DAB486IL-2, a recombinant fusion toxin in which the native receptor binding domain of
diphtheria toxin has been replaced with
interleukin-2 (IL-2), has displayed significant activity in patients with
chemotherapy refractory hematological
cancers. To further investigate the safety and antitumor effect of this agent, we conducted a single arm, dose escalation study of a 90-min infusion of DAB486IL-2 daily for 5 days. Patients with
cancers of a histology previously reported to express the p55 component of the
IL-2 receptor and who could not receive potentially more effective
therapy were eligible for enrollment. Fifteen men and 8 women with a median age of 49 years were given a total of 51 courses of DAB486IL-2. The maximum tolerated dose was 0.3 mg/kg/day defined by
renal insufficiency associated with
hemolysis and
thrombocytopenia. The clearance of DAB486IL-2 from serum fit a one-compartment model with a half-life of 11.5 +/- 4.3 (SD) min at the 0.2-mg/kg dose. Two patients sustained a partial response and 4 patients had
tumor reduction not qualifying for an objective response. No
tumors that were negative for expression of the p55 subunit of the receptor responded to DAB486IL-2 treatment. Reduction in size occurred in 2
tumors in which p55 expression was unknown and 4 patients with
tumors that were known to be p55 positive. Dosing determined by specific activity rather than mass also appeared to be an important determinant of response. This study suggests that the presence of p55 expression on
tumor cells is necessary, but alone may not be sufficient to achieve a
tumor response. The correlation of additional variables such as specific activity of DAB486IL-2 and
tumor expression of the p75 subunit of the
IL-2 receptor and receptor function will also require further study.