Date: 2012-12-05
Type of information:
phase: 1
Announcement: results
Company: 4SC (Germany)
Product: 4SC-205
Action
mechanism: 4SC-205 is a specific small molecule inhibitor of the human kinesin spindle protein Eg5 which is of crucial importance for cell division (mitosis). Eg5 interacts with microtubules, a component of the cellular mitosis machinery, and mediates the segregation of the two spindle poles resulting in the correct distribution of the chromosomes to the daughter cells. Inhibition of Eg5 leads to cell cycle arrest in mitosis und subsequent programmed cell death (apoptosis). In preclinical tests 4SC-205 has proven to be a particularly effective inhibitor of tumour cell proliferation of various cancer origins, both in vitro and in vivo.
Disease: cancer
Therapeutic area: Cancer - Oncology
Country:
Trial details: The \'first-in-man\', two-centre, dose-escalating Phase I study (\'AEGIS\' study) investigated safety, tolerability, pharmacokinetics, and pharmacodynamics of 4SC-205 in 46 patients with advanced solid tumours. In two treatment cycles, each over three weeks, patients were treated with ascending oral doses of 4SC-205 in order to establish the MTD and potential DLTs. Patients were treated in two different dose schedules: in the first dose schedule, patients received once-weekly dosing on days 1 and 8 of each cycle; in a second dose schedule patients received twice-weekly dosing on days 1, 4, 8 and 11 of each cycle.
Latest
news: 4SC AG, a discovery and development company of targeted small molecule drugs for autoimmune diseases and cancer, has announced clinical data of the Phase I \'AEGIS\' trial with the anti-cancer compound 4SC-205 in tumour patients. All primary study objectives were achieved. A comprehensive safety and tolerability profile of 4SC-205 was established. As well as ascertaining the maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), an excellent pharmacokinetic profile of the oral compound was established. In addition, the analysis of pharmacodynamic biomarkers demonstrated the intended mode of action.
In patients receiving once-weekly dosing, the MTD was established at the 150 mg dose level; in patients receiving a twice-weekly dosing, an MTD of 75 mg was established. DLTs were reached at the treatment doses of 200 mg with once-weekly dosing and of 100 mg with twice-weekly dosing. Main side effects at DLT level were neutropenia and stomatitis of grade 3-4.
Moreover, 4SC-205 showed an excellent pharmacokinetic profile with a dose proportional increase of exposure and an elimination half-life of about 10 hours providing the basis for effective dosing schedules since the biological activity of the compound could be demonstrated via biomarker analysis of patients\' skin biopsy samples. Here, a dose dependent accumulation of cells arrested in cell division could be observed. Thus, 4SC-205 effectively exhibits the anticipated mode of action - inhibition of cell division (mitosis) - at clinically tolerated doses.
The study data and new preclinical findings about the therapeutic target warrant further clinical evaluation of 4SC-205 in cancer patients. The Company, therefore, has decided on a study amendment, which will evaluate a new, adapted dosing scheme. The clinical findings generated to date from this trial as well as new preclinical data about the therapeutic target and distribution of 4SC-205 in tissue, strongly support further clinical investigation of the compound applying an additional treatment schedule. The study has, therefore, been amended in order to investigate a new and innovative dosing scheme of 4SC-205 for the first time in cancer patients. According to the amendment, another 9 to 12 eligible patients are expected to be enrolled in the trial. Following recent approval of the amendment by authorities, the first patient has now been treated. The results of the amended AEGIS study protocol are expected for mid 2013.
