TY - JOUR
T1 - Phase Ib of sorafenib in combination with everolimus in patients with advanced solid tumors, selected on the basis of molecular targets
AU - Toffalorio, Francesca
AU - Spitaleri, Gianluca
AU - Catania, Chiara
AU - Zotto, Laura Dal
AU - Noberasco, Cristina
AU - Delmonte, Angelo
AU - Santarpia, Mariacarmela
AU - Vecchio, Fabio
AU - Brunelli, Veronica
AU - Rampinelli, Cristiano
AU - Barberis, Massimo
AU - Fumagalli, Caterina
AU - Zucchetti, Massimo
AU - Zangarini, Monique
AU - Diena, Tullia
AU - Danesi, Romano
AU - De Braud, Filippo
AU - De Pas, Tommaso
PY - 2014
Y1 - 2014
N2 - Background. Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. Methods. Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 313 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. Results. The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma.Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. Conclusion. The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.
AB - Background. Molecular alterations of the PI3K and Ras pathways often occur in human cancer. In this trial, the pharmacokinetics, toxicity, and activity of two drugs inhibiting these pathways-everolimus and sorafenib-were investigated. Methods. Thirteen patients with progressing solid tumors were treated with everolimus and sorafenib, according to a 313 scheme. Patients were selected on the basis of immunohistochemical expression of tumor molecular targets, including phospho-AKT, -p70S6K, and -ERK1/2. Results. The daily recommended dose identified was 2.5 mg of everolimus and 600 mg of sorafenib. Dose-limiting toxicities included grade 3 asthenia and hand-foot skin reaction. No grade 4 adverse events were observed. The most frequent grade 3 toxicities were hypophosphatemia (30.8%), alanine aminotransferase level increase, asthenia, and anorexia (14%). No pharmacokinetic interactions were identified between everolimus and sorafenib. Of 12 evaluable patients, we observed 2 partial responses, with greater than 10% shrinkage in an additional 5 patients. Objective responses were observed in one patient with a thymoma and in one patient with a lung adenocarcinoma.Tumor shrinkage that did not qualify as a partial response was seen in an abdominal leiomyosarcoma and in adenoid cystic carcinomas. Conclusion. The combination of everolimus and sorafenib is safe. The tumor activity observed in different tumor types could be the result of the combined action of these drugs as well as the molecular selection of the treated population. Further research is warranted to better investigate drugs simultaneously blocking the PI3K and the Ras pathways and to refine patient selection.
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U2 - 10.1634/theoncologist.2013-0335
DO - 10.1634/theoncologist.2013-0335
M3 - Article
C2 - 24674875
AN - SCOPUS:84898411259
VL - 19
SP - 344
EP - 345
JO - Oncologist
JF - Oncologist
SN - 1083-7159
IS - 4
ER -