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

Abstract

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.

• Authors: 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
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 22 Issue 7 Pg. 1287-92 (Apr 01 2004) ISSN: 0732-183X [Print] United States
• PMID: 15051776 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Quinolones
• Vascular Endothelial Growth Factor A
• Fibroblast Growth Factor 2
• Alkyl and Aryl Transferases
• Farnesyltranstransferase
• tipifarnib

Topics

• Aged
• Aged, 80 and over
• Alkyl and Aryl Transferases (antagonists & inhibitors)
• Antineoplastic Agents (therapeutic use)
• Enzyme Inhibitors (therapeutic use)
• Farnesyltranstransferase
• Feasibility Studies
• Female
• Fibroblast Growth Factor 2 (metabolism)
• Genes, ras (physiology)
• Humans
• Karyotyping
• Male
• Maximum Tolerated Dose
• Middle Aged
• Mutation
• Myelodysplastic Syndromes (drug therapy, pathology)
• Quinolones (therapeutic use)
• Treatment Outcome
• Vascular Endothelial Growth Factor A (metabolism)