Abstract
Simple SummaryMore 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-1α 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 µg/L.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)-1α 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 µg/L.
Highlights
Intra-tumor hypoxia, present in multiple solid tumors, induces usually aberrant microvasculature and tumor necrosis [1,2,3,4,5,6,7]
Our results showed that this combination was well tolerated without severe toxicities, despite a heavily pretreated population
Most of the patients, where we demonstrated early evidence of activity with this hypoxia-targeting strategy, were having brain tumors (ATRT, ependymomas, medulloblastomas, and high-grade gliomas), as well as osteosarcomas
Summary
Intra-tumor hypoxia, present in multiple solid tumors, induces usually aberrant microvasculature and tumor necrosis [1,2,3,4,5,6,7]. It is known to increase genetic instability through apoptosis and decreased DNA repair capacities, promoting a metastatic and highly chemo- and radio-resistant tumor cell phenotype, like in pediatric brain tumors, sarcomas, or neuroblastomas. HIF-1α accumulation is translocating into the nucleus to increase transcription of downstream signaling, leading to neoangiogenesis, metabolic switch, cell propensity to migrate, and tumor cell stemness features. When inhibiting these proteins, the idea is to prevent the effects of hypoxic signals and subsequently stop cancer cell adaptation, tumor growth, and metastatic evolution
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