Aventis/Genta Genasense Second Confirmatory Trial In Melanoma May Be Needed, FDA Indicates
FDA’s Oncologic Drugs Advisory Committee will likely consider whether Genta and its development partner Aventis must conduct a confirmatory study to validate progression-free survival data for Genasense from a single open-label study.
“Given the open-label nature of [the] study, missing data, and differences in assessment intervals between the two treatment groups, without replication of the results in a second well-controlled study, the results from secondary endpoint analysis may be a false positive,” FDA's briefing materials for the May 3 committee meeting state.
The committee will consider the company’s Genasense (oblimersen) NDA (21-649) for advanced malignant melanoma.
Genta’s single open-label study (GM-301) of Genasense combined with dacarbazine failed to show a statistically significant survival benefit. Patients in the experimental arm had a median survival of 274 days compared to 238 days for dacarbazine alone (p=.18).
Secondary endpoints, however, did achieve statistically significant results.
Progression-free survival was 74 days for Genasense plus dacarbazine vs. 49 days for dacarbazine alone (p=.0003). The antitumor response rate was 11.7% and 6.8%, respectively (p=.019).
“The aggregate of these data shows an internally consistent benefit for patients across all efficacy endpoints and subgroups,” Genta maintained.
However, FDA said that “efficacy results based on secondary endpoints such as progression-free survival and antitumor response rate were only to be supportive or exploratory, provided that there was a statistically significant finding in overall survival.”
The agency told the committee to consider recent regulatory history in its decisionmaking for Genasense.
“To date the division has not considered small differences in PFS to represent clinical benefit for metastatic melanoma patients, especially in an asymptomatic population,” FDA noted.
“This position was most recently reviewed with ODAC when the temozolomide application [Schering-Plough’s Temodar] was presented in 1999. The temozolomide application, like the present Genasense application, did not demonstrate an improvement in survival and had similar effects for PFS. Temozolomide was not approved” for melanoma, FDA emphasized.
“Approval for a melanoma application requires substantial evidence of efficacy. Review of the literature has not shown a correlation of improvement in PFS, [time to tumor progression] or [relative risk] with an improvement in survival. GM-301 is the largest well-conducted Phase III trial in metastatic melanoma to date. Survival was not improved and toxicity was increased,” FDA noted.
On May 4, the committee will consider safety issues related to the use of J&J's Procrit and Amgen's Aranesp in the oncology setting. In addition, the committee will discuss clinical endpoints for colorectal cancer trials.
To watch a webcast of this meeting, click the button below. To arrange for live videoconferencing, or to order videotapes & DVDs, email webcasthelp@elsevier.com or call 800-627-8171.
Posted: Friday, April 30, 2004 |
