In the midst of a flurry of oncology news Eli Lilly and Company announced earlier today that it has suspended its global SUMMIT-1 Phase III study evaluating tasisulam (LY573636-sodium or diarylacylsulfonamide), an investigational, small-molecule anti-cancer compound, as a second-line treatment for those with unresectable or metastatic melanoma. In this trial tasisulam was administered as an intravenous infusion on day 1 of a 28-day cycle vs. paclitaxel as second-line treatment.

Melanoma is the deadliest form of skin cancer and is frequently attributed to exposure to ultraviolet (UV) radiation.[1] Although U.S. incidence rates for many cancers have been on the decline, new cases of melanoma have been increasing for the past 30 years.[1] Recent estimates suggest that more than 68,000 people are diagnosed annually in the U.S. with melanoma.[2] Melanoma has a pathological staging system, starting at 0 and rising to the severity of stage IV.[2] The cancer can metastasize, or spread rapidly, moving from the skin to the blood and lymphatic vessels, and then on to the rest of the body[1] becoming the most deadly form of the disease.[3]

Tasisulam is an acyl-sulfonamide compound with potential antiproliferative activity against a broad range of cancer cell lines, including melanoma. Tasisulam induces apoptosis via activation of the mitochondrial cell death pathway, which leads to cytochrome C release, caspases 2/9 activation, and ultimately apoptosis. Furthermore, tasisulam-mediated mitochondrial dysfunction has been associated with decreased adenosine triphosphate (ATP) production and increased levels of ROS within cancer cells. Unlike elesclomol, which rapidly induces generation of ROS in cancer cells, the impact of tasisulam on ROS level takes much longer to develop.

In terms of pharmacokinetic properties, tasisulam is highly albumin-bound (99.7%) and has a half-life of approximately 13 days. It is administered as a 2-hour IV infusion every 3 weeks using a loading and chronic dose. Dosing is based on weight and targeted a specific end-of-infusion Cmax value. The most common tasisulam-related adverse events (AEs) of any grade in a prior phase I trial were thrombocytopenia, anemia, fatigue, and nausea, and the most common grade 3/4 adverse events were thrombocytopenia, anemia, and neutropenia.

Earlier Phase II trials
Tasisulam was discovered by researchers at Eli Lilly in conjunction with Wayne State University Study results from an earlier trial presented during the 46th Annual Meeting of the American Society of Clinical Oncology (ASCO) held in Chicago, Ill. on June 6, 2010, (Abstract #8541) evaluated the use of tasisulam as a second-line treatment in patients with unresectable or metastatic melanoma, showed encouraging results. “While great strides have been made in treating some cancers over the past decade, others – such as melanoma – continue to be challenging to treat,” said John M. Kirkwood, M.D., co-leader of the Melanoma Program of the University of Pittsburgh Cancer Institute. “Ongoing research is critical if we are to find appropriate treatments for patients who need them most.”

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Suspended trial
Lilly, in consultation with an independent data monitoring committee, recommended a “full clinical hold,” because of safety concerns. A full clinical hold ensures that no new or existing patients in the trial receive additional doses of the compound, allowing researchers the time to fully analyze existing data.

Lilly notified regulatory agencies and contacted all trial investigators to provide details on how to manage individuals enrolled in the trial.

“We are thoroughly reviewing the clinical trial data to understand what modifications to the study protocol or dosing would be needed to improve patient safety on this trial,” noted Richard Gaynor, M.D., vice president, oncology product development and medical affairs for Lilly. Lilly continues to develop tasisulam as part of an extensive clinical development program across a wide range of tumors, including soft tissue sarcoma, breast, ovarian and renal cancers, as well as non-small cell lung cancer and acute leukemia. At this time, these trials continue without modification because the dosing of tasisulam is different. Lilly is closely evaluating patient safety within these trials on an ongoing basis. “We remain committed to Lilly Oncology’s active fight against cancer, especially for patients facing cancers where the need for new treatments is especially great,” added Gaynor.

The Phase III trial sought to compare the efficacy, safety and tolerability of tasisulam versus paclitaxel, as a second-line treatment for those with metastatic melanoma. The study enrolled more than 300 patients in 18 countries. The primary endpoint of this study is overall survival.

Tasisulam was granted orphan drug status for stage 2b-IV melanoma by the U.S. Food and Drug Administration in late 2009

For more information:
Kirkwood JM, Gonzalez R, Reintgen DS, Clingan PR, McWilliams RR, et al. A phase II study of tasisulam sodium (LY573636) as second-line treatment for patients with unresectable or metastatic melanoma. J Clin Oncol (Meeting Abstracts) May 2010 vol. 28 no. 15_suppl 8541

Clinical trials:
A Study of Tasisulam Versus Paclitaxel as Treatment for Metastatic Melanoma (SUMMIT-1)

[1] American Cancer Society, Detailed Guide: Skin Cancer – Melanoma – What Are the Key Statistics About Melanoma? Last Accessed December 13, 2010.
[2] American Cancer Society, Detailed Guide: Skin Cancer ? Melanoma: How Is Melanoma Staged? Last Accessed: December 13, 2010.
[3] American Academy of Dermatology, Malignant Melanoma 2010. Last Accessed on December 13, 2010.

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