A phase I study of intravenous LBH589, a novel cinnamic hydroxamic acid analogue histone deacetylase inhibitor, in patients with refractory hematologic malignancies.

PURPOSE: LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle. EXPERIMENTAL DESIGN: Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m(2)): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation were measured using quantitative flow cytometry and plasma LBH589 concentrations were assayed. RESULTS: Four dose-limiting toxicities (grade 3 QTcF prolongation) were observed, four at 14.0 mg/m(2) and one at 11.5 mg/m(2). QTcF prolongation was asymptomatic and reversed on LBH589 discontinuation. Other potentially LBH589-related toxicities included nausea (40%), diarrhea (33%), vomiting (33%), hypokalemia (27%), loss of appetite (13%), and thrombocytopenia (13%). In 8 of 11 patients with peripheral blasts, transient reductions occurred with a rebound following the 7-day treatment period. H3 acetylation increase was significant in B-cells (CD19(+); P = 0.02) and blasts (CD34(+); P = 0.04). The increase in H2B acetylation was highest in CD19(+) and CD34(+) cells [3.8-fold (P = 0.01) and 4.4-fold (P = 0.03), respectively]. The median acetylation of histones H2B and H3 in CD34(+) and CD19(+) cells significantly increased on therapy as did apoptosis in CD14(+) cells. Area under the curve increased proportionally with dose with a terminal half-life of approximately 11 hours. CONCLUSION: Intravenous administration of LBH589 was well tolerated at doses <11.5 mg/m(2) with consistent transient antileukemic and biological effects.

Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.

BACKGROUND: Resistance to imatinib mesylate can occur in chronic myelogenous leukemia (CML). Preclinical in vitro studies have shown that nilotinib (AMN107), a new BCR-ABL tyrosine kinase inhibitor, is more potent than imatinib against CML cells by a factor of 20 to 50. METHODS: In a phase 1 dose-escalation study, we assigned 119 patients with imatinib-resistant CML or acute lymphoblastic leukemia (ALL) to receive nilotinib orally at doses of 50 mg, 100 mg, 200 mg, 400 mg, 600 mg, 800 mg, and 1200 mg once daily and at 400 mg and 600 mg twice daily. RESULTS: Common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes. Of 33 patients with the blastic phase of disease, 13 had a hematologic response and 9 had a cytogenetic response; of 46 patients with the accelerated phase, 33 had a hematologic response and 22 had a cytogenetic response; 11 of 12 patients with the chronic phase had a complete hematologic remission. CONCLUSIONS: Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML. (ClinicalTrials.gov number, NCT00109707 [ClinicalTrials.gov].).