Glufosfamide: beta-D-Glc-IPM, D 19575

Glufosfamide [D 19575, beta-D-Glc-IPM] is a next-generation glucose conjugate of ifosfamide that is under development with Threshold Pharmaceuticals for the treatment of cancer. It is an alkylating agent in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is glycosidically linked to beta-D-glucose. Cellular uptake of glufosfamide is mediated by a sodium-dependent transmembrane transporter protein of glucose and possibly also by other transporter proteins. Threshold is using its Metabolic Targeting technology to exploit unique aspects of tumour metabolism, particularly the elevated glucose utilisation of tumour cells to selectively target glufosfamide to the tumour site. Glufosfamide was originally developed from a research collaboration between Asta Medica (Degussa) and the Cancer Research Centre (DKFZ) in Heidelberg, Germany. In October 2001, Baxter International acquired the oncology division of ASTA Medica, and renamed it Baxter Oncology GmbH. According to its 2002 Annual Report, Baxter announced that it was terminating development of glufosfamide. Subsequently, Baxter and Threshold Pharmaceuticals entered into an exclusive licensing and development agreement in August 2003. Threshold has responsibility for the development and commercialisation of glufosfamide, primarily for use as an antitumour agent. In addition, Baxter manufactures glufosfamide on Threshold's behalf. Threshold received fast-track status for glufosfamide from the US FDA in the treatment of metastatic pancreatic cancer refractory to gemcitabine in November 2004. In December 2004, Threshold initiated a phase I/II trial (TH-CR-301 Study) investigating glufosfamide in combination with gemcitabine as a first-line treatment of pancreatic cancer or advanced solid tumours. The phase I portion of the study may enroll up to 15 patients. The maximum tolerable dose combination determined will then be used in the phase 2 portion of the study. Up to 42 patients with advanced pancreatic cancer will be enrolled at various sites in the US, Latin America and Brazil.Previously, glufosfamide had been in phase II trials among patients with pancreatic carcinoma in Germany with Baxter Oncology and with the EORTC in the UK as well as Greece. However, development has been discontinued.