{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T14:32:19Z","timestamp":1791124339017,"version":"4.1.0"},"reference-count":24,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2010,3,22]],"date-time":"2010-03-22T00:00:00Z","timestamp":1269216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancer"],"published-print":{"date-parts":[[2010,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>BACKGROUND:<\/jats:title><jats:p>INNO\u2010406, a dual v\u2010abl Abelson murine leukemia viral oncogene homolog (Abl)\/v\u2010yes\u20101 Yamaguchi sarcoma viral\u2010related oncogene homolog (Lyn) tyrosine kinase inhibitor (TKI), has demonstrated specific Lyn kinase inhibitory activity with no or limited activity against other sarcoma (Src) family member kinases. Several breakpoint cluster region (Bcr)\u2010Abl kinase domain mutations are sensitive to INNO\u2010406 in vitro, including mutations that involve a phenylalanine\u2010to\u2010leucine or phenylalanine\u2010to\u2010valine substitution at codon 317 (F317L and F317V, respectively). In the current study, the authors evaluated the use of INNO\u2010406 in patients with Philadelphia (Ph) chromosome\u2010positive chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) after imatinib resistance or intolerance.<\/jats:p><\/jats:sec><jats:sec><jats:title>METHODS:<\/jats:title><jats:p>A dose\u2010escalation study was conducted at a starting dose of oral INNO\u2010406 30 mg once daily. Cohorts of at least 3 patients were treated at each dose level until the maximum tolerated dose (MTD) was reached. Twice\u2010daily dosing also was evaluated. Therapy was allowed to continue for a maximum of 24 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>RESULTS:<\/jats:title><jats:p>INNO\u2010406 was administered to 56 patients with imatinib resistance (n = 40) or intolerance (n = 16). Other previous treatments included nilotinib (n = 20 patients), dasatinib (n = 26 patients), and dasatinib\/nilotinib (n = 9 patients). Common mutations at the time of study entry included a tyrosine\u2010to\u2010histidine substitution at codon 253 (Y253H) (n = 6 patients), a glycine\u2010to\u2010glutamic acid substitution at codon 250 (G250E) (n = 4 patients), a threonine\u2010to\u2010isoleucine substitution at codon 315 (T315I) (n = 4 patients), and F317L (n = 3 patients). Of 31 patients with CML in chronic phase who received INNO\u2010406, the major cytogenetic response rate was 19%. No responses were observed in patients who had CML in accelerated phase, CML in blastic phase, or Ph\u2010positive ALL. The dose\u2010limiting toxicities (DLTs) at an INNO\u2010406 dose of 480 mg twice daily were liver function abnormalities and thrombocytopenia.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS:<\/jats:title><jats:p>INNO\u2010406 had anti\u2010CML efficacy in a heavily pretreated study population. On the basis of the classic determinations of both DLT and MTD, the recommended phase 2 dose of oral INNO\u2010406 was 240 mg twice daily. Lower doses of INNO\u2010406 may be equally effective and should be explored. Cancer 2010. \u00a9 2010 American Cancer Society.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.25079","type":"journal-article","created":{"date-parts":[[2010,3,22]],"date-time":"2010-03-22T16:59:26Z","timestamp":1269277166000},"page":"2665-2672","source":"Crossref","is-referenced-by-count":44,"title":["Phase 1 study of INNO\u2010406, a dual Abl\/Lyn kinase inhibitor, in Philadelphia chromosome\u2010positive leukemias after imatinib resistance or intolerance"],"prefix":"10.1002","volume":"116","author":[{"given":"Hagop","family":"Kantarjian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phillipp 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