Phase I trial of a human-mouse chimeric anti-disialoganglioside monoclonal antibody ch14.18 in patients with refractory neuroblastoma and osteosarcoma.
OBJECTIVE
To evaluate the toxicity, immunogenicity, and pharmacokinetics of a human-mouse chimeric monoclonal antibody (mAb) ch 14.18 directed against disialoganglioside (GD2) and to obtain preliminary information on its clinical efficacy, we conducted a phase I trial in 10 patients with refractory neuroblastoma and one patient with osteosarcoma.


METHODS
Eleven patients were entered onto this phase I trial. They received 20 courses of mAb ch 14.18 at dose levels of 10, 20, 50, 100, and 200 mg/m2. Dose escalation was performed in cohorts of three patients; intrapatient dose escalation was also permitted.


RESULTS
The most prevalent toxicities were pain, tachycardia, hypertension, fever, and urticaria. Most of these toxicities were dose-dependent and rarely noted at dosages of 20 mg/m2 and less. Although the maximum-tolerated dose was not reached in this study, clinical responses were observed. These included one partial (PR) and four mixed responses (MRs) and one stable disease (SD) among 10 assessable patients. Biologic activity of ch 14.18 in vivo was shown by binding of ch 14.18 to tumor cells and complement-dependent cytotoxicity of posttreatment sera against tumor target cells. An anti-ch 14.18 immune response was detectable in seven of 10 patients studied.


CONCLUSIONS
In summary, with the dose schedule used, ch 14.18 appears to be clinically safe and effective, and repeated mAb administration was not associated with increased toxicities. Further clinical trials of mAb ch 14.18 in patients with neuroblastoma are warranted.
Yu
A L
AL
Department of Pediatrics, University of California San Diego 92103-8447, USA. alyu@ucsd.edu
Uttenreuther-Fischer
M M
MM
Huang
C S
CS
Tsui
C C
CC
Gillies
S D
SD
Reisfeld
R A
RA
Kung
F H
FH
D000328:Adult; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003176:Complement C3 / Q000032:analysis; D003181:Complement C4 / Q000032:analysis; D015941:Complement Hemolytic Activity Assay; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005732:Gangliosides / Q000276:immunology*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism / Q000628:therapy*; D012516:Osteosarcoma / Q000628:therapy*; D010146:Pain / Q000139:chemically induced; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D003176:Complement C3; D003181:Complement C4; D005732:Gangliosides; D011993:Recombinant Fusion Proteins; C019403:ganglioside, GD2; C112746:dinutuximab