Abstract

Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell-cycle and survival signaling pathways. In accord with this concept, we have shown that flavopiridol (F), a CDK inhibitor, interacts with Bortezomib (B), a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (

Dai et al,
Oncogene
22
:
7108
,
2003
;
Dai et al,
Blood
104
,
509
,
2004
). These actions were associated with inhibition of NF-kappaB DNA binding, and diminished expression of phospho-JNK, XIAP, and Mcl-1. Based on these findings, we have initiated a phase I trial to identify appropriate doses of B+F for further investigation. Eligible patients (pts) include those with multiple myeloma, indolent B-cell lymphoma, or a related disorder, and must have recurrent or refractory disease following at least 1 prior systemic therapy (excluding allogeneic stem cell transplantation). Pts receive B (iv bolus) immediately followed by F (1 hour infusion) on days 1, 4, 8, and 11; courses are repeated every 21 days. Targeted dose levels are (B/F; mg/m2): 1.0/15, 1.3/15, 1.3/22, 1.3/30, and 1.3/40. Dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelet for > 1 week or grade ≥ 3 non-heme toxicity. 14 pts have been treated at 4 dose levels. There have been no DLT to date. There have been 3 episodes of herpes zoster (2 disseminated), 4 cases of exacerbation of pre-existing peripheral neuropathy, and 8 pts have discontinued study treatment after 1 to 5 cycles due to non-DLT toxicities. Among 11 patients evaluable for response and who are Bortezomib-naive, there has been 1 complete response (mantle cell lymphoma; MCL), 3 partial responses (2 myeloma, 1 lymphoma), and 5 patients with stable disease (3 myeloma, 1 lymphoma, 1 Waldenstrom’s). The patient with MCL who achieved a CR had previously received CHOP, Rituximab-CHOP, and fludarabine-Rituximab x 2. Correlative laboratory studies involving bone marrow CD138+ cells from patients with myeloma revealed a reduction in post-treatment NF-kappaB nuclear localization in 4/5 evaulable patients. Variable effects on myeloma cell expression of phospho-JNK, Mcl-1, and XIAP have been observed. Additional patients who previously received Bortezomib have now been entered on the study, but it is too early to evaluate their responses. Collectively, these findings indicate that a regimen combining Bortezomib and flavopiridol is well tolerated in patients with progressive B-cell malignancies, and has clear activity in some patients refractory to standard therapy. Pending identification of the MTD and RPTD (recommended phase II dose), Phase II evaluation of this therapeutic strategy should define its activity more definitively.

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