The results of recent studies indicate that neoplastic cells, particularly those of hematopoietic origin, are exquisitely sensitive to apoptosis induced by simultaneous disruption of survival signaling and cell cycle regulatory pathways. Bortezomib, the prototypical clinically relevant proteasome inhibitor, has shown impressive activity against multiple myeloma refractory to conventional therapies, as well as mantle cell lymphoma (MCL) and indolent NHL. Flavopiridol (NSC 649890), the first cyclin-dependent kinase inhibitor to enter clinical trials, induces apoptosis in malignant human hematopoietic cells at pharmacologically achievable concentrations. Recent preclinical studies from our laboratory indicate that co-administration of bortezomib and flavopiridol at low concentrations results in a highly synergistic induction of mitochondrial damage and apoptosis in human leukemia and myeloma cell lines as well as in primary patient-derived specimens. These events are associated with multiple perturbations in signaling and survival pathways, including activation of the stress-related JNK cascade, down-regulation of the anti-apoptotic proteins Mcl-1 and XlAP, and inactivation of the cytoprotective NF-kB pathway. The hypothesis that similar events will occur in myeloma and lymphoma cells exposed to these agents in vivo has prompted the development of a Phase I trial of bortezomib and flavopiridol in patients with multiple myeloma, MCL, and indolent B-cell NHL. The goals of this project are: (1) To conduct a Phase I trial of flavopiridol and bortezomib administered as bolus IV infusions BIW (days 1 and 4, 8 and 11) q 3 wks to determine the maximally tolerated drug doses for this schedule; (2) To define dose-limiting toxicities; (3) To assess preliminary clinical activity of this regimen in patients with myeloma and B-cell neoplasms; (4) To conduct correlative laboratory and PK studies to test the hypothesis that in vivo administration of bortezomib and flavopiridol will result in NF-kB inactivation, JNK activation, and down-regulation of Mcl-1 and XIAP in multiple myeloma cells. ? ? ?
