7006 Background: Bosutinib (SKI-606) is an orally available, dual Src/Abl kinase inhibitor. To assess safety and preliminary clinical activity of bosutinib, we conducted a phase 1/2 study in patients (pts) with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who were imatinib resistant/intolerant. Methods: In part 1, 18 pts with imatinib- relapsed/refractory chronic phase (CP) CML received bosutinib 400 mg/day (3 pts), 500 mg/day (3 pts), or 600 mg/day (12 pts). Part 2 was an expanded cohort of 51 pts with all phases of Ph+ CML and ALL dosed at 500 mg daily. Timed blood samples were collected on days 1–3, 15 for PK analysis. Results: Of 69 pts, median age was 59 yrs; 48 were CP; 90% imatinib resistant. Drug-related grade 1/2 adverse events (AEs) occurring in =10% of CP pts: diarrhea (69%), nausea (44%), vomiting (19%), abdominal pain (13%), rash (13%). Grade 3/4 AEs occurring in =5% of CP pts: rash (6%), thrombocytopenia (6%). 17 pts required dose reductions. In evaluable imatinib-resistant CP-CML pts with no prior exposure to other Abl inhibitors, 16/19 (84%) had complete hematologic response (CHR); 4/21 had partial and 7/21 had complete cytogenetic responses for major cytogenetic response (MCyR) rate of 52%. Of 58 pts evaluable for mutations, 13 different imatinib-resistant mutations were found in 32 pts. 12/14 CP pts with non-P-loop mutations and 3/3 with P-loop mutations achieved CHR. 5/11 CP pts with non-P- loop mutations and 1/1 with P-loop mutation achieved MCyR. 4/9 evaluable advanced leukemia pts had CHR, 2 had MCyR. After oral administration, steady state exposure of bosutinib was nearly 2-fold higher than single-dose exposure. Mean elimination half-life was approximately 22–27 hours, supporting a once-daily dosing regimen. Conclusions: Bosutinib was well tolerated in pts with CML, with primarily low-grade gastrointestinal and dermatologic AEs. Bosutinib showed clinical activity in imatinib-resistant pts with cytogenetic responses and CHR across a range of mutations. Durability of response continues to be assessed. [Table: see text]
Phase 1 study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance