SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers.
Fiche publication
Date publication
octobre 2020
Journal
Cancers
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHENARD Marie-Pierre, Pr ENTZ-WERLE Natacha, Dr GUERIN Eric, Dr PENCREACH Erwan, Pr VELTEN Michel, Dr JANNIER Sarah, Dr LHERMITTE Benoît
Tous les auteurs :
Jannier S, Kemmel V, Sebastia Sancho C, Chammas A, Sabo AN, Pencreach E, Farace F, Chenard MP, Lhermitte B, Geoerger B, Aerts I, Frappaz D, Leblond P, André N, Ducassou S, Corradini N, Bertozzi AI, Guérin E, Vincent F, Velten M, Entz-Werle N
Lien Pubmed
Résumé
Hypoxic environment is a prognostic factor linked in pediatric cancers to a worse outcome, favoring tumor progression and resistance to treatments. The activation of mechanistic Target Of Rapamycin (mTor)/hypoxia inducible factor (HIF)-1 pathway can be targeted by rapamycin and irinotecan, respectively. Therefore, we designed a phase I trial associating both drugs in pediatric refractory/relapsing solid tumors. Patients were enrolled according to a 3 + 3 escalation design with ten levels, aiming to determine the MTD (maximum tolerated dose) of rapamycin plus irinotecan. Rapamycin was administered orally once daily in a 28-day cycle (1 to 2.5 mg/m/day), associating biweekly intravenous irinotecan (125 to 240 mg/m/dose). Toxicities, pharmacokinetics, efficacy analyses, and pharmacodynamics were evaluated. Forty-two patients, aged from 2 to 18 years, were included. No MTD was reached. Adverse events were mild to moderate. Only rapamycin doses of 1.5 mg/m/day reached over time clinically active plasma concentrations. Tumor responses and prolonged stable disease were associated with a mean irinotecan area under the curve of more than 400 min.mg/L. Fourteen out of 31 (45.1%) patients had a non-progressive disease at 8 weeks. Most of them were sarcomas and brain tumors. For the phase II trial, we can then propose biweekly 125 mg/m irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m/day, reaching a blood concentration above 10 g/L.
Mots clés
HIF1, intra-tumor hypoxia, mTor, pediatric refractory cancers
Référence
Cancers (Basel). 2020 Oct 20;12(10):