Phase I and pharmacokinetic study of bortezomib in combination with idarubicin and cytarabine in patients with acute myelogenous leukemia.

PURPOSE Proteasome inhibition results in cytotoxicity to the leukemia stem cell in vitro. We conducted this phase I study to determine if the proteasome inhibitor bortezomib could be safely added to induction chemotherapy in patients with acute myelogenous leukemia (AML). EXPERIMENTAL DESIGN Bortezomib was given on days 1, 4, 8, and 11 at doses of 0.7, 1.0, 1.3, or 1.5 mg/m(2) with idarubicin 12 mg/m(2) on days 1 to 3 and cytarabine 100 mg/m(2)/day on days 1 to 7. RESULTS A total of 31 patients were enrolled. The median age was 62 years, and 16 patients were male. Nine patients had relapsed AML (ages, 18-59 years, n = 4 and > or = 60 years, n = 5). There were 22 patients of > or = 60 years with previously untreated AML (eight with prior myelodysplasia/myeloproliferative disorder or cytotoxic therapy). All doses of bortezomib, up to and including 1.5 mg/m(2), were tolerable. Nonhematologic grade 3 or greater toxicities included 12 hypoxia (38%; 11 were grade 3), 4 hyperbilirubinemia (13%), and 6 elevated aspartate aminotransferase (19%). Overall, 19 patients (61%) achieved complete remission (CR) and three had CR with incomplete platelet recovery. Pharmacokinetic studies revealed that the total body clearance of bortezomib decreased significantly (P < 0.01, N = 26) between the first (mean +/- SD, 41.9 +/- 17.1 L/h/m(2)) and third (18.4 +/- 7.0 L/h/m(2)) doses. Increased bone marrow expression of CD74 was associated with CR. CONCLUSIONS The combination of bortezomib, idarubicin, and cytarabine showed a good safety profile. The recommended dose of bortezomib for phase II studies with idarubicin and cytarabine is 1.5 mg/m(2).