Treatment with high dose mouse monoclonal (anti-GD3) antibody R24 in patients with metastatic melanoma.
R24 is a mouse IgG3 monoclonal antibody that reacts with the ganglioside GD3 expressed by melanoma cells and other cells of neuroectodermal origin (e.g. adrenal medulla). Antitumour activity of R24 was demonstrated in initial phase I and pilot trials, but treatment was limited by urticaria at cumulative doses of 400 mg/m2. A trial exploring intensification of the dose of R24 was conducted in eight patients. Planned doses of R24 antibody were 800 and 1200 mg/m2 over 6-8 days by continuous i.v. infusion. All patients received concomitant therapy with hydroxyzine hydrochloride and cimetidine to minimize urticaria. One patient developed anaphylaxis, after which no further therapy was given. All patients developed peripheral blood lymphopenia and marked decreases in serum complement values during treatment, suggesting depletion of two possible effector mechanisms of the antitumour effects of R24. A vascular leak syndrome, manifested by weight gain, oedema and hypotension, was evident in seven patients during the initial 24-36 h of treatment. Serum sickness syndrome was observed in six of seven evaluable patients between days 5 and 8, coincident with the onset of the human anti-globulin response to R24. One patient given 1200 mg/m2 had a minor response (38% reduction in pelvic nodes) lasting 12 months. There was no detectable increase (by immunohistochemical staining) in deposition of R24 within tumour sites at doses used in this trial compared to that observed at doses of 240 and 400 mg/m2. The maximum tolerated dose was 800 mg/m2. Dose-limiting toxicity was manifest as reversible hypertension with end-organ symptoms (chest pain or visual field defects) in patients treated with a dose of 1200 mg/m2.(ABSTRACT TRUNCATED AT 250 WORDS)
Bajorin
D F
DF
Clinical Immunology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10012.
Chapman
P B
PB
Wong
G Y
GY
Cody
B V
BV
Cordon-Cardo
C
C
Dantes
L
L
Templeton
M A
MA
Scheinberg
D
D
Oettgen
H F
HF
Houghton
A N
AN
D000328:Adult; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000097:blood; D000911:Antibodies, Monoclonal / Q000627:therapeutic use* / Q000633:toxicity; D015703:Antigens, CD / Q000032:analysis; D002927:Cimetidine / Q000627:therapeutic use; D003165:Complement System Proteins / Q000032:analysis; D005260:Female; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D006919:Hydroxyzine / Q000627:therapeutic use; D007074:Immunoglobulin G / Q000145:classification / Q000627:therapeutic use; D008212:Lymphocyte Depletion; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D013601:T-Lymphocytes / Q000276:immunology; D014581:Urticaria / Q000517:prevention & control
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D005732:Gangliosides; D007074:Immunoglobulin G; D006919:Hydroxyzine; C026226:ganglioside, GD3; D002927:Cimetidine; D003165:Complement System Proteins