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FDA grants permission to Synta to resume testing of elesclomol in cancer

Friday, March 12 2010 | Comments

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What's This? Synta Pharmaceuticals Corp. received approval from the Food and Drug Administration to resume clinical development of elesclomol, the company's first-in-class oxidative stress inducer, for the treatment of cancer.

In February, Synta suspended the Phase III SYMMETRY trial, in which researchers were comparing a regimen of elesclomol plus paclitaxel versus paclitaxel alone in chemotherapy-naive patients with metastatic melanoma. An analysis by the trial's independent Data Monitoring Committee revealed some safety concerns, including an imbalance in overall survival between the study groups; specifically, a greater number of deaths occurred in the elesclomol-plus-paclitaxel arm than in the paclitaxel-only arm.

Results from subsequent analyses showed a differential response to treatment with elesclomol based on the level of baseline lactate dehydrogenase (LDH), an established prognostic biomarker in melanoma and a prespecified stratification variable in the trial, according to Synta. Progression-free survival, the trial's primary endpoint, was achieved in the normal LDH population, which was 68 percent of the enrolled patients, with "an acceptable safety profile," the firm noted. In the 32 percent of patients with elevated LDH, however, no difference was seen between the two arms in terms of progression-free survival, and a negative impact was seen for the overall survival endpoint.

Further research revealed that, under normal oxygen conditions, elesclomol exhibits potent anticancer activity, but under hypoxic, or low oxygen, conditions, which Synta explained are often associated with elevated LDH levels, cancer cell metabolism shifts away from the mitochondria and elesclomol's anticancer activity is reduced.

Based on these analyses, the company concluded that patients with elevated LDH levels should be excluded from future trials of the drug. The application Synta submitted to the FDA seeking approval to resume development focused on a specific clinical trial protocol that excluded patients with elevated LDH.

The company plans to start one or more clinical trials of elesclomol in the second half of the year, according to Dr. Vojo Vukovic, Synta's chief medical officer.

In June, GlaxoSmithKline Plc (GSK) and Synta ended their collaborative agreement for the clinical development and commercialization of elesclomol. Synta regained the full worldwide rights to the compound, but the firm might still have to pay GSK a low single-digit royalty on future sales of the product.

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