Recent evidence suggests that neoplastic cells are particularly susceptible to a strategy involving simultaneous interruption of survival-associated signal transduction and cell cycle regulatory pathways. Consistent with this notion, we have observed in preclinical studies that the cyclin-dependent kinase inhibitor flavopiridol (NSC 649890) interacts synergistically with the Bcr/Abl kinase inhibitor imatinib (STI571; Gleevec) to induce mitochondrial injury, caspase activation and apoptosis in Bcr/Abl+ human leukemia cells, including those highly resistant to imatinib. These events are associated with multiple perturbations in survival signaling and cell cycle-related pathways, including down-regulation of Mcl-1 and Bcl-xL, reduced expression of cyclin D1, activation of JNK, and inactivation of CREB and Stat5. Based upon these findings, a multi-institutional Phase I trial has been developed in which patients with progressive CML (chronic and accelerated phase) or CML-BC or Philadelphia chromosome+ AML or ALL will be treated with escalating doses of daily imatinib in conjunction with flavopiridol administered as a 1-hr infusion weekly x 3 q month. The goals of this Phase I trial are to define the MTD for these agents, characterize dose-limiting toxicities, and gain preliminary information regarding activity of the regimen. Correlative laboratory studies will test the hypothesis that in vivo administration of imatinib in conjunction with flavopiridol will induce perturbations in apoptotic regulatory proteins in peripheral blood Bcr/Abl+ cells (e.g., diminished expression of Mcl-1, Bcl-xL, and cyclin D1, inactivation of Stat5 and CREB, activation of JNK) similar to those observed in Bcr/Abl+ cell lines exposed to these agents in vitro. Other studies will investigate a) effects of the imatinib/flavopiridol regimen on Stat5 phosphorylation of Bcr/Abl+ peripheral blood cells by flow cytometry; b) the pharmacokinetics of imatinib and flavopiridol when administered together; and c) the presence of Bcr/Abl mutations as well as increased Bcr/Abl expression/activity in cells from imatinib-resistant patients, and their possible relationship to imatinib/flavopiridol pharmacodynamics. Information derived from this trial will provide a foundation for a successor Phase II trial and correlative laboratory studies which will address issues of regimen activity and imatinib/flavopiridol molecular interactions more definitively.
| Bose, Prithviraj; Perkins, Edward B; Honeycut, Connie et al. (2012) Phase I trial of the combination of flavopiridol and imatinib mesylate in patients with Bcr-Abl+ hematological malignancies. Cancer Chemother Pharmacol 69:1657-67 |
