Abstract
Background: Treatment options for patients with metastatic brain cancer are limited and often focus on relief of symptoms. The main obstacle to treatment is the blood–brain barrier (BBB) which prevents most drugs from reaching tumour cells in the brain. Angiopep-2 is a 19 amino acid peptide shown in animal models to cross the BBB using a physiological approach through transcytosis via low-density lipoprotein receptor-related protein (LRP) expressed on the surface of the BBB. ANG1005 is a new chemical entity that combines 1 molecule of Angiopep-2 with 3 molecules of paclitaxel. Preclinical studies demonstrate the brain’s uptake of ANG1005 to be ~100x greater than paclitaxel and ~10x greater than temozolomide. Once in the brain compartment, ANG1005 again uses LRP, which is upregulated on metastatic brain cancer cells, to enter tumour cells where the molecule is cleaved releasing paclitaxel to exert its antimitotic effects. A Phase I clinical trial was initiated in Oct 2007 to explore the maximum tolerated dose and obtain data on safety, tolerability and preliminary evidence of efficacy of ANG1005 in patients with advanced solid tumours and/or brain metastases. Materials and methods: A multicenter, open-label, dose escalation study of ANG1005 is being conducted in the US with sequential dose cohorts ranging from 30-558 mg/m. ANG1005 is administered IV every 21 days. Study participants include adult patients with measurable disease and an ECOG performance status ≤ 2 who are ineligible for standard treatment options. Results: As of 06-Oct-2008, 27 patients with advanced solid tumours (melanoma, n=9; breast cancer, n=5; lung cancer, n=5; hepatocellular carcinoma, n=2; other, n=6) and/or brain metastases (n=18) have received ANG1005. Safety and tolerability have been demonstrated thus far. Anaemia, neutropenia and leucopenia, all established paclitaxel-related effects, were observed in the study to the present time. Conclusion: To date, the safety and tolerability profile of ANG1005 has been good in patients with advanced solid tumours and/or brain metastases. Angiopep conjugates may represent a potentially safe and effective way to treat currently unmanageable CNS diseases; ANG1005 is the first of many compounds to be tested as a means of overcoming restrictions to treatments due to the BBB.
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