RESUMO
PURPOSE: Inhibition of kinesin spindle protein or Eg5 causes the formation of monoastral mitotic spindles, which leads to cell death. AZD4877 is a specific, potent inhibitor of Eg5. METHODS: This was a Phase I, open-label, two-part study to evaluate the maximum tolerated dose (MTD) and safety and tolerability of AZD4877 in patients with advanced solid malignancies. In part A, the MTD of AZD4877, administered as three weekly 1-h intravenous (iv) infusions in a 28-day schedule, was determined by evaluating dose-limiting toxicity (DLT). In part B, the safety, tolerability, and pharmacokinetic profile of AZD4877 at the MTD were evaluated. RESULTS: In part A, 29 patients received at least one dose of AZD4877 (5 mg, n = 4; 7.5 mg, n = 4; 10 mg, n = 3; 15 mg, n = 3; 20 mg, n = 3; 30 mg, n = 6; 36 mg, n = 3; 45 mg, n = 3). The MTD was defined as 30 mg, with the primary DLT being neutropenia. Although exposures appeared to be similar at the AZD4877 20 and 30 mg doses, dose reductions and omissions were higher in the 30-mg cohort; therefore, an intermediate dose, 25 mg, was evaluated in part B (n = 14). In part B, neutropenia remained the most commonly reported causally related adverse event. Exposure to AZD4877 was approximately dose proportional. Severity of neutropenia was related to exposure. CONCLUSION: The MTD of AZD4877 given as a 1-h iv infusion on days 1, 8, and 15 of a 28-day cycle was 30 mg. At the selected 25 mg dose, AZD4877 had an acceptable safety profile.
