title: Phase ib of sorafenib in combination with everolimus in patients with advanced solid tumors, selected on the basis of molecular targets.
abstract: 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 3+3 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: European Institute of Oncology, Milan, Italy;
authors.forename: Francesca
authors.initials: F
authors.lastname: Toffalorio
authors.forename: Gianluca
authors.initials: G
authors.lastname: Spitaleri
authors.forename: Chiara
authors.initials: C
authors.lastname: Catania
authors.forename: Laura
authors.initials: L
authors.lastname: Dal Zotto
authors.forename: Cristina
authors.initials: C
authors.lastname: Noberasco
authors.forename: Angelo
authors.initials: A
authors.lastname: Delmonte
authors.forename: Mariacarmela
authors.initials: M
authors.lastname: Santarpia
authors.forename: Fabio
authors.initials: F
authors.lastname: Vecchio
authors.forename: Veronica
authors.initials: V
authors.lastname: Brunelli
authors.forename: Cristiano
authors.initials: C
authors.lastname: Rampinelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Barberis
authors.forename: Caterina
authors.initials: C
authors.lastname: Fumagalli
authors.forename: Massimo
authors.initials: M
authors.lastname: Zucchetti
authors.forename: Monique
authors.initials: M
authors.lastname: Zangarini
authors.forename: Tullia
authors.initials: T
authors.lastname: Diena
authors.forename: Romano
authors.initials: R
authors.lastname: Danesi
authors.forename: Filippo
authors.initials: F
authors.lastname: de Braud
authors.forename: Tommaso
authors.initials: T
authors.lastname: De Pas
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D000068338:Everolimus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000077157:Sorafenib; D018631:ras Proteins / Q000037:antagonists & inhibitors
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins; D020123:Sirolimus