Washington Editor

Undisclosed safety worries have prompted Vion Pharmaceuticals Inc. to call a halt to a Phase III study of Cloretazine (VNP40101M) in patients with relapsed adult myelogenous leukemia (AML), causing the company's stock to plunge by more than half Wednesday.

Specifically, its shares (NASDAQ:VION) dropped $1.16 to close at 86 cents.

Vion, of New Haven, Conn., suspended enrollment and further patient treatment pending a review of all data, a decision based on the recommendation of an independent data safety monitoring board after a planned interim analysis.

Its members found that any advantage in complete remission "could be compromised" by the observed on-study mortality to date, CEO Alan Kessman said during a conference call.

The randomized, placebo-controlled study will remain blinded during the review.

"This study was halted, not stopped," he reminded listeners, pointing out that no definitive conclusions can be drawn. Further, because the trial remains blinded, there's "limited information" that can be provided at this point.

In other words, the company's executives can't disclose what might have gone wrong, nor can they provide any timeline on completing the data review. Kessman offered something positive, saying "there was not a problem" in terms of Cloretazine's efficacy.

But suffice it to say, there is plenty of concern among investors about the investigational alkylating agent's risk-benefit profile. The trial had been evaluating the chemotherapy Ara-C plus Cloretazine in comparison to Ara-C and placebo. It's designed to accrue patients in first-relapse AML whose first complete remission lasted more than three months but less than two years.

The primary endpoint is the objective response rate, defined as complete remission plus CRp, a complete remission with incomplete recovery of platelet count. Secondary endpoints include time to progression, duration of response, overall survival and toxicity.

The study began more than two years ago under a special protocol assessment with the FDA, and reached the midpoint accrual of 210 patients last November. Prior to that date, no looks into the results triggered the data safety monitoring board to recommend a suspension. (See BioWorld Today, Feb. 11, 2005.)

The company is continuing to evaluate Cloretazine as monotherapy in a pivotal Phase II trial in elderly patients with de novo, poor-risk AML. Accrual is expected to be completed in the next two months, with data due late this year at the American Society of Hematology meeting.

An earlier interim analysis of that study, being conducted in the U.S. and Europe, prompted Vion to continue to move toward full enrollment after recording at least nine responses in the first 42 patients accrued. Its primary endpoint is to determine the complete response rate, while secondary endpoints will look at overall survival, disease-free survival and progression-free survival.

Both the combination and single-agent trials are testing the same dose of Cloretazine, 600 mg/m2. Kessman said he and his colleagues "continue to believe" in the product's potential.

"The drug has demonstrated anti-leukemic activity," said Ann Cahill, Vion's vice president of clinical development, "and will find its place in the treatment of AML."

An additional trial of Cloretazine as a single agent in small-cell lung cancer also is under way.