click to enlarge This diagram represents the hypothetical mechanism of action for cilengitide (EMD 121974) that is currently the subject of clinical trials (Phase II, III). It is not intended to convey any inferences or conclusions regarding the safety or effectiveness of the compound. Neither the safety nor effectiveness of this investigational compound has been established.

Cilengitide is the first in a new class of investigational targeted anti-cancer therapies—called integrin inhibitors—to reach Phase 3 development. Integrin inhibitors potentially work by targeting both the tumor cells directly and inhibiting the formation of new blood vessels (angiogenesis) to the tumor. Cilengitide is a cyclic pentapeptide, which includes the amino acids arginine, glycine, and aspartic acid.

Cilengitide is thought to selectively inhibit specific cell surface integrin receptors, αVβ3 and αVβ5, which are expressed on endothelial cells forming blood vessels during angiogenesis and/or on certain tumor cells. Through targeting these integrins, cilengitide’s mode of action is thought to be two-fold: inhibiting angiogenesis, thus causing the tumor to ‘starve’ and cease growing or spreading, and/or acting on the tumor directly, thus depriving the integrins expressed by the tumor cells of important signals involved in growth, survival, and invasion.1

EMD Serono, Inc., an affiliate of Merck KGaA, Darmstadt, Germany, is currently conducting a randomized Phase 3 trial in glioblastoma with cilengitide called CENTRIC (CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma Phase 3 randomized Clinical trial). CENTRIC is designed to assess the efficacy and safety of the combination of cilengitide with temozolomide and radiation therapy versus temozolomide and radiation therapy alone in newly diagnosed glioblastoma multiforme (GBM) with methylated methylguanine-DNA methyltransferase (MGMT) gene promoter. The CENTRIC Study was initiated in response to the results of a Phase 1/2a multicenter single-arm study that evaluated the combination of cilengitide with temozolomide and radiotherapy in newly diagnosed glioblastoma.2
 
EMD Serono is also currently conducting a companion study to CENTRIC, called CORE (Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter). CORE is a randomized Phase 2 study to assess the efficacy and safety of two cilengitide regimens in combination with temozolomide and radiation therapy versus temozolomide and radiation therapy alone in newly diagnosed glioblastoma with unmethylated MGMT gene promoter.

References
1. Dechansreiter MA, et al. J Med Chem.1999;42 (16):3033-40.
2. Stupp R, et al. Society for Neuro-Oncology, 12th Annual Meeting, Dallas, TX, USA, November 2007, Abstract No. MA-10.