A phase I clinical trial of the hu14.18-IL2 (EMD 273063) as a treatment for children with refractory or recurrent neuroblastoma and melanoma: a study of the Children's Oncology Group.
OBJECTIVE
Evaluate the clinical safety, toxicity, immune activation/modulation, and maximal tolerated dose of hu14.18-IL2 (EMD 273063) in pediatric patients with recurrent/refractory neuroblastoma and other GD2-positive solid tumors.


METHODS
Twenty-seven pediatric patients with recurrent/refractory neuroblastoma and one with melanoma were treated with a humanized anti-GD2 monoclonal antibody linked to human interleukin 2 (IL-2). Cohorts of patients received hu14.18-IL2, administered i.v. over 4 hours for three consecutive days, at varying doses. Patients with stable disease, partial, or complete responses were eligible to receive up to three additional courses of therapy.


RESULTS
Most of the clinical toxicities were anticipated and similar to those reported with IL-2 and anti-GD2 monoclonal antibody therapy and to those noted in the initial phase I study of hu14.18-IL2 in adults with metastatic melanoma. The maximal tolerated dose was determined to be 12 mg/m2/d, with agent-related dose-limiting toxicities of hypotension, allergic reaction, blurred vision, neutropenia, thrombocytopenia, and leukopenia. Three patients developed dose-limiting toxicity during course 1; seven patients in courses 2 to 4. Two patients required dopamine for hypotension. There were no treatment-related deaths, and all toxicity was reversible. Treatment with hu14.18-IL2 led to immune activation/modulation as evidenced by elevated serum levels of soluble IL-2 receptor alpha (sIL2Ralpha) and lymphocytosis. The median half-life of hu14.18-IL2 was 3.1 hours. There were no measurable complete or partial responses to hu14.18-IL2 in this study; however, three patients did show evidence of antitumor activity.


CONCLUSIONS
Hu14.18-IL2 (EMD 273063) can be administered safely with reversible toxicities in pediatric patients at doses that induce immune activation. A phase II clinical trial of hu14.18-IL2, administered at a dose of 12 mg/m2/d x 3 days repeated every 28 days, will be done in pediatric patients with recurrent/refractory neuroblastoma.
Osenga
Kaci L
KL
The University of Wisconsin-Madison, Madison, Wisconsin, USA.
Hank
Jacquelyn A
JA
Albertini
Mark R
MR
Gan
Jacek
J
Sternberg
Adam G
AG
Eickhoff
Jens
J
Seeger
Robert C
RC
Matthay
Katherine K
KK
Reynolds
C Patrick
CP
Twist
Clare
C
Krailo
Mark
M
Adamson
Peter C
PC
Reisfeld
Ralph A
RA
Gillies
Stephen D
SD
Sondel
Paul M
PM
D000293:Adolescent; D000740:Anemia / Q000139:chemically induced; D000906:Antibodies / Q000097:blood; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005334:Fever / Q000139:chemically induced; D006801:Humans; D007022:Hypotension / Q000139:chemically induced; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008657:Metabolic Clearance Rate; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D000906:Antibodies; D000911:Antibodies, Monoclonal; D007376:Interleukin-2; C493743:lorukafusp alfa