SILVER SPRING, MarylandThe Oncologic Drugs Advisory Committee voted 7-to-3 against recommending accelerated approval for Genasense (oblimersen sodium, Genta) to treat relapsed/refractory chronic lymphocytic leukemia (CLL) in combination with fludarabine (Fludara) and cyclophosphamide(Drug information on cyclophosphamide).
Genasense increases the activity of chemotherapy drugs by stimulating apoptosis through downregulation of Bcl-2. Genta presented data from a pivotal, randomized phase III trial in 241 relapsed/refractory CLL patients, with response rate as its primary endpoint. Patients received fludarabine/cyclophosphamide with or without Genasense.
The study showed a significant difference in major response rates (complete response plus nodular partial response) between the Genasense arm and the control group (17% vs 7%), and a significantly more durable response (median 22 months for controls vs not reached at an estimated 3 years for Genasense). The company argued that response rate could serve as a surrogate for clinical benefit.
FDA's medical review team, however, argued that the trial did not meet the standard for accelerated approval, which requires "substantial evidence of safety and efficacy demonstrated in adequate and well-controlled trials (plurality indicating multiple trials)." Nor did it find that the results indicated that Genasense was "reasonably likely" to predict a clinical benefit in CLL patients. The drug did not improve overall response rate (CR/nPR/PR), time to progression, overall survival, or symptoms, compared with controls, and had added toxicity.