title: Phase I study of sorafenib in combination with everolimus (RAD001) in patients with advanced neuroendocrine tumors.
abstract: OBJECTIVE
  Sorafenib and everolimus are both active against neuroendocrine tumors (NET). Because of potential synergy between VEGF pathway and mTOR inhibitors, we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET.
  
  
  METHODS
  Patients were treated with everolimus 10 mg daily in combination with sorafenib (dose level 1: 200 mg twice daily; dose level 2: 200 mg per morning, 400 mg per evening) using standard phase I dose escalation design. Dose-limiting toxicity (DLT) was defined within the first cycle (28 days) of therapy. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Twelve additional patients were treated at the maximum tolerated dose (MTD) level to further characterize safety and a preliminary assessment of activity.
  
  
  RESULTS
  One patient in Cohort 1 experienced DLT (grade 3 skin rash); the cohort was expanded to 6 patients with no further DLTs. All 3 patients in Cohort 2 experienced DLT, consisting of thrombocytopenia, hand-foot skin reaction, and rash/allergic reaction. Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD. Independently reviewed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage. By RECIST, we observed partial response in 1 patient, stable disease in 13 patients, and progressive disease in 3 patients.
  
  
  CONCLUSIONS
  Sorafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET. While the combination is active, toxicity concerns may preclude more widespread use.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. JANG@PARTNERS.ORG
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mayer
authors.forename: Nadine
authors.initials: N
authors.lastname: Jackson
authors.forename: Paige
authors.initials: P
authors.lastname: Malinowski
authors.forename: Eileen
authors.initials: E
authors.lastname: Regan
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Kulke
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018450:Disease Progression; D000068338:Everolimus; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
chemical_list: D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus