title: Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome.
abstract: OBJECTIVE
  To perform a phase II study of the farnesyl transferase inhibitor R115777 (Zarnestra; Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ) in patients with myelodysplastic syndrome (MDS), using doses recommended in a phase I study in relapsed/refractory leukemia.
  
  
  METHODS
  Patients with MDS were treated with R115777 at doses of 600 mg orally (PO) bid in cycles of 4 weeks of therapy followed by a 2-week rest period. Dose reduction rules for toxicity were applied.
  
  
  RESULTS
  Twenty-seven of the 28 patients treated were assessable. Three patients responded (complete remission, n = 2; partial remission, n = 1). Responders included two patients with refractory anemia with excess blasts and one patient with refractory anemia with excess blasts in transformation. Two of the responders had a diploid karyotype and one had multiple cytogenetic abnormalities including monosomy 5 and 7. The starting dose of 600 mg PO bid resulted in side effects (myelosuppression, fatigue, neurotoxicity, rash, or leg pain) necessitating dose reduction (n = 4) or discontinuation of therapy (n = 7) in 11 (41%) of 27 patients during the induction period (12 weeks). Lower doses of 300 mg PO bid were well tolerated. All responses occurred in patients who had been reduced to this dose level during the initial two cycles.
  
  
  CONCLUSIONS
  This study suggests that R115777 has modest activity in MDS patients, but that, in this patient population, 4 weeks of daily doses of 600 mg PO bid is not tolerated. Further exploration of the optimal dose/schedule and correlation with biologic end points are warranted.
authors.affiliation: Department of Bioimmunotherapy, University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA. rkurzroc@mdanderson.org
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Elihu H
authors.initials: EH
authors.lastname: Estey
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Faderl
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Thomas
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Ryback
authors.forename: Alain
authors.initials: A
authors.lastname: Thibault
authors.forename: P
authors.initials: P
authors.lastname: De Porre
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D051231:Farnesyltranstransferase; D005240:Feasibility Studies; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D007621:Karyotyping; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D015363:Quinolones / Q000627:therapeutic use*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D015363:Quinolones; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib