EPT-13
RAPIRI I – PHASE I STUDY OF DAILY ORAL RAPAMYCIN AND INTRAVENOUS IRINOTECAN IN CHILDREN WITH A RECURRENT/REFRACTORY MALIGNANT SOLID TUMOR: GOOD TOLERANCE AND PROMISING RESULTS IN BRAIN TUMORS - A REPORT FROM THE SOCIÉTÉ FRANÇAISE DES CANCERS ET LEUCÉMIES DE L'ENFANT ET DE L'ADOLESCENT (SFCE)

Intratumor hypoxia is a key factor in tumor cell resistance to therapies. Its presence is considered as a factor of poor prognosis in several pediatric cancers. In a preclinical setting, rapamycin, a mTor inhibitor, associated with irinotecan, a topoisomerase I and HIF-1a inhibitor, were able to induce tumor cell apoptosis. Therefore, a phase I study with this combination was proposed to children with refractory cancers. 42 eligible children were enrolled using a 3 + 3 design to determine the maximum tolerated dose (MTD) of rapamycin and irinotecan combination. Rapamycin was administered orally once daily and irinotecan intravenously on D1 and D15 of a 28-day cycle. A dose escalation scheme included 10 levels, where rapamycin was administered from 1 to 2.5 mg/m² and irinotecan from 125 to 240 mg/m². Pharmacokinetics and UGT1A1 polymorphism were characterized. 1 out of 6 patients experienced dose-limiting toxicity at 3 different levels; dose escalation was achieved until level 10 and MTD was not defined. Toxicity was mild to moderate and systematically reversible. 32 patients were assessable for tumor response, whereas 10 patients had no measurable disease. Among 14 brain tumors, 1 ependymoma and 1 ATRT had a partial response and 6 (2 medulloblastomas, 1 PNET, 1 ependymoma and 1 high grade glioma) were in stable disease during 4 to 6 months. The upcoming phase II study will focus on brain tumors, in which optimal doses, determined by pharmacokinetics, toxicity and tumor responses, might be 125 mg/m² for irinotecan and 1.5 mg/m² for rapamycin associated with secondary pharmacokinetic adaptation.