A phase I dose-escalation study of the novel KSP inhibitor ARRY-520 in advanced leukemias

Abstract

7022 ARRY-520 is a potent, selective KSP inhibitor that arrests cells in mitosis with the subsequent onset of apoptosis. ARRY-520 has shown potent activity in preclinical models of hematological cancers and is being evaluated in a phase I trial in patients with advanced or refractory leukemias. The primary objectives of this study are to establish the safety and the MTD of ARRY-520 given as a single dose each cycle. Secondary objectives are to characterize the pharmacokinetics (PK) of ARRY-520, to assess evidence of preliminary clinical activity, and to explore biomarkers of KSP inhibition. ARRY-520 is administered as a 1-h IV infusion as a single dose per cycle in a “3 + 3 phase I design”. Dose escalations are following a prespecified schema. PK analyses for ARRY-520 are performed on plasma samples collected during cycle 1 and cycle 2. Pretreatment and post-treatment peripheral blood samples are collected for analysis of markers of KSP activity. To date, 15 patients, with a median age of 69 yrs (range 44–84 yrs), have been enrolled in the single dose schedule, 3 patients each at doses of 2.5 mg/m2, 3.75 mg/m2, and 5.6 mg/m2 and 6 patients at 4.5 mg/m2 per cycle. All patients had disease refractory to, and/or relapsed from, 1 or more prior therapies with a median of 3 prior regimens (range 1–10). Two patients at 5.6 mg/m2 experienced a DLT of gr3 mucositis. ARRY-520 was well tolerated at doses below 5.6 mg/m2. 4.5 mg/m2 has been determined to be the MTD. ARRY-520 has shown promising signs of clinical activity at doses of 3.75 mg/m2 and above. 2 patients had a complete reduction in their peripheral blasts on day 5 of cycle 1. Of these, one patient experienced a 70% reduction in bone marrow blasts while on study. One patient without peripheral blood blasts at baseline had a 43% reduction in bone marrow blasts and four additional patients had marked reductions in WBC counts. This is the first reported use of a KSP inhibitor in refractory and/or relapsed leukemias. ARRY-520 has been well tolerated in patients on a single dose schedule. Mucositis was observed as the DLT at 5.6 mg/m2. At doses 3.75 mg/m2 and above, ARRY-520 has shown signs of clinical activity. Based on these data, an alternative dose schedule is being explored. Updated data including safety, PK, PD, and preliminary activity of ARRY 520 from this study will be presented. [Table: see text]