Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes

Jorge Cortes, Stefan Faderl, Elihu Estey, Razelle Kurzrock, Deborah Thomas, Miloslav Beran, Guillermo Garcia-Manero, Alessandra Ferrajoli, Francis Giles, Charles Koller, Susan O'Brien, John Wright, Stephen A. Bai, Hagop Kantarjian

Research output: Contribution to journalArticle

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/m 2). 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.

Original languageEnglish (US)
Pages (from-to)2805-2812
Number of pages8
JournalJournal of Clinical Oncology
Volume23
Issue number12
DOIs
StatePublished - Apr 20 2005
Externally publishedYes

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Myelodysplastic Syndromes
Transferases
Leukemia
Maximum Tolerated Dose
Hypokalemia
Nausea
Vomiting
7-cyano-2,3,4,5-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-(phenylmethyl)-4-(2-thienylsulfonyl)-1H-1,4-benzodiazepine
Diarrhea
Appointments and Schedules
Blood Platelets
Drug Therapy

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes. / Cortes, Jorge; Faderl, Stefan; Estey, Elihu; Kurzrock, Razelle; Thomas, Deborah; Beran, Miloslav; Garcia-Manero, Guillermo; Ferrajoli, Alessandra; Giles, Francis; Koller, Charles; O'Brien, Susan; Wright, John; Bai, Stephen A.; Kantarjian, Hagop.

In: Journal of Clinical Oncology, Vol. 23, No. 12, 20.04.2005, p. 2805-2812.

Research output: Contribution to journalArticle

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 2005, 'Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes', Journal of Clinical Oncology, vol. 23, no. 12, pp. 2805-2812. https://doi.org/10.1200/JCO.2005.09.005
Cortes, Jorge ; Faderl, Stefan ; Estey, Elihu ; Kurzrock, Razelle ; Thomas, Deborah ; Beran, Miloslav ; Garcia-Manero, Guillermo ; Ferrajoli, Alessandra ; Giles, Francis ; Koller, Charles ; O'Brien, Susan ; Wright, John ; Bai, Stephen A. ; Kantarjian, Hagop. / Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes. In: Journal of Clinical Oncology. 2005 ; Vol. 23, No. 12. pp. 2805-2812.
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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/m 2). 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.",
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T1 - Phase I study of BMS-214662, a farnesyl transferase inhibitor in patients with acute leukemias and high-risk myelodysplastic syndromes

AU - Cortes, Jorge

AU - Faderl, Stefan

AU - Estey, Elihu

AU - Kurzrock, Razelle

AU - Thomas, Deborah

AU - Beran, Miloslav

AU - Garcia-Manero, Guillermo

AU - Ferrajoli, Alessandra

AU - Giles, Francis

AU - Koller, Charles

AU - O'Brien, Susan

AU - Wright, John

AU - Bai, Stephen A.

AU - Kantarjian, Hagop

PY - 2005/4/20

Y1 - 2005/4/20

N2 - 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/m 2). 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.

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