Oxidative stress inducer ups survival in advanced melanoma

November 1, 2007

A new type of agent, an oxidative stress inducer, combined with paclitaxel improved survival in patients with metastatic melanoma, compared with paclitaxel alone

BARCELONA—A new type of agent, an oxidative stress inducer, combined with paclitaxel improved survival in patients with metastatic melanoma, compared with paclitaxel alone, according to a phase IIb study presented at the European Cancer Conference (ECCO 14, abstract 7002).

The study included 81 patients with stage IV melanoma: 53 received treatment with the experimental drug (elesclomol, formerly STA-4783) plus paclitaxel and 28 received paclitaxel alone. The median progression-free survival was 1.8 months for paclitaxel alone vs 3.7 months for the combination (P = .035).

"This doubling in progression-free survival is impressive for this cancer, and the result was achieved without substantial additional toxicity," said investigator Anthony Williams, MD, vice president of clinical research at Synta Pharmaceuticals Corp., Lexington, Massachusetts, which is developing the new agent and funded the study.

Dr. Williams noted that progression-free survival was linked to improvements in overall survival. Patients on the combination survived on average for 12 months after diagnosis, compared with 7.8 months for those on paclitaxel alone. The analysis included paclitaxel patients crossed over to elesclomol.

"This is the first time an improvement in survival has been seen in a randomized, double-blind, multicenter, controlled trial for metastatic melanoma," Dr. Williams maintained.

How it works

Elesclomol, the first in a new class called oxidative stress inducers, works by increasing the amount of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide, in cells. When the level exceeds the antioxidant capacity of cells, the cells are in a state of oxidative stress.

All cells have some low level of ROS, but cancer cells naturally operate with a higher level of ROS and oxidative stress relative to normal cells. However, too much oxidative stress for too long results in cell death.

Elesclomol kills only tumor cells because the additional stress pushes cancer cells, but not healthy cells, over the critical threshold. Melanoma is one of several cancer types that are known to operate at a higher level of oxidative stress.

The study also indicated that elesclomol might boost the efficiency of chemotherapy drugs that induce cell death because it appears to lower the hurdle for activating apoptosis, Dr. Williams said.

"These results are encouraging not only because of the findings in themselves, but also because there are so few treatment options for patients with advanced melanoma. We believe STA-4783 has the potential to improve survival with a manageable side effect profile," he said.

A pivotal phase III study of elesclomol in advanced melanoma patients is now under way. Dr. Williams added that the new agent could have applications in other types of cancer as well.