Originally published as JCO Early Release 10.1200/JCO.2005.09.005 on February 22 2005

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Phase I Study of BMS-214662, a Farnesyl Transferase Inhibitor in Patients With Acute Leukemias and High-Risk Myelodysplastic Syndromes

From the Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD; and Bristol-Myers Squibb, Princeton, NJ

Address reprint requests to Jorge Cortes, MD, The University of Texas MD Anderson Cancer Center, Department of Leukemia, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030; e-mail: jcortes{at}mdanderson.org

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.

Supported in part by grant No. 2057-01 from the Leukemia and Lymphoma Society. J.C. is a Clinical Research Scholar for the Leukemia and Lymphoma Society.

Presented in part at the 43rd annual meeting of the American Society of Hematology, December 2001.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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