Pharmacokinetically guided phase 1 trial of the IGF-1 receptor antagonist RG1507 in children with recurrent or refractory solid tumors.
OBJECTIVE
This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieves exposures equivalent to those achieved in adults at recommended doses.


METHODS
Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 (3 and 9 mg/kg/wk, and 16 mg/kg every 3 weeks [q3W]) as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the first dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/wk and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred.


RESULTS
Thirty-one evaluable patients aged 3-17 years were enrolled at 3 mg/kg/wk (n = 3), 9 mg/kg/wk (n = 18), or 16 mg/kg q3W (n = 10). There were no DLTs. At 9 mg/kg/wk the mean AUC(0-7d) (21,000 μg h/mL) exceeded the target (16,000 μg h/mL). At 16 mg/kg q3W, the mean AUC(021d) (70,000 μg h/mL) exceeded the target (59,400 μg h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for >12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks.


CONCLUSIONS
The recommended doses of RG1507 in children with solid tumors are 9 mg/kg/wk and 16 mg/kg q3W. This flexible design is well suited for trials of agents associated with limited toxicity.
Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19066, USA. bagatellr@email.chop.edu
R
R
Bagatell
C E
CE
Herzog
T M
TM
Trippett
J F
JF
Grippo
G
G
Cirrincione-Dall
E
E
Fox
M
M
Macy
J
J
Bish
P
P
Whitcomb
A
A
Aikin
G
G
Wright
S
S
Yurasov
F M
FM
Balis
L
L
Gore
D000293:Adolescent; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000188:drug therapy*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D012008:Recurrence
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C558734:RG-1507 monoclonal antibody; D017526:Receptor, IGF Type 1