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.
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.
Rolland
Delphine
D
INSERM U836 Equipe 7, Faculte de Medecine, Universite Joseph Fourier, Grenoble, France.
Ribrag
Vincent
V
Haioun
Corinne
C
Ghesquieres
Herve
H
Jardin
Fabrice
F
Bouabdallah
Reda
R
Franchi
Patricia
P
Briere
Josette
J
De Kerviler
Eric
E
Chassagne-Clement
Catherine
C
Raponi
Mitch
M
Houlgatte
Remi
R
Jais
Jean-Philippe
JP
Thieblemont
Catherine
C
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
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