A phase I-II open-label trial of ispinesib on an alternate dosing schedule in chemotherapy-naive patients with locally advanced or metastatic breast cancer (MBC)

Abstract

1143 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. In the first-in-humans trial, the maximum tolerated dose (MTD) was 18 mg/m2 q21 days (d). Neutropenia, the dose-limiting toxicity (DLT), reached nadir at 7–10 d and recovered fully by d15. Other toxicities ≥ grade 3 were uncommon and unrelated to dose. A prior phase II trial evaluating ispinesib at 18 mg/m2 q21d in patients (pts) with locally advanced or MBC which recurred or progressed after treatment with anthracyclines and taxanes identified partial responses (RECIST) in 4 of 45 evaluable pts in this heavily pre-treated population. Ispinesib was also well tolerated in this trial; neutropenia again reached nadir at 7–10 d and recovered by d15 with no cumulative effect, suggesting ispinesib may be given on d1 and d15 q28d, thus increasing dose density (and possibly efficacy) while maintaining favorable tolerability. Methods: Phase I of this trial determines the DLT and MTD of ispinesib given d1 and d15 q28d as 1st-line therapy for locally advanced (Stage IIIB) or MBC (Stage IV). Pts are either chemotherapy-naïve or ≥ 1 year has elapsed since adjuvant or neoadjuvant treatment with anthracycline-based chemotherapy. Ispinesib is given to cohorts of 3 pts on d1 and d15 q28d, starting at 10 mg/m2 and escalates based on tolerability. A cohort expands to 6 pts if 1/3 pts have a DLT. Phase II of this trial evaluates the potential efficacy of ispinesib at the phase I MTD in pts with locally advanced or MBC who have had no prior chemotherapy. The primary endpoint is response rate by RECIST. Results and Conclusions: Enrollment initiated with ispinesib at 10 mg/m2 given d1 and d15 q28d. Data from phase I (DLT, MTD, and potential efficacy) will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Cytokinetics