A Phase I-II Trial of Ispinesib, a Kinesin Spindle Protein Inhibitor, Dosed Every Two Weeks as First Line Chemotherapy for Advanced Locally Recurrent or Metastatic Breast Cancer.

Abstract

Abstract Background: 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) was18 mg/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 as 1st line chemotherapy (CT) in LA or MBC given on d1 and d15 q28d, which may increase 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 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 (cy) 1. Pharmacokinetic data are collected on d1 and d15 of Cy 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, 16 pts were treated at 3 dose levels: 10 (1 cy, n=1; 3 cy, n=1; 6 cy, n=1), 12 (≤1063 cy, n=4; 6 cy, n=1; 10 cy, n=1) and 14 mg/m2 (≤3 cy, n=4; 4 cy, n=2; 12+ cy, n=1). Mean age was 50 yr. 9 pts were Stage IV, 7 Stage IIIB/C; 11 were chemo-naïve; 5 had prior anthracycline and/or taxane; 4 were HER2+ and 5 ER-, PR-, HER2-. The most frequent toxicity was neutropenia: 88% of pts in Cy 1; grade 3/4 in 75%; duration ≤5d; no febrile neutropenia. Diarrhea was reported in 25% and nausea in 19%; all grade 1/2. There was no neuropathy or alopecia. Increased ALT, AST and alkaline phosphatase were reported in 56%, 31% and 19% of pts, respectively. 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 pt had liver metastases; neither pt had significant increases in alkaline phosphatase or bilirubin. The 12 mg/m2 cohort was expanded to 6 pts without DLT. There was no cumulative toxicity with continued dosing. 3 pts had partial response, after 1 (n=1) and 4 (n=2) cy, respectively; 1 confirmed by RECIST with duration of 24 weeks; 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 and above, as warranted by safety and tolerability, is planned. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6103.