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

Abstract

2000 Background: SB-743921, a potent and selective inhibitor of KSP (Ki =100 pM; >40,000-fold selectivity vs other kinesins), causes mitotic arrest, potent inhibition of tumor cell proliferation, and demonstrates activity in a broad range of human tumor xenografts. Methods: A phase I study was conducted to determine the maximum tolerated dose (MTD) and PK profile of SB-743921 when administered IV over 60 minutes every 21 (Q 21) days (d). Results: 44 patients (pts) (M/F 19/25), median age 61.5 yrs (range 32–80, with solid tumors were treated at doses of 2 (n=2), 4 (n=27), 5 (n=6), 6 (n=3), and 8 (n=6) mg/m2 (median cycles 2, range 1–10, total cycles 101). Frequent tumor types included colorectal (n=11), ovarian (n=5), NSCLC (n=5), esophageal (n=4), and pancreatic (n=4). Dose-limiting toxicities (DLTs) at 8 mg/m2 consisted of (max CTC grade/pt) prolonged grade (gr) 4 neutropenia (n=2), gr 3 elevated ALT/AST (n=1), and gr 3 elevated bilirubin (n=1). DLTs at 6 mg/m2 were gr 3 hyponatremia (n=1) and prolonged gr 4 neutropenia (n=1). DLTs at 5 mg/m2 were limited to febrile neutropenia (n=2). The 4 mg/m2 dose level was determined as the phase II dose. Toxicities at 4 mg/m2 included gr 1 fatigue (n=8) and neutropenia [gr 1 (n=4), gr 2 (n=7), gr 3 (n=3), gr 4 (n=2)]. Neutropenia nadir was day 6–8 with recovery to gr ≤2 by day 15. Gr 3 non-hematologic toxicities at 4 mg/m2 included gr 3 ALT (n=1), gr 3 AST (n=2), gr 3 hyperbilirubinemia (n=1), gr 3 hypophosphatemia (n=1), and gr 3 alkaline phosphatase elevation (n=1). Median PK values in cycle 1 at 4 mg/m2 were: Cmax 473 ng/ml, AUC0-∞ 5207 ng.hr/ml, and t½ 36 hr. AUC0-∞ and Cmax were proportional to dose. No consistent correlation was observed between DLTs and PK parameters. Stable disease for ≥ 4 cycles (range 4–11) was observed in 6 pts (4 pts at 4 mg/m2; 1 pt at 6 mg/m2; 1 pt at 8 mg/m2). A pt with cholangiocarcinoma had evidence of radiographic tumor regression (post cycle 10) and a >50% decrease in her CA 19–9. Conclusions: The recommended phase II dose of SB-743921 on the Q 21 day schedule is 4 mg/m2. The observed toxicities at the recommended phase II dose are manageable and reversible. The onset and duration of neutropenia is predictable. [Table: see text]