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.
Tepler
I
I
Division of Hematology/Oncology, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215.
Schwartz
G
G
Parker
K
K
Charette
J
J
Kadin
M E
ME
Woodworth
T G
TG
Schnipper
L E
LE
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007107:Immune System / Q000187:drug effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012074:Remission Induction
D000970:Antineoplastic Agents; D015415:Biomarkers; C054780:DAB(486)-interleukin 2; D004167:Diphtheria Toxin; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins