Threshold Pharmaceuticals Inc. began patient enrollment in a Phase III trial of glufosfamide for pancreatic cancer.

The pivotal study is designed to test the company's lead product in patients with metastatic pancreatic cancer refractory to first-line treatment. Its primary endpoint will compare the median survival of patients treated with glufosfamide and best supportive care to those solely receiving best supportive care - all medical or surgical interventions that a pancreatic cancer patient should receive to palliate the cancer but excluding treatment with systemic therapies intended to kill the cancer cells.

At present, there are no approved therapies for those patients, who generally have an expected survival of about three months.

"In fact, one would really say there are no proven options for systemic treatment of their cancer," Threshold President George Tidmarsh told BioWorld Today. Of the 31,860 patients expected to be diagnosed with pancreatic cancer in the U.S. this year, about 31,270 will die from the disease, according to American Cancer Society statistics.

The South San Francisco-based company agreed with the FDA on a special protocol assessment, which indicates that if the trial successfully meets its primary endpoint, the data will provide support for an efficacy claim in an eventual marketing application. Tidmarsh said the FDA requested only a few minor wording changes to Threshold's study design, case-reporting system and statistical analyses plans as both parties came to an agreement in the process.

Enrollment is under way in the U.S., while more sites will be added in Eastern Europe and South America. Eventually the trial will involve about 306 patients; recruitment is expected to last between 12 months and 15 months. Eligible patients will be randomized to receive glufosfamide every three weeks in addition to best supportive care, or best supportive care alone.

"There is a planned analysis on an interim data set that we project to have in about 15 months," Tidmarsh said, noting that the timeline would depend on enrollment. "Our anticipation is that the complete data, with all finalized study reports, would be available in approximately 18 to 24 months."

Secondary endpoints in the trial include disease-free survival and time to disease progression, as well as response and safety evaluations. A next-generation chemotherapeutic agent from the alkylator class, it is designed to enter cells through up-regulated glucose transport proteins.

"The toxin is attached to the glucose molecule, so we believe that it allows the drug to target specifically to the cancer through a mechanism we call metabolic targeting," Tidmarsh said. "And metabolic targeting is based on the dramatic increased consumption of glucose that tumor cells have relative to normal cells."

He added that glufosfamide produces fewer side effects than prior-generation alkylators, which generated toxins that led to hemorrhagic cystitis. Prior studies have provided a glimpse at the drug's potential efficacy in fighting pancreatic cancer.

Data from a Phase II trial, reported at the America Association for Cancer Research meeting in 2002 and published in the November 2003 issue of the European Journal of Cancer, revealed objective tumor shrinkage. An updated analysis of the survival shows an estimated 9 percent two-year survival, which the company said compares to 1 percent or less in historical studies with other first-line therapies. The fully enrolled study included 35 chemotherapyna ve patients with locally advanced or metastatic pancreatic cancer.

Findings from an initial Phase I trial, published in the October 2000 edition of the Journal of Clinical Oncology, showed that its only pancreatic cancer participant achieved a complete remission of disease and remained in remission more than five years later after receiving glufosfamide treatment alone.

Threshold owns all rights to the compound, and Tidmarsh said the company would continue to steer development on its own. It also has demonstrated glufosfamide's activity in Phase II studies in breast and colon cancers, findings which were reported at this year's American Society of Clinical Oncology meeting, and plans to explore its use in lymphoma.

Outside of glufosfamide's development, Threshold is developing two other clinical-stage products, both of which also are based on the company's metabolic targeting approach. A compound labeled TH-070 is in Phase II for benign prostatic hyperplasia, while its 2-deoxyglucose product is in Phase I for solid tumors.

Earlier this year, Threshold filed to go public, though its initial public offering has yet to price. (See BioWorld Today, April 15, 2004.)