Phase I study of alternate-week administration of tipifarnib in patients with myelodysplastic syndrome. Clin Cancer Res 2008 Jan 15;14(2):509-14
Date
01/29/2008Pubmed ID
18223226DOI
10.1158/1078-0432.CCR-07-1532Scopus ID
2-s2.0-38949159210 (requires institutional sign-in at Scopus site) 19 CitationsAbstract
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 (11 of 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.
Author List
Kurzrock R, Kantarjian HM, Blascovich MA, Bucher C, Verstovsek S, Wright JJ, Pilat SR, Cortes JE, Estey EH, Giles FJ, Beran M, Sebti SMAuthor
Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Aged, 80 and over
Cohort Studies
Drug Administration Schedule
Farnesyltranstransferase
Female
Humans
Male
Middle Aged
Myelodysplastic Syndromes
Quinolones