A phase 1 trial of everolimus and bevacizumab in children with recurrent solid tumors
| Autor: | Olivia Campagne, Natasha Sahr, Lisa M. McGregor, April Sykes, Wayne L. Furman, Ruth G. Tatevossian, Clinton F. Stewart, Sujuan Jia, Victor M. Santana |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Adolescent Maximum Tolerated Dose Bevacizumab Angiogenesis Inhibitors Antineoplastic Agents Peripheral blood mononuclear cell Gastroenterology Article 03 medical and health sciences 0302 clinical medicine Refractory Neoplasms Internal medicine Antineoplastic Combined Chemotherapy Protocols medicine Humans Everolimus 030212 general & internal medicine Child PI3K/AKT/mTOR pathway business.industry Prognosis medicine.disease Progression-Free Survival Oncology Child Preschool 030220 oncology & carcinogenesis Toxicity Biomarker (medicine) Female Neoplasm Recurrence Local business Progressive disease medicine.drug |
| Zdroj: | Cancer |
| ISSN: | 1097-0142 0008-543X |
| Popis: | Background The prognosis for children with recurrent solid tumors generally is poor. Targeting mammalian target of rapamycin (mTOR) and vascular endothelial growth factor A with everolimus and bevacizumab, respectively, synergistically improves progression-free survival and is well tolerated in adults with solid tumors. Methods In the current phase 1 study, a total of 15 children with recurrent or refractory solid tumors were treated with bevacizumab and everolimus to establish the maximum tolerated dose, toxicity, and preliminary antitumor response (ClinicalTrials.gov identifier NCT00756340). The authors also evaluated everolimus-mediated inhibition of the mTOR pathway in the peripheral blood mononuclear cells of treated patients. Results Tumors predominantly were soft tissue and/or bone sarcomas (8 cases) and brain tumors (5 cases). The first 2 patients enrolled at dose level 1 (10 mg/kg of bevacizumab and 4 mg/m2 of everolimus) experienced dose-limiting toxicities (DLTs). The next 5 patients were enrolled at dose level 0 (8 mg/kg of bevacizumab and 4 mg/m2 of everolimus), and DLTs occurred in 2 patients. The authors then modified the protocol to permit expansion of dose 0, and 8 additional patients were added, with no DLTs reported. Of all the patients, stable disease occurred in 4 patients (30.8%; median, 2 courses), and progressive disease occurred in 9 patients (69.2%). Overall survival was 0.59 years (95% CI, 0.24-1.05 years). The mTOR biomarker phospho-4EBP1 Thr/37/46 significantly decreased from baseline to day 27 in peripheral blood mononuclear cells (P = .045). Phospho-AKT levels also decreased from those at baseline. Conclusions The maximum tolerated dose of cotreatment with bevacizumab and everolimus was 8 mg/kg of bevacizumab and 4 mg/m2 of everolimus in a 4-week cycle for children with recurrent solid tumors. |
| Databáze: | OpenAIRE |
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