Genta's Bcl-2 inhibitor Genasense has not demonstrated a clinical benefit in relapsed/refractory chronic lymphocytic leukemia patients, FDA's Oncologic Drugs Advisory Committee said Sept. 6.

The panel voted seven to three that data from Genta's randomized Phase III trial of Genasense (oblimersen) did not show substantial evidence of clinical benefit.

[Editor's note: To ¹ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

Genta is seeking an indication for Genasense, in combination with fludarabine and cyclophosphamide, for treatment of patients with CLL who are refractory to or have relapsed after fludarabine therapy.

Genta's pivotal trial compared the combination to fludarabine and cyclophosphamide alone; while the Genasense arm was associated with a statistically significant benefit on the trial's primary endpoint of composite response rate (16.7% vs. 6.6%), there was not a difference between the treatment arms with regard to time to tumor progression and overall survival (² Also see "Genta Genasense Fails To Demonstrate “Any Clinical Benefit” Improvements, FDA Tells Cmte." - Pink Sheet, 5 September, 2006.).

FDA had objected to the use of the composite response rate as a primary endpoint for the Phase III trial prior to the initiation of the study. Instead, the agency preferred a time to progression endpoint.

During the Sept. 6 meeting, Genta emphasized that previous therapies for relapsed/refractory CLL had received accelerated approval based on similar response rates and maintained that, consequently, Genasense warranted accelerated approval as well; the company said it is planning a confirmatory trial using progression-free survival as a primary endpoint.

However, FDA and committee members said that Genasense's failure to show a benefit on clinical endpoints in a randomized trial makes accelerated approval inappropriate, regardless of the agent's impact on tumor response.

FDA Office of Oncology Drug Products Director Richard Pazdur explained that accelerated approval is generally reserved for drugs that do not have evidence of clinical benefit, but have shown effect in a single arm trial or on an endpoint reasonably likely to predict benefit.

In Genasense's case, however, the situation "is a bit different" since Genta has completed a randomized trial that evaluated oblimersen's impact on clinically meaningful outcomes such as TTP and survival, he said.

We have "mature data" that shows that Genasense did not have "any impact on TTP," Pazdur noted.

Committee chair Maha Hussain (University of Michigan) added that "the fact that things were accepted historically is no justification" to accept the composite response data in this case.

Committee members voting in favor of approval highlighted Genasense's limited toxicity relative to other therapies for second-line CLL patients as well as the need for additional treatment options.

The Genasense NDA has a late October user fee action date.

-Andrew Kasper (a.kasper@elsevier.com)

Genta CLL Agent Genasense Has Not Shown Clinical Benefit, FDA Panel Says

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