STATEMENT OF TRANSLATIONAL RELEVANCE
Although chemotherapy has been used in most clinical trials for children with high-grade glioma, no drug regimen has so far stood out as particularly beneficial for these patients.
Based on pre-clinical and clinical experience in adults with similar tumors, we report for the first time the results of a Phase I study which used erlotinib during and after radiotherapy in children with high-grade glioma. We characterized the acute and chronic toxicities associated with erlotinib therapy. Within the context of a Phase I study, we also performed extensive pharmacokinetic and molecular studies.
We observed preliminary encouraging outcome in a subgroup of our patients, particularly those with anaplastic astrocytoma. Therefore, the current study established a platform for future clinical trials to incorporate erlotinib in the treatment of high-grade glioma in children.
To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy (RT), and to describe the pharmacokinetics of erlotinib and its metabolite OSI-420 in patients between 3 and 25 years with newly diagnosed high-grade glioma who did not require enzyme-inducing anticonvulsants.
Five dosage levels (70, 90, 120, 160, and 200mg/m2 per day) were planned in this Phase I study. Dose-limiting toxicities (DLTs) were evaluated during first 8 weeks of therapy. Local RT (dose between 54 and 59.4 Gy) and erlotinib started preferentially on the same day. Erlotinib was administered once daily for a maximum of 3 years. Pharmacokinetic studies were obtained after first dose and on day 8 of therapy. Mutational analysis of EGFR kinase domain, PIK3CA, and PTEN was performed in tumor tissue.
Median age at diagnosis of 23 patients was 10.7 years (range, 3.7 to 22.5 years). MTD of erlotinib was 120mg/m2 per day. Skin rash and diarrhea were generally well controlled with supportive care. DLTs were diarrhea (n=1), increase in serum lipase (n=1), and rash with pruritus (n=1). The pharmacokinetic parameters of erlotinib and OSI-420 in children were similar to those described in adults. However, there was no relationship between erlotinib dosage and drug exposure. No EGFR kinase domain mutations were observed. Two patients with glioblastoma harbored mutations in PIK3CA (n=1) or PTEN (n=1).
Although the MTD of erlotinib in children with newly diagnosed high-grade glioma was 120mg/m2 per day, pharmacokinetic studies demonstrated wide inter-patient variability in drug exposure.