title: 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: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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: INSERM U836 Equipe 7, Faculte de Medecine, Universite Joseph Fourier, Grenoble, France.
authors: Delphine
authors: D
authors: Rolland
authors: Vincent
authors: V
authors: Ribrag
authors: Corinne
authors: C
authors: Haioun
authors: Herve
authors: H
authors: Ghesquieres
authors: Fabrice
authors: F
authors: Jardin
authors: Reda
authors: R
authors: Bouabdallah
authors: Patricia
authors: P
authors: Franchi
authors: Josette
authors: J
authors: Briere
authors: Eric
authors: E
authors: De Kerviler
authors: Catherine
authors: C
authors: Chassagne-Clement
authors: Mitch
authors: M
authors: Raponi
authors: Remi
authors: R
authors: Houlgatte
authors: Jean-Philippe
authors: JP
authors: Jais
authors: Catherine
authors: C
authors: Thieblemont
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics; D000284:Administration, Oral; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000235:genetics; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D015778:Minor Histocompatibility Antigens; D009364:Neoplasm Recurrence, Local; D009687:Nuclear Proteins / Q000235:genetics; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics; D015363:Quinolones / Q000008:administration & dosage / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D054758:A Kinase Anchor Proteins; C085467:AKAP13 protein, human; C438188:APTX protein, human; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D015778:Minor Histocompatibility Antigens; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D015363:Quinolones; C491790:RASGRP1 protein, human; C402769:tipifarnib