Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. J Clin Oncol 2004 Apr 01;22(7):1287-92
Date
03/31/2004Pubmed ID
15051776DOI
10.1200/JCO.2004.08.082Scopus ID
2-s2.0-2142712474 (requires institutional sign-in at Scopus site) 149 CitationsAbstract
PURPOSE: 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.
PATIENTS AND 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.
CONCLUSION: 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.
Author List
Kurzrock R, Albitar M, Cortes JE, Estey EH, Faderl SH, Garcia-Manero G, Thomas DA, Giles FJ, Ryback ME, Thibault A, De Porre P, Kantarjian HMAuthor
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
AgedAged, 80 and over
Alkyl and Aryl Transferases
Antineoplastic Agents
Enzyme Inhibitors
Farnesyltranstransferase
Feasibility Studies
Female
Fibroblast Growth Factor 2
Genes, ras
Humans
Karyotyping
Male
Maximum Tolerated Dose
Middle Aged
Mutation
Myelodysplastic Syndromes
Quinolones
Treatment Outcome
Vascular Endothelial Growth Factor A
