Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure.
BACKGROUND
The tolerability and efficacy of the combination of tipifarnib, an orally bioavailable nonpeptidomimetic farnesyl transferase inhibitor, and imatinib was investigated in patients with chronic myelogenous leukemia in chronic phase who had failed imatinib.


METHODS
Twenty-six patients (13 [50%] with Abl kinase domain mutations) were treated. The initial dose level was tipifarnib at a dose of 300 mg twice daily and imatinib at a dose of 300 mg daily. Therapy was escalated following a '3 + 3' phase 1 design and the maximum tolerated dose was defined as tipifarnib at a dose of 400 mg twice daily and imatinib at a dose of 400 mg daily. Therapy was administered for a median of 26 weeks (range, 3-150 weeks).


RESULTS
Adverse events included diarrhea in 21 patients (81%) and nausea in 18 patients (69%), but were generally grade 2 or less (using the revised National Cancer Institute Common Toxicity Criteria). Grade 3-4 neutropenia and thrombocytopenia occurred in 11 patients (42%) and 8 patients (31%), respectively. Sixteen patients discontinued therapy (5 due to toxicity and 11 due to lack of response or disease progression). Hematologic responses were attained by 17 (68%) of 25 assessable patients. Nine patients (36%) also achieved a cytogenetic response (3 complete responses, 4 partial responses, and 2 minimal responses), including 4 patients harboring mutant Bcr-Abl tyrosine kinases. One patient bearing the highly imatinib-resistant T315I mutant achieved a partial cytogenetic response. The median response duration was 3 months (range, 2-30+ months).


CONCLUSIONS
The combination of tipifarnib and imatinib is well tolerated and has activity against several Abl kinase domain mutants. Combinations of tipifarnib with more potent tyrosine kinase inhibitors warrant further investigation.
Cortes
Jorge
J
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. jcortes@mdahderson.org
Quintás-Cardama
Alfonso
A
Garcia-Manero
Guillermo
G
O'Brien
Susan
S
Jones
Dan
D
Faderl
Stefan
S
Ebarb
Theresa
T
Giles
Francis
F
Thomas
Deborah
D
Kantarjian
Hagop
H
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D015363:Quinolones; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C402769:tipifarnib