A phase I/II trial of ispinesib, a kinesin spindle protein (KSP) inhibitor, dosed q14d in patients with advanced breast cancer previously untreated with chemotherapy for metastatic disease or recurrence

Abstract

1077 Background: KSP is a mitotic kinesin essential for cell cycle progression. Ispinesib, a selective KSP inhibitor, blocks mitotic spindle assembly with cell cycle arrest in mitosis and subsequent cell death. On a q21d schedule, the MTD was 18 mg/m2. In a phase II trial of ispinesib dosed at 18 mg/m2 q21d in patients (pts) with advanced breast cancer after anthracycline and taxane failure, the response rate was 4/45 (9%). This trial evaluates ispinesib given on d1 and d15 q28d, thus increasing dose density. Methods: In phase I of this phase I/II trial, DLT and MTD of ispinesib given d1 and d15 q28d will be determined. Eligibility criteria: advanced breast cancer; no prior chemotherapy (CT) except neoadjuvant or adjuvant and ≥ 1 yr elapsed since CT; no CNS metastases; ECOG 0–1. This is a standard 3+3 dose escalation trial design, starting at 10 mg/m2 and escalating based on tolerability in cycle (cy) 1. Pharmacokinetic data are collected in cy 1. Results: Phase I of the trial is ongoing. 16 pts were treated at 3 dose levels: 10 (n = 3), 12 (n = 6), and 14 mg/m2 (n = 7). 9 pts were stage IV; 11 were chemo-naïve; 5 had prior anthracycline and/or taxane; 4 were HER-2+ and 5 ER-, PR-, HER-2-. The most frequent toxicity was neutropenia. 88% of pts in cy 1 (grade 3/4 in 75%; no febrile neutropenia). Mild GI toxicity occurred in <37.5% of pts. There was no neuropathy or alopecia. At the 14 mg/m2 dose level, 2/7 pts had DLTs of transient grade 3 AST and ALT increases after cy 1 d15 dosing; both without increases upon retreatment; 1 in a pt with liver metastases; neither pt had significant increases in alkaline phosphatase or bilirubin. The 12 mg/m2 cohort was expanded to 6 pts without DLT. 3 pts had partial response (after 1 [n = 1] and 4 [n = 2] cy, respectively); 1 confirmed and ongoing after 8+ cy; 4 pts had stable disease ≥4 mo. Conclusions: Ispinesib appears to be well tolerated on a q14d dosing schedule at doses tested to date. A dose-density equal to that given in the prior phase II trial (0.86 mg/m2/d) was tolerated with the q14d schedule with preliminary evidence of efficacy. Further exploration of the 14 mg/m2 dose level is planned. [Table: see text]