No dose-dependent trends have been observed in clinical or laboratory adverse events, including liver function tests (LFT). As previously presented at the ASCO 2010 meeting, a patient with advanced pancreatic neuroendocrine cancer with extensive involvement of the liver developed hepatic failure five days following the second dose at 0.7 mg/kg, and subsequently died; this was deemed possibly related to study drug. At 1.25 mg/kg, a patient experienced grade three thrombocytopenia after the first dose; this was deemed related to study drug and was resolved within five days. There have been three acute infusion reactions at 0.4, 0.7, and 1.25 mg/kg; all three patients tolerated further treatment with prolongation of infusion duration. None of these events preclude further dose-escalation.

This Phase I trial is also designed to obtain tumor biopsies from patient volunteers. To date, 17 biopsies have been obtained from nine patients. These include liver and extrahepatic tumors biopsies that have been obtained in patients who have received ALN-VSP at doses ranging from 0.4 to 1.25 mg/kg. Histopathological and molecular analyses are ongoing to assess drug delivery, RNAi mediated activity, and mRNA target engagement. Alnylam anticipates obtaining multiple additional biopsies as the study progresses.

As previously presented at the ASCO 2010 meeting, DCE-MRI results from patients treated at the 0.1 to 0.7 mg/kg dose levels were suggestive of an anti-VEGF effect in the majority of treated patients. In 62% of evaluable liver tumors, there was a greater than 40% decline in Ktrans (measure of blood flow), an effect that is comparable to what has been observed with other anti-VEGF drugs in solid tumors (Cannistra et al., Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S, 2006; and Siegel et al., Journal of Clinical Oncology, Vol 26, No 18: pp. 2992-2998, 2008). Also, as previously presented at ASCO 2010, pharmacokinetic data shows that Cmax (peak serum concentration of drug) and area under the curve (AUC) were dose proportional with no evidence of drug accumulation.

Source: Alnylam Pharmaceuticals, Inc.