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Blood, 15 December 2003, Vol. 102, No. 13, pp. 4527-4534.
Prepublished online as a Blood First Edition Paper on August 28, 2003; DOI 10.1182/blood-2002-11-3359.
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NEOPLASIA
Farnesyltransferase inhibitor R115777 in myelodysplastic syndrome: clinical and biologic activities in the phase 1 setting
Razelle Kurzrock,
Hagop M. Kantarjian,
Jorge E. Cortes,
Neil Singhania,
Deborah A. Thomas,
Edward F. Wilson,
John J. Wright,
Emil J. Freireich,
Moshe Talpaz, and
Saïd M. Sebti
From the Departments of Bioimmunotherapy and Leukemia, The University of Texas MD Anderson Cancer Center, Houston; the Department of Internal Medicine, University of Colorado Health Science Center, Denver; the Drug Discovery Program, H. Lee Moffitt Cancer Center and Research Institute, Department of Oncology, University of South Florida, Tampa; and the National Cancer Institute, Bethesda, MD.
R115777 is a potent farnesyltransferase (FTase) inhibitor with substantial antitumor activity in preclinical models. We conducted a phase 1 study (3 + 3 design) of R115777 in patients with myelodysplastic syndrome (MDS). R115777 was administered twice daily (3-weeks-on/1-week-off schedule for 8 weeks) (starting dosage, 300 mg by mouth twice daily; total, 600 mg). Maintenance therapy at the dose/schedule tolerated during induction could be continued until toxicity or lack of benefit. Twenty-one patients with MDS were treated (median age, 66 years). Four (19%) patients had ras mutations (n-ras,3; k-ras, 1). Objective responses (hematologic improvement, 3; partial remission, 2; or complete remission, 1) were seen in 6 of 20 (30%) evaluable patients, only 2 of whom had ras mutations. Response sequences were unusual in some patients who had increases in platelet counts without intervening aplasia. Other responders demonstrated an initial, albeit modest, myelosuppressive effect. The maximum tolerated dose was 400 mg by mouth twice a day. The most frequent side effect was myelosuppression. Dose-limiting toxicities (fatigue and confusion) occurred at 900 mg by mouth total daily dose. R115777 inhibited HDJ-2 prenylation and suppressed the activity of FTase, but not of the related geranylgeranyltransferase I enzyme, in peripheral blood mononuclear cells. Modulation of Akt, Erk, and signal transducer and activator of transcription 3 (STAT3) phosphorylation was variable, and responses occurred even without their down-regulation. Reductions in serum tumor necrosis factor- (TNF-) levels by day 7 showed a trend toward correlation with response (P = .09). We conclude that, at doses that are well tolerated, R115777 markedly inhibits the FTase target and has antitumor activity in MDS. (Blood. 2003;102:4527-4534)
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