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

Bhuvaneswari Ramaswamy, Mitch A. Phelps, Robert Baiocchi, Tanios Bekaii-Saab, Wenjun Ni, Ju Ping Lai, Anna Wolfson, Mark E. Lustberg, Lai Wei, Deidre Wilkins, Angela Campbell, Daria Arbogast, Austin Doyle, John C. Byrd, Michael R. Grever, Manisha H. Shah

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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 (AUC0-∞) 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.

Original languageEnglish (US)
Pages (from-to)629-638
Number of pages10
JournalInvestigational New Drugs
Issue number2
StatePublished - Apr 2012


  • CDK inhibitor
  • Flavopiridol
  • Phase I trial
  • Solid tumors

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)


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