \)) ranged from 4.31 to 32.2 μM⋅hr with an overall mean of 13.6 ± 7.0 μM⋅hr. Plasma flavopiridol concentrations and AUC increased proportionally with dose. There was no correlation between cytokine levels and clinical outcomes. Conclusions: The maximum-tolerated dose of flavopiridol is 20 mg/m2 bolus followed by 20 mg/m2 infusion over 4 h given weekly for 4 weeks on a 6-week cycle in patients with advanced solid tumors. Flavopiridol PK was notably different, and there was a higher frequency of CKRS, despite prophylactic steroids, seen in this patient group compared to previous studies with CLL using a similar dosing schedule.

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Acknowledgements

This work was supported by Grant No. U01 CA76576 from the National Cancer Institute.

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Authors and Affiliations

  1. Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA

    Bhuvaneswari Ramaswamy, Robert Baiocchi, Tanios Bekaii-Saab, Anna Wolfson, Mark E. Lustberg, Deidre Wilkins, Angela Campbell, Daria Arbogast, John C. Byrd, Michael R. Grever & Manisha H. Shah

  2. Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    Mitch A. Phelps, Wenjun Ni & Ju-Ping Lai

  3. Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    Lai Wei

  4. Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, USA

    Austin Doyle

  5. A438 Starling-Loving Hall, 320W 10th Ave, Columbus, OH, 43210, USA

    Manisha H. Shah

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  1. Bhuvaneswari Ramaswamy
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Correspondence to Manisha H. Shah.

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Ramaswamy, B., Phelps, M.A., Baiocchi, R. et al. A dose-finding, pharmacokinetic and pharmacodynamic study of a novel schedule of flavopiridol in patients with advanced solid tumors. Invest New Drugs 30, 629–638 (2012). https://doi.org/10.1007/s10637-010-9563-7

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  • DOI: https://doi.org/10.1007/s10637-010-9563-7

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