CD44v6 is an isoform of the CD44 family of transmembrane glycoproteins for hyaluronan. High CD44v6 expression was correlated with tumor invasion, metastasis, recurrence and chemoresistance. CD44v6 is a co-receptor of the receptor tyrosine kinases c-Met, RON and VEGFR-2 that play a critical role in the development and progression of many types of cancer. Inhibition of CD44v6 efficiently blocks activation of c-Met, RON and VEGFR-2 and intracellular downstream signaling processes. AMC303 is a highly specific and selective inhibitor of CD44v6 for which strong anti-tumor activity was demonstrated in vitro and in vivo. In xenotransplantation animal models, intermittent application of AMC303 resulted in a marked reduction of the primary tumor, prevention of metastatic spread and regression of existing metastases. Good safety and tolerability were demonstrated in pre-clinical studies. The starting dose of 0.1 mg/kg and dose escalation steps are based on the safety profile and are supported by modelling of human pharmacokinetic (PK) profiles from animal exposure studies. Blocking of CD44v6 by AMC303 represents a novel and promising approach to block cancer related RTK pathways by an extracellular acting drug.
A First-in-Human Phase I/Ib study in cancer patients was initiated (NCT03009214). The study was designed as a two part open-label, non-randomized, multicentre, dose escalation study with a 3 + 3 design (Part 1) and an expansion cohort at the Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) (Part 2). Inclusion and exclusion criteria are: Type of cancer (e.g. epithelial cancer for which CD44v6 is known to be highly expressed), ECOG status 0-2, and adequate hematological, renal and hepatic function. Cancer patients are enrolled after failure of conventional therapy or for whom no standard treatment is available. The primary endpoints in Part 1 are safety and tolerability and PK properties. The effects of AMC303 on RTK pathways are analysed in plasma samples (ELISA and Luminex) and mandatory tumor biopsies (immunohistochemistry, protein profiling). Part 2 will focus on selected tumor types as evaluated from the pharmacological effects of AMC303 in part 1.
Clinical trial identification
EudraCT number: 2016-001358-16
Legal entity responsible for the study
H. Bender, K. Dembowsky: Employee by amcure GmbH and stock holder. All other authors have declared no conflicts of interest.