Mantle cell lymphoma (MCL) and indolent B-cell non-Hodgkin's lymphomas (B-NHL) such as follicle center lymphoma are not curable with current therapies, and many patients with relapsed aggressive B-NHL are not candidates for autologous stem cell transplantation. Thus, novel treatments for relapsed B-NHL are needed. Flavopiridol is a cyclin-dependent kinase inhibitor that induces apoptosis in lymphoid tumor cells in vitro. Clinical trials using 24-72-hour continuous IV infusion or 1-hour bolus dosing showed modest clinical activity in MCL and chronic lymphocytic leukemia (CLL). We subsequently demonstrated that flavopiridol has high serum protein binding. Pharmacokinetic modeling suggested that administration of flavopiridol by 30-minute IV bolus followed by 4-hour IV infusion would achieve in vivo plasma drug concentrations needed to induce apoptosis. An ongoing phase I trial using this schedule in relapsed and refractory CLL has shown remarkable clinical activity, with acute tumor lysis and a response rate of 43%. We seek to explore our novel dosing regimen of flavopiridol in patients with relapsed B-NHL.
Specific Aim 1 is to perform a phase I study of flavopiridol using this dosing schedule in patients with relapsed B-NHL, in order to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and toxicity profile of this dosing schedule in 1) indolent B-NHL, 2) MCL, and 3) aggressive B-NHL. We seek to gain preliminary evidence on the clinical activity of this dosing schedule, in order to identify specific B-NHL types in which to pursue subsequent phase II studies.
Specific Aim 2 is to determine the pharmacokinetics and pharmacodynamics of flavopiridol, given by this schedule, in patients with relapsed B-NHL. We will determine whether Cmax, Css and AUC correlate with modulation of pharmacodynamic targets including 1) RNA polymerase II phosphorylation at the serine 2 and 5 C-terminal domain (CTD) sites and 2) mRNA and protein expression of Mel-1, Bcl-6 and cyclin D1. In addition, we will assess the effect of flavopiridol on T, B and NK-cells and quantitative immunoglobulin levels. Finally, we will examine whether acute infusion toxicity to flavopiridol is accompanied by release of inflammatory cytokines such as TNF-a, IFN-y, IL-6, IL-8 and IL-10. ? ? ?
