Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV days 1, 8, 15 q 28 days

Abstract

2004 Background: The mitotic kinesin KSP plays an exclusive and essential role in assembly and function of the mitotic spindle. KSP represents a novel target for development of therapeutics against cancer. SB-715992 is a unique and selective inhibitor of KSP, that is preferentially overexpressed in malignant cells, functions exclusively in mitosis, and is not expressed in terminally differentiated neurons. In pre-clinical studies in a broad range of human tumor xenografts, doses of SB-715992 below the MTD produced tumor regression and cures. Methods: The current study determines the safety, MTD, and PK profile of SB-715992 administered over 1-hour on days 1, 8, 15 q 28 days. Results: 27 patients (pts) (M/F 15/12) with solid tumors were treated at doses of 1 to 8 mg/m2. Median age was 53 years (range 29–78). Common tumor types included CRC (5), RCC (4), breast (4), and lung (3). 2 pts developed DLT at 8 mg/m2 consisting of Grade (Gr) 3 neutropenia, resulting in the inability to administer the d 15 dose. The 7 mg/m2 dose level was expanded as a potential recommended phase II dose. No Gr 3 or 4 toxicities have been observed at this dose level. At dose levels < 4 mg/m2 drug-related Gr 2 constipation (n=1) and Gr 2 anemia (n=1) were observed. At dose levels ≥ 4 mg/m2, Gr 2 neutropenia (n=2), Gr 3 neutropenia (n=1), Gr 2 anemia (n=1), Gr 3 anemia (n=1), and Gr 3 transaminitis (n=1) have been noted. Increases in AUC0-∞ and Cmax are dose-related without accumulation following multiple doses. SD was observed for 3–4 cycles in 3 pts with RCC, SCCHN, and CRC. For the 7 mg/m2 dose level in Cycle 1, Day 1and 15 median PK values (n=6) were Cmax = 349 and 218 ng/mL; AUC0-∞ = 2965 and 1994 ng.h/mL; t1/2 = 37 and 22 hrs; CL = 5196 and 7546 mL/hr; and Vss = 235 and 240 L. Conclusion: SB-715992 administered on days 1, 8, 15 q 28 days at 7 mg/m2 is the MTD and is recommended for phase II investigations. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline