title: A phase I, dose-finding study of sorafenib in combination with gemcitabine and radiation therapy in patients with unresectable pancreatic adenocarcinoma: a Grupo Español Multidisciplinario en Cáncer Digestivo (GEMCAD) study.
abstract: OBJECTIVE
  Sorafenib, an oral inhibitor of B-raf, VEGFR2, and PDGFR2-beta, acts against pancreatic cancer in preclinical models. Due to the radio-sensitization activity of both sorafenib and gemcitabine, we designed a multicenter, phase I trial to evaluate the safety profile and the recommended dose of this combination used with concomitant radiation therapy.
  
  
  METHODS
  Patients with biopsy-proven, unresectable pancreatic adenocarcinoma (based on vascular invasion detected by computed tomography) were treated with gemcitabine (300 mg/m2 i.v. weekly ×5 weeks) concurrently with radiation therapy (45 Gy in 25 fractions) and sorafenib (escalated doses in a 3+3 design, from 200 to 800 mg/day). Radiation portals included the primary tumor but not the regional lymph nodes. Patients with planning target volumes (PTV) over 500 cc were excluded. Cases not progressing during chemoradiation were allowed to continue with sorafenib until disease progression.
  
  
  RESULTS
  Twelve patients were included. Three patients received 200 mg/day, 6 received 400 mg/day, and 3 received 800 mg/day; PTVs ranged from 105 to 500 cc. No dose-limiting toxicities occurred. The most common grade 2 toxicities were fatigue, neutropenia, nausea, and raised serum transaminases. Treatment was discontinued in one patient because of a reversible posterior leukoencephalopathy. There were no treatment-related deaths.
  
  
  CONCLUSIONS
  The addition of sorafenib to concurrent gemcitabine and radiation therapy showed a favorable safety profile in unresectable pancreatic adenocarcinoma. A dose of 800 mg/day is recommended for phase II evaluation.
  
  
  BACKGROUND
  EudraCT 2007-003211-31 ClinicalTrials.gov 00789763.
authors.affiliation: Department of Medical Oncology, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Aparicio
authors.affiliation: Department of Radiation Oncology, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Mora
authors.affiliation: Department of Medical Oncology, Hospital de Sant Pau, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Martín
authors.affiliation: Department of Radiation Oncology, Hospital de Sant Pau, Barcelona, Spain.
authors.forename: Ma Lourdes
authors.initials: ML
authors.lastname: Petriz
authors.affiliation: Department of Medical Oncology, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Feliu
authors.affiliation: Department of Radiation Oncology, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Ma Elena
authors.initials: ME
authors.lastname: Sánchez-Santos
authors.affiliation: Department of Radiology, Hospital Clínic, Barcelona, Spain.
authors.forename: Juan Ramón
authors.initials: JR
authors.lastname: Ayuso
authors.affiliation: Department of Nuclear Medicine, Hospital Clínic, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Fuster
authors.affiliation: Department of Radiation Oncology, Hospital Clínic, Barcelona, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Conill
authors.affiliation: Department of Medical Oncology, Hospital Clínic, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Maurel
mesh_terms: D000230:Adenocarcinoma / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy* / Q000601:surgery; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010190:Pancreatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000532:radiotherapy* / Q000601:surgery; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000627:therapeutic use*; D049268:Positron-Emission Tomography; D000077157:Sorafenib; D014057:Tomography, X-Ray Computed; D000093542:Gemcitabine
chemical_list: D010671:Phenylurea Compounds; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; D000093542:Gemcitabine