HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure.

AbstractBACKGROUND:
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.
AuthorsJorge Cortes, Alfonso Quintás-Cardama, Guillermo Garcia-Manero, Susan O'Brien, Dan Jones, Stefan Faderl, Theresa Ebarb, Francis Giles, Deborah Thomas, Hagop Kantarjian
JournalCancer (Cancer) Vol. 110 Issue 9 Pg. 2000-6 (Nov 01 2007) ISSN: 0008-543X [Print] United States
PMID17849425 (Publication Type: Clinical Trial, Phase I, Journal Article)
Chemical References
  • Benzamides
  • Piperazines
  • Pyrimidines
  • Quinolones
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • tipifarnib
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols (adverse effects)
  • Benzamides
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl (drug effects)
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
  • Maximum Tolerated Dose
  • Middle Aged
  • Piperazines (administration & dosage, adverse effects)
  • Pyrimidines (administration & dosage, adverse effects)
  • Quinolones (administration & dosage, adverse effects)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: