SFCE-RAPIRI Phase I Study of Rapamycin Plus Irinotecan: A New Way to Target Intra-Tumor Hypoxia in Pediatric Refractory Cancers
by
, , , , ,
Sarah Jannier
1,†, 
Véronique Kemmel
2,3,†,
Consuelo Sebastia Sancho
4,
Agathe Chammas
4,
Amelia-Naomie Sabo
2,3,
Erwan Pencreach
5,
Françoise Farace
6, 
Marie Pierre Chenard
7,8,
Benoit Lhermitte
7,
Birgit Geoerger
9,
Isabelle Aerts
10,
Didier Frappaz
11,
Pierre Leblond
11,12,
Nicolas André
13,
Stephane Ducassou
14,
Nadège Corradini
11,15,
Anne Isabelle Bertozzi
16,
Eric Guérin
2,
Florence Vincent
1,
Michel Velten
17 and
Natacha Entz-Werle
1,18,*add
Show full author list
1
Pediatric Onco-Hematology Unit, University Hospital of Strasbourg, 67098 Strasbourg, France
2
Laboratory of Biochemistry, University Hospital of Strasbourg, 67098 Strasbourg, France
3
Laboratory of Pharmacology and Toxicology in Neurocardiology-EA7296, University of Strasbourg,
67000 Strasbourg, France
4
Radiology Department, Pediatric Unit, University Hospital of Strasbourg, 67098 Strasbourg, France
5
Oncobiology Platform, Laboratory of Biochemistry and Molecular Biology,
University Hospital of Strasbourg, 67098 Strasbourg, France
6
«Circulating Tumor Cells» Translational Platform, Gustave Roussy, University of Paris-Saclay,
94800 Villejuif, France
7
Pathology Department, University Hospital of Strasbourg, 67098 Strasbourg, France
8
Centre de Ressources Biologiques, University Hospital of Strasbourg, 67098 Strasbourg, France
9
Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Université Paris-Saclay,
INSERM U1015, 94800 Villejuif, France
10
Oncology Center SIREDO, Institut Curie, PSL Research University, 75005 Paris, France
11
Pediatric Oncology Department, Léon Berard Institute, 69373 Lyon, France
12
Pediatric Oncology Unit, Oscar Lambret Center, 59020 Lille, France
13
Pediatric Onco-Hematology Unit, CHU La Timone, 13005 Marseille, France
14
Pediatric Onco-Hematology Department, University Hospital of Bordeaux, 33000 Bordeaux, France
15
Pediatric Oncology Unit, University Hospital of Nantes, 44093 Nantes, France
16
Pediatric Onco-Hematology Department, University Hospital of Toulouse, 31059 Toulouse, France
17
Clinical Research Department, ICANS, 67200 Strasbourg, France
18
UMR CNRS 7021, Laboratory Bioimaging and Pathologies, Tumoral Signaling and Therapeutic Targets,
Faculty of Pharmacy, 67401 Illkirch, France
*
Author to whom correspondence should be addressed.
†
Equivalent work for those authors, to be considered as first authors.
Cancers 2020, 12(10), 3051; https://doi.org/10.3390/cancers12103051
Submission received: 21 August 2020
/
Revised: 9 October 2020
/
Accepted: 9 October 2020
/
Published: 20 October 2020
Simple Summary
More and more relapsing or refractory pediatric cancers are described to present hypoxic features linked to a worse outcome. Therefore, the aim of our phase I study RAPIRI was the targeting of the central node mTor/HIF-1 with rapamycin plus irinotecan and determine the appropriated dose of this combination. As expected, the tolerance was optimal across all dose levels and no maximum tolerated dose of both drugs was reached. The pharmacokinetics (PK) helped us to refine the doses to use in the future phase II trial and the importance of PK follow-up in such combination. We also confirmed in almost half of the interpretable patients for tumor response a non-progressive disease. All those observations additionally to the ancillary’s studies provide strong evidence to propose a next trial focusing on brain tumors and sarcomas and using biweekly 125 mg/m2 irinotecan dose with a PK follow-up and a rapamycin dose of 1.5 mg/m2/day, reaching a blood concentration above 10 g/L.
Abstract
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.
Keywords:
intra-tumor hypoxia; mTor; HIF1; pediatric refractory cancers
