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

• Published in: Cancer 2007-11, Vol.110 (9), p.2000-2006
• Main Authors: Cortes, Jorge, Quintás‐Cardama, Alfonso, Garcia‐Manero, Guillermo, O'Brien, Susan, Jones, Dan, Faderl, Stefan, Ebarb, Theresa, Giles, Francis, Thomas, Deborah, Kantarjian, Hagop
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - adverse effects; BCR‐ABL; Benzamides; Biological and medical sciences; chronic myelogenous leukemia; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl - drug effects; Hematologic and hematopoietic diseases; Humans; imatinib; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Maximum Tolerated Dose; Medical sciences; Middle Aged; mutations; Piperazines - administration & dosage; Piperazines - adverse effects; Pyrimidines - administration & dosage; Pyrimidines - adverse effects; Quinolones - administration & dosage; Quinolones - adverse effects; tipifarnib; Tumors
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.23006

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. © 2007 American Cancer Society. Therapy with imatinib mesylate induces complete cytogenetic response in the majority of patients with newly diagnosed chronic myelogenous leukemia (CML). Unfortunately, a significant proportion of patients develop resistance to imatinib therapy, mainly through mutations in the kinase domain of BCR‐ABL, and most harbor detectable levels of molecular residual disease. A potential strategy to overcome these limitations of imatinib therapy is to interfere with BCR‐ABL downstream pathways such as the Ras pathways. Tipifarnib is a farnesyl transferase inhibitor that has shown in vitro synergism with imatinib. In the current phase 1 study, the combi