For the patients with major cytogenetic responses, the pretreatment regimens and the associated reasons for changes in therapy are listed in Table 4, which also provides the mutation status at baseline. Two additional epigallocatechin (-)-Epigallocatechin gallate patients achieved a minimal cytogenetic response. Complete and partial hematologic responses were observed in 3 patients. Pharmacokinetics Illustrative of the pharmacokinetic data seen in the full analyses, the pharmacokinetic parameters of INNO 406 in the 240 mg BID cohort are presented here. This cohort was selected based on clinical safety and efficacy evaluations that took events at the higher doses into consideration. As illustrated in Figure 2, accumulation of INNO 406 was observed on day 15 for both the 360 and 480 mg BID cohorts.
For the 240 mg BID cohort, the mean time to achieve peak concentration was 1.3 hours. Pharmacokinetic analyses performed in the entire study population also demonstrated an increase in Cmax with increasing INNO 406 doses for both QD and BID dosing. The halflife was relatively short, mean half lives for BID dosing on day 1 and day 15 were Brivanib 1.99 hours and 2.28 hours, respectively. For BID dosing, the mean accumulation factor was 2.73. The maximum concentration and area under the curve were dose proportional, however, dose proportionality for AUC was not demonstrable with BID dosing. Mutational Analyses Mutational analysis performed at the central laboratories revealed mutations in 22 of 49 patients analyzed. Common mutations included Y253H in 6 patients, G250E in 4 patients, T315I in 4 patients, and F317L in 3 patients.
DISCUSSION This phase 1 study of INNO 406, a novel, potent dual BCR AbL/Lyn TKI, evaluated dose levels ranging from once daily doses of 30 to 480 mg and from BID doses of 120 to 480 mg. The DLTs observed included liver dysfunction and myelosuppression. The proposed INNO 406 dose scheduled for phase 2 study is 240 mg orally BID, and this value is based on the classical determinations of DLT and MTD from phase I studies. Lower dose schedules of INNO 406 may be as effective and should be explored. In this heavily pretreated study group of 56 patients, INNO 406 therapy resulted in 6 major cytogenetic responses, all in 31 patients treated for CML CP, for a major cytogenetic response rate of 19%. Of the 56 patients treated in this study, 71% were resistant to and 29% were intolerant of imatinib.
In addition, 26 patients experienced resistance to or intolerance of dasatinib, and 20 patients, resistance to or intolerance of nilotinib. In the majority of patients, therefore, prior treatment with multiple Bcr Abl TKIs had failed. As many of the patients in this study were being treated in the third line setting, a lower response rate would be expected than seen in the second line setting represented by the dasatinib and nilotinib studies. In this study, no responses were seen in patients with CML AP, CML BP, or Ph positive ALL. Major cytogenetic responses were noted in 6 patients with CML CP. Four of the responses occurred in patients in the cohort that received a starting INNO 406 dose of 240 mg BID or greater. This represents a major cytogenetic responses rate of 11% for all patients enrolled and a rate of 19% for patients with CMLCP. Major cytogenetic responses