LILY SUSPENS STUDY OF TASISULAM FOR MELANOMA

December 14, 2010 — Eli Lilly and Company announced that it is suspending a phase 3 trial that is evaluating the investigational agent tasisulam as a second-line treatment for unresectable or metastatic melanoma.

The trial, which has been ongoing since December 2009, has been put on "full clinical hold" because of safety concerns. Since the trial began a year ago, there have been 12 deaths that are potentially related to the treatment, explained Amy Sousa, a spokesperson for Lilly.

This has caused great concern, and consultation with an independent monitoring committee prompted Lilly to ensure that no new or existing patients in the trial receive additional doses until the matter is investigated.

"We want to analyze the existing data to see if we can appropriately amend the protocol," Ms. Sousa told Medscape Medical News. "We want to try to identify the patients who may be at a higher risk. It does seem to be occurring in a specific population, but we need to thoroughly analyze the existing data."

The randomized phase 3 trial sought to compare the efficacy, safety, and tolerability of tasisulam with that of paclitaxel as a second-line treatment in the metastatic setting. The study had enrolled more than 300 patients in 18 countries, and the trial's primary end point was overall survival. The study's estimated completion date is August 2012.

Novel Mechanism of Action

Tasisulam is a novel anticancer agent with a unique mechanism of action, and it has demonstrated activity across a broad range of malignancies, including melanoma. It is an acyl-sulfonamide and appears to induce apoptosis by activating the mitochondrial cell death pathway, which leads to cytochrome C release, activation of caspases, loss of mitochondrial membrane potential, production of reactive oxygen species, and eventually apoptosis.

Results of a phase 2 trial that sought to determine the overall response rate in patients with unresectable or metastatic melanoma were presented at the 2010 annual meeting of the American Society of Clinical Oncology (abstract 8541). The findings showed that tasisulam demonstrated activity and tolerable toxicity as a second-line treatment in this population.

Last December, tasisulam was granted orphan drug status for stage IIb to IV melanoma by the US Food and Drug Administration (FDA). However, Ms. Sousa emphasized that the drug is not approved. "The FDA may grant orphan drug status during the clinical trial period, so that when the agent is approved, it will already have orphan drug status," she said. "Tasisulam is not being marketed right now; it is only available in clinical trials."

In addition to melanoma, Lilly is studying the efficacy and safety of tasisulam across a wide range of cancers, including soft tissue sarcoma, nonsmall-cell lung cancer, acute leukemia, and breast, ovarian, and renal cancers. These trials are continuing without any modification, explained Ms. Sousa. "We have phase 1 and phase 2 trials ongoing, and they are very different from the melanoma trial. We have not seen any safety concerns at all."

One reason is that the dosing is very different in the other studies. "The dose is lower, and tasisulam is also being used in combination with other approved chemotherapies," she said. "We are continuing to move forward and, of course, are keeping a very close watch on patient safety."

She added that the company is hoping to provide the FDA with a new plan of action in the first quarter of next year in the hope that the trial will resume, with appropriate modifications.