Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days

Abstract

2078 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: A phase I study was conducted to determine the MTD, safety, and PK profile of SB-715992 Q 21 d IV.Results: 42 patients (pts) (M/F 31/11) with solid tumors were treated at doses of 1 to 21 mg/m2. Median age 61 years (range 37–85). Common tumor types included CRC (15), RCC (5) sarcoma (4), and lung (4). 2 pts developed DLT at 21 mg/m2 consisting of Grade (Gr) 4 neutropenia ≥ 5 days (1 pt) and Gr 4 neutropenic fever (1 pt). The 18 mg/m2dose level was expanded as a recommended phase II dose; 12 pts (18 cycles of safety data) have been treated. 2 DLTs have been observed at this dose level consisting of Gr 4 neutropenia ≥ 5 d; non-dose limiting Gr 3 or 4 neutropenia and Gr 4 leukopenia occurred in 7 (58%) and 1 (8%) pts. Neutropenic nadir occurred on day 8 and lasted 2–4 d. Common ≥ Gr 2 drug related toxicities at ≥ 6 mg/m2 included fatigue, leukopenia, and anemia. SD was observed for 5–11 cycles in 4 pts with CRC, HCC, SCCHN, & RCC. Increases in AUC0-∞and Cmax were dose-related. For the 18 mg/m2 dose level in Cycle 1, median PK values (n=6) were Cmax = 473 ng/mL; AUC0-∞= 5074 ng.h/mL; t1/2 = 33 hrs; CL = 6656 mL/hr; and Vss = 236 L. Monopolar mitotic spindles were observed in a tumor biopsy from a pt w/ SCCHN at 16 mg/m2.Conclusion: Based on the toxicities noted, 18 mg/m2 Q 21 d IV, which has been demonstrated to induce relevant biological effects in vivo, is recommended for phase II investigations. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cytokinetics, Inc.