|
SPC2996, a novel investigational drug that blocks expression of Bcl-2, appears to be active in advanced chronic lymphocytic leukemia.
Dr. Hervé Tilly of the Centre Henri Becquerel in Rouen, France, and his colleagues reported in a poster presentation partial responses, stable disease, downregulation of Bcl-2 concentrations, and reduced lymphocyte counts in findings from an open-label, dose-escalating phase I/II study that administered SPC2996 to 25 patients with relapsed or refractory chronic lymphocytic leukemia (CLL) requiring therapy.
Santaris Pharma, which is developing SPC2996, sponsored the study. One of Dr. Tilly's colleagues is vice president of clinical development at Santaris Pharma.
SPC2996 is a Bcl-2 mRNA antagonist that is based on a locked nucleic acid (LNA). LNAs are RNA analogs that can recognize and block endogenous gene expression at the chromosome level. Bcl-2 is an antiapoptotic member of a family of proteins that regulate programmed cell death. Overexpression is thought to be linked with a poor prognosis in many types of cancer, including CLL.
SPC2996 was administered six times over a 2-week period. Patients were treated in five cohorts that received 0.2 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, or 4.0 mg/kg and followed for 6 months. Most patients were men. Overall, the mean age was 64 years, and mean disease duration 6.5 years.
Regression analysis showed a significant trend toward downregulation of Bcl-2 concentrations over the treatment period in the six patients given the highest dose. In addition, all patients in that group had a decrease in lymphocyte count that started within 24 hours of the first infusion. Five had maximum reductions of at least 50%, "indicating a clinically beneficial response," wrote the authors, who are still studying dosing regimens.
"A dose response effect of SPC2996 on lymphocyte counts was also apparent in this study," the researchers wrote. Doses of 2 mg/kg resulted in transient downregulation of up to 30%. Doses of 1 mg/kg had little or no effect.
One patient in the 2-mg/kg group and two in the 4-mg/kg group had lymph node reductions of at least 50% in the sum of the products of the perpendicular diameters.
One patient in highest-dose group had a partial response that lasted 182 days. Another had a less durable partial response (28-42 days), but continued with stable disease for 4 months. Three other patients in this group also had stable disease. The median estimated time to progression reached 122 days at the highest dose.
Three cases of grade 3 thrombocytopenia were reported. One patient died after two 2-mg /kg infusions, with a diagnosis of tumor lysis syndrome. The data monitoring committee judged the diagnosis to be possibly related to the study medication.
Tilly H. et al. Phase I/II study of SPC2996, an RNA antagonist of Bcl-2, in patients with advanced chronic lymphocytic leukemia (CLL). Abstract 7036.
Commentary |
The Bcl-2 protein is an appealing target for cancer therapy because it is a critical molecule interfering with programmed cell death. A number of strategies have been developed to inhibit either the production or the activity of this protein, with apparent therapeutic efficacy. SPC2996 is a Bcl-2 mRNA antagonist that may have a unique mechanism of inhibition. The activity of this experimental compound was witnessed in this phase I/II study of 25 patients with CLL. Downregulation of Bcl-2 concentrations occurred with treatment, as did a reduction in lymphocyte counts. Ongoing partial responses and stabilization of disease was observed. It is anticipated that Bcl-2 antagonists will be most effective when combined with chemotherapy. — Steven T. Rosen, M.D.
|