SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers

• Main Authors: Sarah Jannier, Véronique Kemmel, Consuelo Sebastia Sancho, Agathe Chammas, Amelia-Naomie Sabo, Erwan Pencreach, Françoise Farace, Marie Pierre Chenard, Benoit Lhermitte, Birgit Geoerger, Isabelle Aerts, Didier Frappaz, Pierre Leblond, Nicolas André, Stephane Ducassou, Nadège Corradini, Anne Isabelle Bertozzi, Eric Guérin, Florence Vincent, Michel Velten, Natacha Entz-Werle
• Format: Article
• Language: English
• Published: MDPI AG 2020-10-01
• Series: Cancers
• Subjects: intra-tumor hypoxia; mTor; HIF1; pediatric refractory cancers
• Online Access: https://www.mdpi.com/2072-6694/12/10/3051

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/m²/day), associating biweekly intravenous irinotecan (125 to 240 mg/m²/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/m²/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/m² irinotecan dose with a pharmacokinetic (PK) follow-up and a rapamycin dose of 1.5 mg/m²/day, reaching a blood concentration above 10 g/L.