Phase II trial and prediction of response of single agent tipifarnib in patients with relapsed/refractory mantle cell lymphoma: a Groupe d'Etude des Lymphomes de l'Adulte trial.

Abstract

PURPOSE:

Farnesyltransferase (Ftase) was identified by gene-expression profiling and by preclinical evaluation in in vitro and in vivo mantle cell lymphoma (MCL) models as a rational therapeutic target in MCL, one of the most refractory B-cell lymphomas. We conducted a multicenter phase II study of a potent Ftase inhibitor, tipifarnib, in patients with relapsed or refractory MCL.

METHODS:

Tipifarnib was administered at 300 mg orally twice daily for the first 21 days of each 28-day cycle for 4 cycles, and in case of response for 6 cycles. Study endpoints were objective response at 4 and 6 cycles, progression free survival (PFS), overall survival, and toxicity. Prediction of response was retrospectively evaluated in the initial tumor biopsy by the RASGRP1/APTX gene expression ratio, and the AKAP13 expression level.

RESULTS:

Eleven patients (median age, 71 years) were enrolled. Patients received a median number of three prior therapies (range 1-11). Nine patients completed at least 3 cycles of tipifarnib. No grade III-IV hematological toxicities were recorded. One patient presented a complete response (CR) after 4 and a persistent CR at 6 cycles (ORR = 9%). Median PFS was 3 months (range 0.7-14.2). The RASGRP1/APTX gene expression ratio was higher in the responder (n = 1) while the AKAP13 expression was higher in the non-responders (n = 2). This corresponds to the expected result for predicting response to tipifarnib.

CONCLUSION:

Treatment with tipifarnib relapsed or refractory MCL is associated with low response rates. Limited gene expression studies suggest that response may be associated with molecular targets.

• Authors: Delphine Rolland, Vincent Ribrag, Corinne Haioun, Herve Ghesquieres, Fabrice Jardin, Reda Bouabdallah, Patricia Franchi, Josette Briere, Eric De Kerviler, Catherine Chassagne-Clement, Mitch Raponi, Remi Houlgatte, Jean-Philippe Jais, Catherine Thieblemont
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 65 Issue 4 Pg. 781-90 (Mar 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19960345 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study)

Chemical References

• A Kinase Anchor Proteins
• AKAP13 protein, human
• APTX protein, human
• Antineoplastic Agents
• DNA-Binding Proteins
• Guanine Nucleotide Exchange Factors
• Minor Histocompatibility Antigens
• Nuclear Proteins
• Proto-Oncogene Proteins
• Quinolones
• RASGRP1 protein, human
• tipifarnib

Topics

• A Kinase Anchor Proteins (genetics)
• Administration, Oral
• Aged
• Antineoplastic Agents (administration & dosage, therapeutic use)
• DNA-Binding Proteins (genetics)
• Drug Administration Schedule
• Drug Resistance, Neoplasm
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Guanine Nucleotide Exchange Factors (genetics)
• Humans
• Lymphoma, Mantle-Cell (drug therapy, genetics)
• Male
• Minor Histocompatibility Antigens
• Neoplasm Recurrence, Local
• Nuclear Proteins (genetics)
• Predictive Value of Tests
• Prognosis
• Prospective Studies
• Proto-Oncogene Proteins (genetics)
• Quinolones (administration & dosage, therapeutic use)
• Reverse Transcriptase Polymerase Chain Reaction
• Survival Analysis
• Treatment Outcome