Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome

Razelle Kurzrock, Maher Albitar, Jorge E. Cortes, Elihu H. Estey, Stefan H. Faderl, Guillermo Garcia-Manero, Deborah A. Thomas, Francis J. Giles, Mary Ellen Ryback, Alain Thibault, P. De Porre, Hagop M. Kantarjian

Research output: Contribution to journalArticle

Abstract

Purpose: To perform a phase II study of the farnesyltransferase 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.

Original languageEnglish (US)
Pages (from-to)1287-1292
Number of pages6
JournalJournal of Clinical Oncology
Volume22
Issue number7
DOIs
StatePublished - Dec 1 2004
Externally publishedYes

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tipifarnib
Myelodysplastic Syndromes
Transferases
Refractory Anemia with Excess of Blasts
Farnesyltranstransferase
Multiple Abnormalities
Lymphocyte Activation
Exanthema
Diploidy
Karyotype

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kurzrock, R., Albitar, M., Cortes, J. E., Estey, E. H., Faderl, S. H., Garcia-Manero, G., ... Kantarjian, H. M. (2004). Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. Journal of Clinical Oncology, 22(7), 1287-1292. https://doi.org/10.1200/JCO.2004.08.082

Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. / Kurzrock, Razelle; Albitar, Maher; Cortes, Jorge E.; Estey, Elihu H.; Faderl, Stefan H.; Garcia-Manero, Guillermo; Thomas, Deborah A.; Giles, Francis J.; Ryback, Mary Ellen; Thibault, Alain; De Porre, P.; Kantarjian, Hagop M.

In: Journal of Clinical Oncology, Vol. 22, No. 7, 01.12.2004, p. 1287-1292.

Research output: Contribution to journalArticle

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, HM 2004, 'Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome', Journal of Clinical Oncology, vol. 22, no. 7, pp. 1287-1292. https://doi.org/10.1200/JCO.2004.08.082
Kurzrock, Razelle ; Albitar, Maher ; Cortes, Jorge E. ; Estey, Elihu H. ; Faderl, Stefan H. ; Garcia-Manero, Guillermo ; Thomas, Deborah A. ; Giles, Francis J. ; Ryback, Mary Ellen ; Thibault, Alain ; De Porre, P. ; Kantarjian, Hagop M. / Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome. In: Journal of Clinical Oncology. 2004 ; Vol. 22, No. 7. pp. 1287-1292.
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T1 - Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome

AU - Kurzrock, Razelle

AU - Albitar, Maher

AU - Cortes, Jorge E.

AU - Estey, Elihu H.

AU - Faderl, Stefan H.

AU - Garcia-Manero, Guillermo

AU - Thomas, Deborah A.

AU - Giles, Francis J.

AU - Ryback, Mary Ellen

AU - Thibault, Alain

AU - De Porre, P.

AU - Kantarjian, Hagop M.

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N2 - Purpose: To perform a phase II study of the farnesyltransferase 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.

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