Safety concerns prompted Titan Pharmaceuticals Inc. to stop a year-old Phase IIb study of its cancer drug Pivanex.

The South San Francisco-based company said an interim analysis conducted by an independent data monitoring committee identified safety issues in the combination treatment of Pivanex with docetaxel for non-small-cell lung cancer patients. Robert Farrell, Titan's executive vice president and chief financial officer, declined to provide specifics on the problems that have arisen in the two-arm trial.

But the company said the safety issues were significant, and Titan disclosed that it discontinued treatment with the combination regimen for patients in the fully enrolled study. It also plans to withhold further treatment and enrollment in open-label Phase IIa studies of Pivanex in patients with chronic lymphocytic leukemia and melanoma until further analysis is available.

"We need to see the data and review it, and then determine what appropriate next steps we can take," Farrell told BioWorld Today. "We've already had initial discussions with the committee, and we're going to be getting the data within the next few days."

The news sent the firm's stock down 20 percent on Monday. Shares (AMEX:TTP) dropped 69 cents to close at $2.75.

The 225-patient study, which began last June, was designed to compare the combination treatment vs. docetaxel alone. It was conducted in seven countries, including the U.S. Farrell declined to confirm whether the Phase IIb interim analysis was the study's first.

Titan noted that previous single-agent Phase I and II studies did not produce evidence of significant toxicity, and a prior Phase I dose-ranging study of Pivanex in combination with docetaxel also had no toxicity issues.

The previous trials also demonstrated the drug's potential efficacy. In the single-agent Phase II study, which involved 47 non-small-cell lung cancer patients, results showed disease stabilization of 12 weeks or more in 30 percent and responses in 4.3 percent. In 29 patients whose cancer had progressed after one or two prior chemotherapy regimens, one-year survival was 31 percent and median survival was 7.9 months.

Pivanex is a cancer agent that inhibits histone deacetylases, a class of enzymes involved in cell growth. It is designed to activate gene expression to stop cancer cell growth and induce cell differentiation leading to apoptosis.

Beyond the Pivanex program, Titan has five other clinical-stage products in development, including three under its direction.

The company is conducting a Phase I/II study of gallium maltolate in four cancers - bladder, prostate, multiple myeloma and refractory lymphoma. Titan plans to begin Phase II testing of Ditpa (3,5 diiodothyroproprionic acid) in the second half of this year in Class III and Class IV congestive heart failure patients who have low serum thyroid hormone levels through a program funded by a $3.8 million grant from the U.S. Department of Veterans Affairs. Phase I/II testing is complete for Probuphine, a treatment for opiate addiction that uses Titan's long-term ProNeura drug delivery system to deliver buprenorphine.

Two of the company's clinical products are partnered. Iloperidone is in Phase III testing for schizophrenia and related disorders by Vanda Pharmaceuticals Inc., of Rockville, Md. It had been paired with Basel, Switzerland-based Novartis Pharma AG, which licensed the drug to Vanda earlier this month. (See BioWorld Today, June 10, 2004.)

A 68-patient Phase IIb study of Spheramine is evaluating its use in advanced Parkinson's disease patients. Expected to be complete by the end of next year, the trial is funded by Schering AG, of Berlin.

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