Panel Supports Approval of Label Expansion for Ceprate SC System

ROCKVILLE, Md--Without taking a formal vote, the FDA’s Biological Response Modifiers Advisory Committee (BRMAC) indicated its support for the approval of a label expansion for CellPro’s Ceprate SC System.

The company is seeking approval for the device’s use in processing autologous peripheral blood stem cells for infusion into some cancer patients. The panel disagreed, however, on whether the labeling for the system should restrict its proposed use to patients with multiple myeloma or should indicate its more general use in treating other malignancies, including breast cancer and lymphoma.

The Ceprate SC Stem Cell Concentration System is a fully automated device for the concentration and harvesting of CD34+ cells. It won FDA approval in December 1996 for the processing of autologous bone marrow for hematopoietic support after myeloablative therapy.

CellPro presented results from a phase III trial that included 130 randomized multiple myeloma patients treated by autologous transplant at 15 centers. Sixty-six of the patients received CD34+ selected peripheral blood stem cells obtained using the Ceprate SC System and 64 got unselected peripheral blood stem cells.

The study met its two primary endpoints: A significant reduction in the number of tumor cells after processing with Ceprate SC and equivalence between the two groups in the proportion of patients with neutrophil engraftment by day 14, the company said. The mean log depletion of tumor cells was 3.29, resulting in 54% of the selected group getting a blood product with no detectable tumor cells versus 14% in the unselected arm.

The study found no significant differences between the two groups for three of the four main secondary endpoints: Time to neutrophil engraftment, incidence of infections, or survival. A significant difference did appear in the time to platelet engraftment, with a median time of 11 days in the CD34+ selected arm and 9 days in the unselected arm. However, the 108 patients who received at least 2 million CD34+ cells/kg showed no significant difference in platelet engraftment between the two trial arms.

"Follow-up data collected at 1 year indicate that the treatment arms were comparable with respect to the percent of patients who progressed, the percent who died, and hematologic status," CellPro told the committee. This prompted several committee members to urge that these findings be highlighted in the labeling, if the application is approved.

"I think the labeling would make very clear to physicians that there are no data indicating a beneficial outcome," said Jay P. Siegel, MD, of the FDA senior staff. However, the panel also expressed the view that infusing the fewest cancer cells possible is desirable, and that physicians and their patients should have the choice of whether to use the Ceprate SC System, despite the lack of any documented positive effect on outcome.

Patients in the study were closely monitored for hypertension, bradycardia, second- and third-degree heart block, and atrial arrhythmia in the 24 hours after infusion. Of the unselected patients, 53% experienced at least one episode of hypertension, a significantly greater proportion than the 33% of selected patients.

The proportion of patients with at least one bradycardia episode was 9% in the unselected arm and 2% in the selected group. Monitoring showed no significant differences between the two arms in the incidence of heart block or atrial arrhythmia.

The study also found no significant difference between the two arms in the number of days from start of mobilization to first leukapheresis. It did, however, report a significant difference in the number of leukaphereses (mean of 3 for CD4+ selected and 2.3 for unselected).

"There appear to be multiple factors influencing the number of leukaphereses, including differences between the patient populations at baseline; the protocol criteria for collection of leukaphereses; and the time of leukaphereses during mobilization," CellPro told the committee.

The percentage of patients who received platelet transfusions did not differ significantly: 98% in the selected arm versus 92% in the unselected arm. However, the number of transfusions did differ, with a median of three in the selected arm and two in the unselected group.

"Although the difference was significant, the magnitude of the difference was small and was not accompanied by any differences between arms in the incidence of bleeding events or in the number of red blood cell transfusions per patient," the company told the committee.

In its one vote, the panel addressed this question from the FDA: "Are the findings of additional leukapheresis procedures, platelet transfusions, and, in certain patients, impaired platelet engraftment acceptable, given the potential benefits of a 2- to 3-log tumor depletion?" The nine committee members voted unanimously in the affirmative.

The panel also supported including in the labeling the recommendation that patients treated with concentrated CD34+ cells be given at least 2 million cells/kg.