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Pharmacokinetically guided phase 1 trial of the IGF-1 receptor antagonist RG1507 in children with recurrent or
R Bagatell1, C E Herzog, T M Trippett
1Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19066, USA. bagatellr@email.chop.edu
Insights
This study determined optimal RG1507 doses for children with solid tumors, finding 9 mg/kg/wk and 16 mg/kg q3W achieve adult-equivalent exposures. The monoclonal antibody RG1507 showed no dose-limiting toxicities in pediatric patients.
Area of Science:
- Pediatric Oncology
- Pharmacokinetics
- Monoclonal Antibody Therapy
Background:
- RG1507 is a monoclonal antibody targeting the Type 1 Insulin-like Growth Factor Receptor (IGF1R).
- Pediatric studies are crucial to establish safe and effective dosing for novel cancer therapies.
Purpose of the Study:
- To identify RG1507 doses in children with solid tumors that achieve pharmacokinetic exposures comparable to adult recommended doses.
- To evaluate the safety and tolerability of RG1507 in a pediatric population.
Main Methods:
- A phase I, open-label study treated children (3-17 years) with relapsed/refractory solid tumors.
- RG1507 was administered at 3 mg/kg/wk, 9 mg/kg/wk, or 16 mg/kg every 3 weeks (q3W).
- Pharmacokinetic sampling assessed exposure (AUC) against predefined targets based on adult data; dose-limiting toxicities (DLTs) were monitored.
Main Results:
- Thirty-one patients were enrolled; no DLTs were observed.
- The 9 mg/kg/wk dose achieved a mean AUC(0-7d) of 21,000 µg·h/mL (target: 16,000 µg·h/mL).
- The 16 mg/kg q3W dose achieved a mean AUC(0-21d) of 70,000 µg·h/mL (target: 59,400 µg·h/mL).
- Age-dependent body weight-normalized clearance was noted. Seven patients achieved stable disease for over 12 weeks.
Conclusions:
- Recommended RG1507 doses for pediatric solid tumors are 9 mg/kg/wk and 16 mg/kg q3W.
- These doses ensure exposures equivalent to those in adults.
- The flexible study design is suitable for evaluating agents with low toxicity in pediatric trials.
Purpose:
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.
Experimental Design:
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 microg h/mL) exceeded the target (16,000 microg h/mL). At 16 mg/kg q3W, the mean AUC(021d) (70,000 microg h/mL) exceeded the target (59,400 microg 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.
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