Phase I trial of an interleukin-2 fusion toxin (DAB486IL-2) in hematologic malignancies: complete response in a patient with Hodgkin's disease refractory to chemotherapy.

BACKGROUND

DAB486IL-2 is a recombinant fusion toxin in which the native diphtheria toxin-receptor binding-domain has been replaced with human interleukin-2 (IL-2). This molecule is specifically cytotoxic in vitro within 30 minutes for cells that express the high-affinity IL-2 receptor (IL-2R).

METHODS

This was a Phase I/II study of DAB486IL-2 as a brief infusion in 15 patients with refractory lymphoid malignancies. Five patients per cohort received DAB486IL-2 as a 30-60 minute intravenous infusion at dose levels of 0.075, 0.115, and 0.2 mg/kg daily for 5 days.

RESULTS

The maximal tolerated dose (MTD) of DAB486IL-2 was determined to be 0.2 mg/kg daily on the basis of hypersensitivity-like symptoms and reversible hepatic transaminase elevations. Other adverse effects included mild creatinine elevations, proteinuria, and hypoalbuminemia. The presence of antibodies to diphtheria toxin or DAB486IL-2 was correlated with hypersensitivity-like effects but did not prevent an antitumor effect. One complete response was observed in a patient with Hodgkin's disease in relapse with bilateral pulmonary nodules after autologous bone marrow transplantation. He remains free of disease more than 2 years after completion of therapy.

CONCLUSIONS

The dramatic antitumor response seen in one patient and the relative tolerability of DAB486IL-2 indicates the potential utility of this targeted agent in IL-2-expressing hematologic malignancies.