Phase I study to determine tolerability and pharmacokinetics (PK) of SB-743921, a novel kinesin spindle protein (KSP) inhibitor

Abstract

2010 Background: The mitotic kinesin KSP, plays an exclusive and essential role in assembly and function of the mitotic spindle. It is expressed in proliferating tumor cells, but is not expressed in terminally differentiated neurons. Targeting KSP may lead to the development of novel anti-mitotic drugs that lack neurotoxicity associated with anti-tubulin agents. SB-743921, the second KSP inhibitor to be evaluated in clinical trials, is a potent and selective inhibitor of KSP with a Ki of 100 pM and > 40,000-fold selectivity versus other kinesins. In pre-clinical studies, SB-743921 caused mitotic arrest and potent inhibition of tumor cell proliferation. SB-743921 was active in a broad range of human tumor xenografts. In some models, doses well below the maximum tolerated dose (MTD) of SB-743921 produced tumor regressions and cures. Methods: We initiated a phase I study to determine the MTD, tolerability, and PK profile of SB-743921 administered, IV over 60-minutes every 21 (Q 21) days (d). Interim Results: Eleven patients (pts) (M/F 6/5), median age 62 yrs (range 32- 73), with solid tumors were treated at doses of 2 - 8 mg/m2. Common tumor types included NSCLC (n=2), HCC (n=2), and CRC (n=2). Prolonged (≥5 d) Grade (Gr) 4 neutropenia was observed in 1 pt at 8 mg/m2 leading to an expanded cohort of 6 pts. Three further pts experienced a DLT in this cohort: prolonged Gr 4 neutropenia (n=2), Gr 3 elevated ALT/AST (n=1), and Gr 3 elevated bilirubin (n=1). The most common toxicities (all Gr 1) observed during this study included headaches (n=3), chills (n=3), nausea (n=3), myalgias (n=2), and injection site reactions (n=2). Gr 3 toxicities included neutropenia (n=1), acute abdominal pain (n=1), ileus (n=1), and fatigue (n=1). Median PK values in cycle 1 at 8 mg/m2 were as follows: Cmax 803.6 ng/ml, AUC0-∞ 10350.7 ng.hr/ml, and t½ 30.3 hr. Increases in AUC0-∞ and Cmax were dose-related. Conclusion: This is the first study of SB-743921 in humans. The MTD was exceeded at 8 mg/m2 Q 21 days due to prolonged neutropenia and hepatic lab abnormalities. Further dose exploration will continue at 6 mg/m2 to determine a MTD. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline Amgen, GlaxoSmithKline, Kosan, Pfizer, Roche, sanofi-aventis