Faculty Collaboration Database

Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes. J Clin Oncol 2005 Apr 20;23(12):2805-12

Date

02/25/2005

Pubmed ID

15728224

DOI

10.1200/JCO.2005.09.005

Scopus ID

2-s2.0-21044459973 (requires institutional sign-in at Scopus site)   49 Citations

Abstract

PURPOSE: To investigate the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of BMS-214662, a farnesyl transferase (FTase) inhibitor, in patients with acute leukemias and high-risk myelodysplastic syndromes (MDS).

PATIENTS AND METHODS: Patients with relapsed or refractory acute leukemias or MDS, or previously untreated but poor candidates for chemotherapy, were included in this phase I study with a 3 + 3 dose escalation design. BMS-214662 was administered as a 1-hour bolus once weekly at doses of 42 to 157 mg/m2. Once the MTD was identified, the schedule was changed to a 24-hour continuous infusion once weekly (starting dose, 300 mg/m2).

RESULTS: Thirty patients were treated at a dose of 42 (n = 1), 56 (n = 3), 84 (n = 3), 118 (n = 13), 157 (n = 6) or 300 mg/m2 (n = 4). DLT occurred in 3 patients at 157 mg/m2, including nausea, vomiting, diarrhea, hypokalemia and cardiovascular problems. No DLT occurred with 24-hour continuous infusion. MTD with a 1-hour infusion was 118 mg/m2, with no MTD identified with the 24-hour infusion. Plasma concentrations of BMS-214662 correlated with the dose. Inhibition of FTase activity of approximately 60% occurred after the infusion with recovery to near baseline after 24 hours. Five patients had evidence of antileukemia activity, including two with complete remission with incomplete platelet recovery, one with hematologic improvement, and two with morphologic leukemia-free state.

CONCLUSION: BMS-214662 is well tolerated at doses of up to 118 mg/m2 as a 1-hour infusion. The toxicity profile and efficacy may be improved with prolonged exposure. Further investigation of this agent in leukemia is warranted.

Author List

Cortes J, Faderl S, Estey E, Kurzrock R, Thomas D, Beran M, Garcia-Manero G, Ferrajoli A, Giles F, Koller C, O'Brien S, Wright J, Bai SA, Kantarjian H

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acute Disease
Adult
Aged
Aged, 80 and over
Benzodiazepines
Drug Administration Schedule
Female
Humans
Imidazoles
Infusions, Intravenous
Leukemia, Myeloid
Male
Maximum Tolerated Dose
Middle Aged
Myelodysplastic Syndromes
Precursor Cell Lymphoblastic Leukemia-Lymphoma