Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 7006
© 2007 American Society of Clinical Oncology

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Abstract

Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib

Opedale San Gerardo-Monza, Monza, Italy; Universitaetsklinikum Hamburg, Hamburg, Germany; MD Anderson Cancer Center, Houston, TX; University of Bologna, Bologna, Italy; New York Medical College, Valhalla, NY; Universitaetsklinikum Mainz, Mainz, Germany; Wyeth Research, Cambridge, MA; Wyeth Research, Collegeville, PA

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.

Author Disclosure

Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Expert Testimony Other Remuneration Wyeth Research Wyeth Research Wyeth Research

Abstract presentation from the 2007 ASCO Annual Meeting

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