95% of patients display a reciprocal translocation between chromosomes 9 and 22. The resulting Philadelphia chromosome abnormality yields a fusion gene encoding a constitutively active Bcr Abl tyrosine kinase that is considered essential for the pathophysiology of CML. 1, 2 In the United States, about 5000 people are diagnosed with CML each year.3 Historically, the  5 year survival rate for Ecdysone patients with CML in chronic phase was approximately 40%.4 Since the introduction in 2001 of the first specific Bcr Abl tyrosine kinase inhibitor, imatinib mesylate, the estimated 5 to 7 year survival rates for newly diagnosed patients with CML CP have increased to over 90%.5 8 As patients with CML live longer, prevalence of the disease is expected to increase over the coming years.
The success of imatinib demonstrates that specific inhibition of Bcr Abl kinase has clinical benefits in the treatment of CML. However, based on the findings of a 5 year follow up assessment, imatinib resistance occurs at a rate of approximately 4% per year.7, 8 Resistance is believed to be due to 3 main mechanisms: increased expression of Bcr Abl, Bcr MK-2206 Abl mutations, and the development of Bcr Abl independent resistance pathways, such as Lyn kinase activation.6, 9, 10 In patients with Ph positive acute lymphocytic leukemia, or those with CML in accelerated phase or blastic phase, imatinib treatment often fails to achieve high rates of complete cytogenetic response, these patients frequently develop resistance to therapy and relapse.
In 20% to 55% of such patients, treatment resistance can be attributed to the emergence of clones with mutant forms of Bcr Abl, which exhibit a decreased sensitivity to imatinib. More than 60 mutant forms of Bcr Abl have been detected,11 14 the most common of which are E255K, T315I, and M351T. Mutants have varying degrees of imatinib resistance,15 17 and thus more potent Bcr Abl inhibitors or dual Abl/Lyn inhibitors may improve treatment results. INNO 406, a dual Abl/Lyn tyrosine kinase inhibitor, may be an effective treatment for certain leukemias. INNO 406, was developed to overcome imatinib resistance.11, 12 Unlike other second generation TKIs, INNO 406 demonstrates specific Lyn kinase activity with no or limited activity against other Src family member kinases. Numerous Bcr Abl kinase domain mutations are sensitive to INNO 406 in vitro, including the F317L and F317V mutations.
INNO 406 is 25 to 55 times more potent than imatinib against Bcr Abl positive leukemic cell lines K562 and KU812 and against BaF3 cells overexpressing unmutated Bcr Abl. Autophosphorylation of unmutated Bcr Abl is also more potently inhibited by INNO 406 than by imatinib. In vivo, INNO 406 is at least 10 times more potent than imatinib.18, 19 Chemically, INNO 406 is a 2 phenlaminopyrimidine with structural resemblance to both imatinib and nilotinib. The molecular structure of INNO 406 is shown in Figure 1. This phase 1, open label, nonrandomized dose escalation study was conducted at 6 international sites from July 17, 2006, to November 28, 2007, to determine the safety, tolerability, pharmacokinetic profile, and clinical activity of INNO 406 administered orally daily in adult patients with Ph positive CML or ALL post imatinib resistance or intolerance. METHODS Patients