Abstract
9564 Background: The combination of GB and IRN is expected synergy because GB inhibits ABCG2, which pumps IRN out of the tumor cells. The most common single IRN therapy in pediatric oncology is a protracted regimen for 10-day or 5-day. We adopted 5-day regimen with respect to safety and patient convenience to develop multi-agent regimens. We conducted a pilot phase I trial of the combination of GB and IRN for AYA cancer patients to estimate dose-limiting toxicity (DLT) and pharmacokinetics (PK). Expression of ABCG2 and EGFR on pathology samples was also investigated. Methods: Patients (pts) under 40 and with recurrent bone or CNS tumor were eligible. GB 112.5mg/m2 was administered orally once a day for 12 days, concurrently with IRN 35mg/m2 for 5 consecutive days. Antibiotics (cefixime or cefpodoxime) were used to reduce IRN induced diarrhea. Courses were repeated every 3 weeks. PK analysis was performed during the first course. Results: Four pts with a median of 17.5 prior treatment courses were enrolled and received 15 courses (Table). DLT occurred in the only one pt who has UGT1A1 *28/*6 variants and had a intrathoracic hemorrhage episode just before registered this study. No grade4 non-hematologic toxicity occurred in 15 courses, while G2-3 diarrhea caused more than three days earlier discontinuation of GB in every courses and more than 10% weight loss in all pts. The median SN-38 lactone AUC at this dose was 101 ng*hr/ml, almost same to that reported with single IRN 5days regimen. Conclusions: A certain clinical benefit was observed in a patient with metastatic osteosarcoma. However, toxicities including grade 2-3 diarrhea were not always tolerable in heavily-pretreated AYA pts. Especially the exacerbation of gastrointestinal toxicity by GB seemed to be difficult to maximize anti-tumor effect of IRN by dosing up. This pilot phase I trial resulted in early termination. 35y M 13y M 21y F 25y M Histology Ganglioglioma Osteosarcoma Glioblastoma Ewing’s sarcoma EGFR expression + + + – ABCG2 expression – – + + DLT – Thrombocytopenia anemia – – Treatment courses 2 7 (30mg/m2/day after 2nd course) 3 3
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