A month after signing a billion-dollar deal with GlaxoSmithKline plc for elesclomol (formerly STA-4783), Synta Pharmaceuticals Corp. kicked off a pivotal Phase III trial of the drug in metastatic melanoma.
The trial is designed to support a label in first-line treatment of melanoma, Synta's president and CEO Safi Bahcall told BioWorld Today. Hence, enrollment will include about 630 Stage IV metastatic melanoma patients who have not previously received chemotherapy, although they might have received prior treatment with biologics or surgery. Those patients will be randomized to receive elesclomol plus paclitaxel or paclitaxel alone until their disease progresses.
The primary endpoint of progression-free survival will be evaluated twice: first in an interim analysis designed to assess safety and nonfutility, which Bahcall estimated will occur in the second quarter of 2008; and again sometime around the completion of enrollment, which is targeted for late 2008.
If the late 2008 primary endpoint analysis is positive, Bahcall said Synta would "plan to move forward" with a new drug application filing in the first half of 2009.
The company potentially could file for approval before finishing the trial because not all 630 patients are needed to establish progression-free survival, Bahcall explained. In fact, only about 300 to 400 patients are needed, but the trial is enrolling more to get data on a secondary endpoint of overall survival. Other secondary endpoints include response rate, clinical benefit rate and duration of response.
The Phase III trial, which is being conducted under a special protocol assessment, bears a strong resemblance to Synta's Phase IIb trial. Both trials share the same treatment combination, dosage, administration schedule and primary endpoint. The Phase IIb trial hit that primary endpoint by doubling progression-free survival compared to paclitaxel alone (p=0.035). Additionally, overall survival was 12 months for elesclomol-treated patients compared to 7.8 months for those who initially received paclitaxel alone. (See BioWorld Today, June 6, 2007.)
The Phase IIb data provide one reason Synta thinks elesclomol may succeed where other melanoma treatments have failed. "This is the first Phase III trial in the history of melanoma that is preceded by a positive, blinded, randomized Phase II trial," Bahcall said.
Elesclomol's other advantage, Bahcall continued, is its mechanism. Melanoma has proven difficult to treat with chemotherapy, with immunotherapies such as Canvaxin (CancerVax Corp.), with Bcl-2 inhibitors like Genasense (oblimersen sodium, Genta Inc.), and with kinase inhibitors like Nexavar (sorafenib, Onyx Pharmaceuticals Inc. and Bayer Pharmaceuticals Corp.) - all of which have stumbled in Phase III trials.
But elesclomol has a different mechanism. The drug is a small molecule designed to increase the oxidative stress level in cancer cells to the point at which they undergo apoptosis. That approach "works particularly well in melanoma," Bahcall said, because melanoma cells have a high level of oxidative stress to begin with.
Elesclomol also might work in other types of cancer, a theory Synta plans to explore in Phase II trials next year. The company also is conducting Phase II trials with the anti-inflammatory drug STA-5326, Phase I trials with the heat-shock protein 90 (Hsp90) inhibitor STA-9090 and preclinical studies with additional compounds for cancer and inflammation.
Synta reported $64.5 million in cash and equivalents at the end of the second quarter, prior to receiving an $80 million up-front cash payment from GSK as part of the elesclomol deal. That deal also included up to $885 million in milestone payments, $135 million of which are tied to events prior to elesclomol's approval in melanoma. In exchange, GSK got U.S. co-promotion and ex-U.S. commercialization rights to the drug. (See BioWorld Today, Oct. 11, 2007.)
Bahcall said the Phase III trial initiation did not trigger a milestone payment. Synta has yet to achieve any milestones under the GSK deal, but Bahcall said the company will provide more detail on expected milestone payments in its third-quarter earnings conference call today.
Shares of Lexington, Mass.-based Synta (NASDAQ:SNTA) traded flat to close at $8.01 on Monday.