Phase I trial of recombinant immunotoxin anti-Tac(Fv)-PE38 (LMB-2) in patients with hematologic malignancies.
OBJECTIVE
To evaluate the toxicity, pharmacokinetics, immunogenicity, and antitumor activity of anti-Tac(Fv)-PE38 (LMB-2), an anti-CD25 recombinant immunotoxin that contains an antibody Fv fragment fused to truncated Pseudomonas exotoxin.


METHODS
Patients with CD25(+) hematologic malignancies for whom standard and salvage therapies failed were treated with LMB-2 at dose levels that ranged from 2 to 63 microg/kg administered intravenously over 30 minutes on alternate days for three doses (QOD x 3).


RESULTS
LMB-2 was administered to 35 patients for a total of 59 cycles. Dose-limiting toxicity at the 63 microg/kg level was reversible and included transaminase elevations in one patient and diarrhea and cardiomyopathy in another. LMB-2 was well tolerated in nine patients at the maximum-tolerated dose (40 microg/kg QOD x 3); toxicity was transient and most commonly included transaminase elevations (eight patients) and fever (seven patients). Only six of 35 patients developed significant neutralizing antibodies after the first cycle. The median half-life was 4 hours. One hairy cell leukemia (HCL) patient achieved a complete remission, which is ongoing at 20 months. Seven partial responses were observed in cutaneous T-cell lymphoma (one patient), HCL (three patients), chronic lymphocytic leukemia (one patient), Hodgkin's disease (one patient), and adult T-cell leukemia (one patient). Responding patients had 2 to 5 log reductions of circulating malignant cells, improvement in skin lesions, and regression of lymphomatous masses and splenomegaly. All four patients with HCL responded to treatment.


CONCLUSIONS
LMB-2 has clinical activity in CD25(+) hematologic malignancies and is relatively nonimmunogenic. It is the first recombinant immunotoxin to induce major responses in cancer. LMB-2 and similar agents that target other cancer antigens merit further clinical development.
Kreitman
R J
RJ
Laboratory of Clinical Pathology, Metabolism Branch, Medicine Branch, and Biopharmaceutical Development Program, Science Applications International Corporation Frederick, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
Wilson
W H
WH
White
J D
JD
Stetler-Stevenson
M
M
Jaffe
E S
ES
Giardina
S
S
Waldmann
T A
TA
Pastan
I
I
D000328:Adult; D000368:Aged; D000906:Antibodies / Q000032:analysis; D000911:Antibodies, Monoclonal; D004797:Enzyme-Linked Immunosorbent Assay; D005098:Exotoxins; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007938:Leukemia / Q000188:drug therapy* / Q000276:immunology; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000032:analysis
D000906:Antibodies; D000911:Antibodies, Monoclonal; C077707:B3(Fv)-PE38KDEL recombinant immunotoxin; D005098:Exotoxins; D000922:Immunotoxins; D015375:Receptors, Interleukin-2