Citing concerns about the safety profile of the device, the FDA’s Oncologic Drugs Advisory Committee (ODAC) Thursday unanimously recommended against the approval of the Melblez chemosaturation system for use with melphalan hydrochloride in the treatment of patients with ocular melanoma metastasized to the liver.
The 16-0 vote was cast despite the lack of other effective treatments for the deadly condition and the fact that the applicant, Delcath Systems of Queensbury, New York, has had its chemosaturation system cleared for sale in Europe.
Panelist Takami Sato, MD, PhD, a medical oncologist at Thomas Jefferson University in Philadelphia, voted against approval after hearing testimony about a 7% rate of death due to toxicities from the treatment, and a high rate of serious adverse events. While Sato called the Melblez Kit “a very promising approach,” he suggested that it “needs improvement in decreasing toxicity and risk for the patient.”
Fellow panelist Kenneth Najarian, MD, of the University of Vermont College of Medicine, added that, despite the desperate need for new therapies for patients with this condition, “we can’t let our emotions take over, and must do the best thing based on the facts and what has been presented.”
In a document submitted prior to the hearing, Delcath pointed out that there is no standard of treatment for patients with the disease, and argued that treatment with the Melblez Kit “has been demonstrated to alter the disease course, as evidenced by the consistent, statistically significant, and clinically meaningful benefits seen with melphalan/PHP treatment across the tumor-related efficacy endpoints in the pivotal Phase III study.”
The company added that “the toxicities associated with (the Melblez Kit) need to be viewed within the context of the aggressive natural history of disease in these patients and the ability of (this treatment) to alter the disease course.”
Delcath’s system of chemosaturation via percutaneous hepatic perfusion involves isolating the liver with a specially designed catheter, saturating tumor tissue with chemotherapy agents using direct hepatic arterial infusion, and then filtering the blood to reduce the drug’s concentration.
In a phase III clinical trial, 39 patients treated with chemosaturation achieved a statistically significant advantage in hepatic progression-free survival (hPFS), the primary endpoint, compared with 44 patients who received best alternative care (BAC), with a difference of 7 months versus 1.6 months, respectively (hazard ratio [HR] = 0.42), according to results of Protocol DSI MEL 2005-001 (Study 1), an open-label, multicenter, randomized trial cited in an FDA briefing document associated with today’s meeting. The improvement in overall PFS was three months (median 4.7 vs 1.6; HR = 0.40).
However, “substantial and severe toxicity” was identified in the trial, and two trials that preceded it, with a toxic death rate of 7%, the FDA’s briefing document reported. Serious adverse reactions included severe hypotension during treatment, prolonged and severe marrow suppression in ≥ 80% of patients, grade 3-5 infections in 23%, grade 3-5 hemorrhage in 6%, grade 3-4 elevations in transaminases or bilirubin in ≥ 20%, gastrointestinal perforation or ulceration due to reflux of melphalan into the gastrointestinal branches of the hepatic artery, and severe electrolyte abnormalities, according to the document.
In a statement Thursday evening, Delcath noted that the FDA is not required to follow ODAC’s recommendation; the agency is due to make a final decision on the company’s new drug application by September 13, 2013.
"As we conveyed during the presentation to the ODAC, we believe our clinical trial data support Melblez Kit as an effective treatment option,” said Eamonn P. Hobbs, president and CEO of Delcath. "While we were disappointed in today's outcome, we will continue to work closely with the FDA throughout its ongoing evaluation of Melblez Kit. We remain committed to providing access to this promising new treatment for patients who have few choices with regard to treatments."