Alnylam Pharmaceuticals this week released additional data from an ongoing phase I study of its liver cancer drug ALN-VSP in conjunction with the presentation of the findings at this year's American Society of Clinical Oncology annual meeting.
"The initial data with ALN-VSP are encouraging and we look forward to continued dose escalation to explore tolerability and potential for tumor response," Josep Tabernero, who is heading up the study at Vall d'Hebron University Hospital in Barcelona, said in a statement.
ALN-VSP comprises two siRNAs: one targeting vascular endothelial growth factor, which is associated with angiogenesis, and the other targeting kinesin spindle protein, which has been linked to cell proliferation in various cancers. It is formulated in a lipid nanoparticle developed by Tekmira Pharmaceuticals.
The phase I, open-label trial is designed to enroll roughly 55 patients with advanced liver cancers, including hepatocellular carcinoma and other solid tumors with liver involvement, who are refractory to the standard of care.
Eight dose levels of ALN-VSP are being examined, ranging from 0.1 to 1.7 mg/kg, when administered via 15-minute intravenous infusions every two weeks. The primary endpoints are safety, tolerability, and pharmacokinetics, including a demonstration of the drug's maximum tolerated dose, Alnylam said.
Other objectives include the assessment of tumor response through published guidelines that define when a patient's disease improves, stabilizes, or progresses during treatment; change in tumor blood flow or vascular permeability; change in plasma biomarkers of angiogenesis; and an analysis of the pharmacodynamic effect of the drug on tumor biopsies.
According to Alnylam, 62 doses of the drug have been administered to 19 patients who received 0.1, 0.2, 0.4, or 0.7 mg/kg doses of ALN-VSP. The majority of the patients had colorectal cancer, which often metastasizes to the liver, the firm noted.
"There were two mild acute infusion reactions at 0.4 and 0.7 mg/kg … [but] both patients had no further reactions with slowing of the infusion and stayed on the trial," Alnylam said.
As previously disclosed, one patient with advanced pancreatic neuroendocrine cancer with extensive involvement of the liver developed hepatic failure five days following a second 0.7 mg/kg dose and died.
Although the death was "deemed possibly related to the study drug," Alnylam told Gene Silencing News last month that serious adverse events "are common in advanced malignancy phase I studies."
At the same time, six other patients receiving the 0.7 mg/kg dose did not exhibit any evidence of hepatotoxicity. Furthermore, the maximum tolerated dose of ALN-VSP has not been reached and active patient enrollment continues, the company said this week.
Pharmacokinetic data available from the study showed that the peak serum concentration of drug and area under the curve were "dose proportional with no evidence of drug accumulation," Alnylam said.
In addition, imaging results suggested an anti-VEGF effect in the majority of treated patients.
In 62 percent of evaluable liver tumors, there was a greater than 40 percent decline in the measure of blood flow, "an effect that is comparable to what has been observed with other anti-VEGF drugs in solid tumors," Alnylam said.
Further analyses of biopsy samples are ongoing, it added.