INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib against CML cell line and BaF3 cells over expressing wild type Bcr-Abl. Numerous Bcr-Abl mutant proteins (except T315I) are sensitive to INNO-406 in vitro. INNO-406 inhibits ABL, KIT and PDGFR kinases and demonstrates specific Src kinase activity against Lyn kinase, resulting in greater selectivity than the dual ABL/SRC inhibitor dasatinib. This differential selectivity may result in an improved safety profile. In this phase I study, patients with imatinib-resistant or intolerant Philadelphia (Ph+) chromosome-positive leukemias were eligible for treatment with INNO-406. 12 pts [median age: 58 yrs (range 18-74); 5 male, 7 female; median CML duration: 53 months (range 5-266); median time on imatinib: 39 months (range 5-129); chronic phase CML (6 pts), accelerated phase CML (2 pts), blast phase CML (1 pt), Ph+ ALL (3 pts); previous treatment with nilotinib (5 pts) or dasatinib (2 pts)] have been enrolled in the following dose cohorts (mg/day): 30 (3 pts), 60 (3 pts) and 120 (6 pts), and have been on treatment between 7 and 123 days. 8/12 pts remain on study; 4 pts discontinued with disease progression: chronic phase CML (2 pts), blast phase CML (1 pt), Ph+ ALL (1 pt) [all data unmonitored]. The only INNO-406-related AE that has been reported was a grade 1 QTc interval elevation in one patient without any clinical sequelae. No fluid retention events have been reported. Early pharmacokinetic data have demonstrated INNO-406 blood levels comparable to drug concentrations found to be potent against Bcr-Abl cell lines in vitro.
Of the six patients who have completed at least 1 month of treatment, three have evidence of clinical response. Patient 5, a chronic phase CML treated with imatinib for 69 months before developing resistant disease with a Y253H mutation, has a cytogenetic response (minimal; 75% Ph+) after 1 month of INNO-406 therapy. Patient 4, an accelerated phase CML treated with imatinib and nilotinib for 16 and 6 months, respectively, before becoming intolerant to nilotinib, has maintained a complete hematologic remission following 3 months of INNO-406 therapy at a dose of 60 mg/day. Patient 1, a chronic phase CML treated with imatinib for 51 months before developing resistant disease without a mutation, has maintained stable white cell counts after 4 months of therapy at a dose of 30-60 mg/day, with a 55-fold reduction in Bcr-Abl transcript levels after 1 month of INNO-406 therapy.
INNO-406 is well tolerated in patients with CML and Ph+ ALL when administered at a dose of 120 mg/day, with encouraging evidence of clinical activity in imatinib-resistant and nilotinib-intolerant patients at the hematologic, cytogenetic, and molecular levels. In the absence of DLTs, dose escalation continues to identify a recommended phase II dose.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA