A phase I-II trial of Ispinesib, a kinesin spindle protein inhibitor, dosed every two weeks in patients with locally advanced or metastatic breast cancer previously untreated with chemotherapy for metastatic disease or recurrence.

Abstract

Abstract Abstract #2148 Kinesin Spindle Protein (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. When dosed on a q21d schedule, the maximum tolerated dose (MTD) was 18mg/m2 and neutropenia was the dose-limiting toxicity (DLT), with nadir at 7-10 d and recovery by d15. Activity was observed in a Phase II trial of ispinesib dosed at 18 mg/m2 q21d in patients (pts) with locally-advanced (LA) or metastatic breast cancer (MBC) after anthracycline and taxane failure (response rate 4/45 [9%]). This trial evaluates safety and efficacy of ispinesib in LA or MBC, given on d1 and d15 q28d, thus increasing dose density.
 Methods: This is a multicenter Phase I-II trial. In Phase I, DLT and MTD of ispinesib given d1 and d15 q28d will be determined. Eligibility criteria: LA or MBC; no prior chemotherapy (CT) except neoadjuvant or adjuvant and ≥ 1 year elapsed since CT; no CNS or leptomeningeal 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 1. Pharmacokinetic data are collected on d1 and d15 of Cycle 1. Phase II of this trial will evaluate efficacy (response rate by RECIST) of ispinesib at the MTD.
 Results: Phase I of the trial is ongoing. To date, 13 pts have been treated at 3 dose levels: 10 (n=2; 2 cycles, n=1; 6 cycles), 12 (n=1; 1 cycle, n=2; 3 cycles) and 14 mg/m2 (n=7; Cycle 1 ongoing). Among the first 6 pts, 4 were Stage IV, 3 had prior neoadjuvant and 2 adjuvant CT; 2 were chemo-naïve. Four had prior anthracycline and 3 prior taxane. Biomarker status was ER+, PR+, HER2- (n=3), ER+, PR-, HER2- (n=1), ER-, PR-, HER2+ (n=3), ER-, PR-, HER2- (n=4), and unknown (n=2). Mean age was 55 yr; for the first 2 dose levels (n=6 pts), the most frequent toxicity was neutropenia (n=4). Other events included mild GI toxicity. No neuropathy or alopecia has been reported. The only grade 3 or 4 toxicity was neutropenia (n=2). At the 14 mg/m2 dose level, one DLT has been reported: a grade 3 transaminase (AST) elevation in a patient with liver metastases which resolved with a dose delay of 4 days. As a result, this cohort was expanded to include 6 evaluable pts. One additional patient at the 14mg/m2 dose had a dose delay of 5 days due to non-DLT neutropenia.
 Conclusions: Ispinesib appears to be well tolerated on a q2w dosing schedule at doses tested to date. A dose-density equal to that administered in the prior Phase II trial (0.86 mg/m2/day) was tolerated with the new q2w schedule. Dose escalation is ongoing. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2148.