Researchers report positive results from a Phase I/II clinical trial of a novel anti-cancer drug which offers two modes of action. In 26 patients with advanced solid tumors, treatment with ECO-4601 is safe and well tolerated, including at doses yielding plasma concentrations above the expected therapeutic threshold, says Pierre Falardeau, Ph.D., chief operating officer at Thallion Pharmaceuticals in Montreal, Canada. Thallion has produced and tested ECO-4601 in association with the Segal Cancer Centre of McGill University.
Falardeau says that ECO-4601 has a unique mechanism of action comprising two distinct activities. It inhibits the RAS/MAPK intracellular signaling pathway, which is mutated in many cancer types, and which is the target of several approved cancer drugs such as Erbitux, Avastin, Tarceva, Nexavar, and Sutent. "However, unlike these drugs, our preclinical experiments suggest that ECO-4601 acts at a unique point within the pathway, specifically at the level of RAS itself," Falardeau said.
As a target for inhibition, RAS presented researchers with a chance to affect the signaling pathway with less fear that loops in the pathway will compensate for its loss. "Because RAS sits at a crossroad of multiple signaling pathways, targeting RAS may avoid some of the redundancies inherent in intracellular signaling," Falardeau said.
The agent also binds to the peripheral benzodiazepine receptor (PBR), which is over-expressed in multiple cancers. This intracellular PBR binding may allow the drug to accumulate within tumor cells, providing a more efficient way to inhibit the RAS/MAPK signaling pathway. "In other words, ECO-4601 may preferentially target and accumulate within tumor cells because of the over-expression of the PBR," Falardeau said.
In addition to its safety, the researchers also found that, while blood concentrations of the drug increased linearly along with an increase in dosage, at the end of the treatment's two-week infusion, ECO-4601 was cleared from the blood relatively quickly. "Therefore, there is unlikely to be drug accumulation from cycle to cycle. This is important as the drug is intended to be used chronically and if a drug accumulates, side effects and toxicities may develop," Falardeau said. The anti-tumor activity of ECO-461 is further maximized by continuous infusion, he explains.
The researchers say that of seven patients who completed three cycles of drug treatment in the dose escalation portion of the trial, six demonstrated stable disease, which Falardeau suggests is a preliminary sign of efficacy. "These data, together with extensive non-clinical data and the data presented at this conference, support the continued development of ECO-4601 for the treatment of cancer," said Falardeau.
Materials provided by American Association for Cancer Research. Note: Content may be edited for style and length.
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