Dasatinib 140 mg QD compared to 70 mg BID in advanced-phase CML or Ph(+) ALL resistant or intolerant to imatinib: One-year results of CA180–035

Abstract

7025 Background: Dasatinib, an oral multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, has been shown to be safe and effective at 70 mg BID in advanced phase CML and Ph(+) ALL resistant or intolerant to imatinib. QD and BID schedules were equipotent in Phase I which led to this dose-optimization study. Methods: In this Phase-III, open-label, prospective study, patients with imatinib-resistant or intolerant advanced phase CML or Ph(+) ALL were randomized to dasatinib 140 mg QD or 70 mg BID. The primary objective compared the major hematologic response (HR) rate between the 2 regimens. Dose escalation was allowed for inadequate response and dose reduction for drug toxicity. Results: From June 2005 through March 2006, 611 patients (56% male) were randomized (median age 55 years). 42% of patients received imatinib at doses >600 mg/d and 37% were treated for >3 y. Response rates, with a median follow-up of 6.5 mo (range <1 to 17 mo), are summarized in the table below. Median durations of HR and progression-free survival were 10.2 and 7.9 mo for the 140-mg QD regimen vs 12.3 and 11.7 mo in the 70-mg BID arm. Drug-related toxicities in 140-mg QD (n=304) vs 70-mg BID (n=305) arms, respectively, listed as all grades (grade 3–4), were: pleural effusion 16% vs 23%, P=0.024 (5% vs 6%); peripheral edema 6% vs 13%, P=0.004 (<1%/1%); pericardial effusion <1% vs 4%, P=0.012 (0% vs 1%); neutropenia 85% vs 87% (65% vs 70%); thrombocytopenia 89% vs 92% (68% vs 70%). Dose reductions (24% vs 36%, P=0.002) and interruptions (47% vs 54%, P=0.105) were required less frequently for the 140-mg QD regimen, whereas dose escalations were more prevalent (33% vs 22%, P=0.005). Conclusions: Dasatinib 140 mg QD shows comparable hematologic and cytogenetic response and a trend for improved tolerability in relation to 70 mg BID. Further follow-up is ongoing to assess the long-term benefit of these two schedules in patients with ABP-CML or Ph(+) ALL; 1-year follow-up will be presented. [Table: see text] [Table: see text]