A phase I study of INNO-406, a dual inhibitor of Abl and Lyn kinases, in adult patients with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) relapsed, refractory, or intolerant of imatinib

Abstract

7046 Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl cell lines. Numerous Bcr-Abl mutant proteins (not T315I) are sensitive to INNO-406 in vitro. INNO-406 demonstrates specific Src kinase activity against Lyn kinase. Methods: In this phase I study, patients with imatinib-resistant or intolerant Philadelphia (Ph+) chromosome- positive leukemias were eligible for treatment with INNO-406 once a day, orally. Results: 14 pts [median age: 58 yrs (range 18–74); 7 male, 7 female; median CML duration: 53 mo. (range 14–266); and median time on imatinib 45 months (range 12–129); chronic phase CML (8 pts), accelerated phase CML (2 pts), blast phase CML (1 pt), Ph+ ALL (3 pts); previous treatment with nilotinib (5 pts), dasatinib (6 pts)] have been enrolled in the following dose cohorts (mg/day): 30 (3 pts), 60 (3), 120 (6) and 240 mg (2), and have been on treatment between 7 and 123 days. 3 pts remain on study; 10 pts discontinued with disease progression [data unmonitored]. 6 patients who have completed >1 month of treatment, 3 have evidence of clinical response. Patient 5, a chronic phase CML treated with imatinib for 69 mo. before developing resistant disease with an Y253H mutation, had a minimal cytogenetic response after 1 month of INNO-406 therapy. Patient 4, an accelerated phase CML treated with imatinib and nilotinib for 16 and 6 mo., respectively, before becoming intolerant to nilotinib due to thrombocytopenia, has maintained a complete hematologic response following 4.5 months of INNO-406 therapy at a dose of 120 mg/day. Patient 1, a chronic phase CML treated with imatinib for 51 mo. 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. Conclusions: INNO-406 is well tolerated in patients at a dose of 240 mg/day, with encouraging evidence of clinical activity in imatinib-resistant and nilotinib-intolerant patients. In the absence of dose limiting toxicity, dose escalation continues. No significant financial relationships to disclose.