{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T01:33:59Z","timestamp":1790732039315,"version":"4.1.0"},"reference-count":53,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T00:00:00Z","timestamp":1603152000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006364","name":"Institut National Du Cancer","doi-asserted-by":"publisher","award":["N\u00b0 Eudract: 2010-022329-13"],"award-info":[{"award-number":["N\u00b0 Eudract: 2010-022329-13"]}],"id":[{"id":"10.13039\/501100006364","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers12103051","type":"journal-article","created":{"date-parts":[[2020,10,20]],"date-time":"2020-10-20T20:50:07Z","timestamp":1603227007000},"page":"3051","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers"],"prefix":"10.3390","volume":"12","author":[{"given":"Sarah","family":"Jannier","sequence":"first","affiliation":[{"name":"Pediatric Onco-Hematology Unit, University Hospital of Strasbourg, 67098 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Kemmel","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, University Hospital of Strasbourg, 67098 Strasbourg, France"},{"name":"Laboratory of Pharmacology and Toxicology in Neurocardiology-EA7296, University of Strasbourg,\r\n67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4680-4293","authenticated-orcid":false,"given":"Consuelo","family":"Sebastia Sancho","sequence":"additional","affiliation":[{"name":"Radiology Department, Pediatric Unit, University Hospital of Strasbourg, 67098 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agathe","family":"Chammas","sequence":"additional","affiliation":[{"name":"Radiology Department, Pediatric Unit, University Hospital of Strasbourg, 67098 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1388-2834","authenticated-orcid":false,"given":"Amelia-Naomie","family":"Sabo","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, University Hospital of Strasbourg, 67098 Strasbourg, France"},{"name":"Laboratory of Pharmacology and Toxicology in Neurocardiology-EA7296, University of Strasbourg,\r\n67000 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwan","family":"Pencreach","sequence":"additional","affiliation":[{"name":"Oncobiology Platform, Laboratory of Biochemistry and Molecular Biology,\r\nUniversity Hospital of Strasbourg, 67098 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Farace","sequence":"additional","affiliation":[{"name":"\u00abCirculating Tumor Cells\u00bb Translational Platform, Gustave Roussy, University of Paris-Saclay,\r\n94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie Pierre","family":"Chenard","sequence":"additional","affiliation":[{"name":"Pathology Department, University Hospital of Strasbourg, 67098 Strasbourg, France"},{"name":"Centre de Ressources Biologiques, University Hospital of Strasbourg, 67098 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benoit","family":"Lhermitte","sequence":"additional","affiliation":[{"name":"Pathology Department, University Hospital of Strasbourg, 67098 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Geoerger","sequence":"additional","affiliation":[{"name":"Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Universit\u00e9 Paris-Saclay,\r\nINSERM U1015, 94800 Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Aerts","sequence":"additional","affiliation":[{"name":"Oncology Center SIREDO, Institut Curie, PSL Research University, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4361-3643","authenticated-orcid":false,"given":"Didier","family":"Frappaz","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Department, L\u00e9on Berard Institute, 69373 Lyon, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Leblond","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Department, L\u00e9on Berard Institute, 69373 Lyon, France"},{"name":"Pediatric Oncology Unit, Oscar Lambret Center, 59020 Lille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6786-4968","authenticated-orcid":false,"given":"Nicolas","family":"Andr\u00e9","sequence":"additional","affiliation":[{"name":"Pediatric Onco-Hematology Unit, CHU La Timone, 13005 Marseille, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane","family":"Ducassou","sequence":"additional","affiliation":[{"name":"Pediatric Onco-Hematology Department, University Hospital of Bordeaux, 33000 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nad\u00e8ge","family":"Corradini","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Department, L\u00e9on Berard Institute, 69373 Lyon, France"},{"name":"Pediatric Oncology Unit, University Hospital of Nantes, 44093 Nantes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6786-4968","authenticated-orcid":false,"given":"Anne Isabelle","family":"Bertozzi","sequence":"additional","affiliation":[{"name":"Pediatric Onco-Hematology Department, University Hospital of Toulouse, 31059 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Gu\u00e9rin","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry, University Hospital of Strasbourg, 67098 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florence","family":"Vincent","sequence":"additional","affiliation":[{"name":"Pediatric Onco-Hematology Unit, University Hospital of Strasbourg, 67098 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Velten","sequence":"additional","affiliation":[{"name":"Clinical Research Department, ICANS, 67200 Strasbourg, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natacha","family":"Entz-Werle","sequence":"additional","affiliation":[{"name":"Pediatric Onco-Hematology Unit, University Hospital of Strasbourg, 67098 Strasbourg, France"},{"name":"UMR CNRS 7021, Laboratory Bioimaging and Pathologies, Tumoral Signaling and Therapeutic Targets,\r\nFaculty of Pharmacy, 67401 Illkirch, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7267","DOI":"10.1158\/0008-5472.CAN-04-4575","article-title":"A hypoxia-drivenvascular endothelial growth factor\/Flt1 autocrine loop interacts with hypoxia-inducible factor-1alpha through mitogen-activated protein kinase\/extracellular signal-regulated kinase 1\/2 pathway in neuroblastoma","volume":"65","author":"Das","year":"2005","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2052","DOI":"10.1007\/s11999-008-0328-y","article-title":"Hypoxia markers in human osteosarcoma: An exploratory 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