A Novel Dosing Schedule of Flavopiridol in CLL

Ohio State University, Columbus OH

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Progression of chronic lymphocytic leukemia (CLL) is associated with mutation or deletion of the p53 gene. CLL patients with dysfunctional p53 have a poor prognosis and do not respond to fludarabine or rituximab. Alemtuzumab, the only current effective therapy in this population, has significant infusion, hematologic and infectious toxicities. Thus, novel therapies that are effective in p53-dysfunctional CLL patients are urgently needed. Flavopiridol, a cyclin-dependent kinase inhibitor, induces apoptosis in CLL cells irrespective of p53 status. Initial studies using a 24-72-hour continuous IV infusion schedule in CLL showed no clinical activity. We subsequently demonstrated that favopiridol has high serum protein binding. Pharmacokinetic modeling suggested that administration of favopiridol by 30-minute IV bolus followed by 4-hour IV infusion would achieve in vivo plasma drug concentrations that induce apoptosis in CLL cells. Preliminary results of an ongoing phase I trial using this schedule have achieved clinical responses in relapsed CLL patients with p53 dysfunction, and acute tumor lysis has been observed as a dose limiting toxicity (DLT). Specific Aim 1 is to perform a phase I study of favopiridol using this dosing schedule in patients with relapsed CLL. In order to safely define this drug's toxicity profile and DLT (other than tumor lysis), intra-patient dose escalation will be performed in patients with fludarabine-refractory CLL who do not experience severe tumor lysis and do respond to cycle 1. We will gain preliminary data on the clinical activity of favopiridol in patients with high-risk genetic features. In Specific Aim 2, we will examine the pharmacokinetics and pharmacodynamics of favopiridol using this schedule. We will determine whether Cmax, Css and AUC correlate with tumor lysis or modulation of pharmacodynamic targets, specifically RNA polymerase II phosphorylation and Mcl-1 expression. We will also develop and validate a population pharmacokinetic model to interpret and predict the relationship between plasma favopiridol concentrations, toxicity and pharmacologic response. We hypothesize that this dosing schedule will modulate pharmacodynamic targets and show clinical activity. We plan to proceed to phase II studies of this schedule in high-risk CLL patients. [unreadable] [unreadable]