Overcoming the proliferation rate paradox: Clinical evaluation of a continuous dosing scheme of the novel oral Eg5 inhibitor 4SC-205.

2528 Background: Mitotic proteins, like Eg5, are exclusively expressed during mitosis. Targeted therapy directed against such proteins prevents side-effects like peripheral neuropathies. However, mitosis is a timely restricted event and doubling times of human solid tumours (~120d) largely exceed the ones observed in preclinical models. Therefore, continuous exposure at the target site is mandatory. Here we present a clinical dosing scheme for the Eg5i 4SC-205 to address these challenges Methods: Time-dependent anti-proliferative effect of 4SC-205 on spindle check point (SAC) deficient (H929, HT29) and proficient (HCT116, NCCIT) cell lines was investigated. Apoptosis induction was assessed by western blot analysis for Noxa, Mcl-1 and caspase 3. 59 patients (pts) with solid tumours were enrolled in a Phase I study and dosed either once weekly (ow) at days 1 and 8 or twice weekly (tw) at days 1, 4, 8, and 11 or continuously (con) within a 21-day cycle. Results: Effects on proliferation and apoptosis inducti...