Phase I study of alternate-week administration of tipifarnib in patients with myelodysplastic syndrome

Razelle Kurzrock, Hagop M. Kantarjian, Michelle A. Blascovich, Cindy Bucher, Srdan Verstovsek, John J. Wright, Susan R. Pilat, Jorge E. Cortes, Elihu H. Estey, Francis J. Giles, Miloslav Beran, Said M. Sebti

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Purpose: To determine the safety and describe the antitumor activity of tipifarnib in patients with myelodysplastic syndrome (MDS) using an alternate-week schedule. Experimental Design: Patients with MDS were given tipifarnib, escalating from 100 mg orally twice daily until the maximum tolerated dose for 8 weeks followed by maintenance therapy (same dose/schedule) for patients with stable disease or better. Results: Sixty-three patients were treated. The most common toxicity was myelosuppression (60% of patients). Twenty percent of patients had no side effects. Nonhematologic toxicities included fatigue (20%), skin rash (9%), diarrhea (16%), increase in liver transaminases (14%) and bilirubin (11%), and nausea (11%). Dose-limiting toxicities of ataxia (n = 1), fatigue (n = 1), nausea (n = 1), and neutropenic fever (n = 2) occurred at tipifarnib doses above 1,200 mg/d. Sixteen of 61 (26%) evaluable patients responded (3 complete remissions and 13 hematologic improvements) with major platelet responses being most common (11of 16 responders). There was no obvious dose-response relationship. Four of the 16 responders (25%; including a complete responder) were treated at the lowest dose level (100 mg twice daily). Only one responder had a Ras mutation. Giving tipifarnib resulted in potent inhibition of farnesyl transferase (usually more than 75%) in peripheral blood mononuclear cells regardless of dose. Partial farnesyl transferase inhibition persisted during the week off. Conclusions: Alternate-week tipifarnib is active and well tolerated in patients with MDS at doses up to and including 600 mg orally twice daily. The biological activity of tipifarnib is not dependent on dose.

Original languageEnglish (US)
Pages (from-to)509-514
Number of pages6
JournalClinical Cancer Research
Volume14
Issue number2
DOIs
StatePublished - Jan 15 2008

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kurzrock, R., Kantarjian, H. M., Blascovich, M. A., Bucher, C., Verstovsek, S., Wright, J. J., Pilat, S. R., Cortes, J. E., Estey, E. H., Giles, F. J., Beran, M., & Sebti, S. M. (2008). Phase I study of alternate-week administration of tipifarnib in patients with myelodysplastic syndrome. Clinical Cancer Research, 14(2), 509-514. https://doi.org/10.1158/1078-0432.CCR-07-1532