title: Phase II trial of sorafenib in metastatic thyroid cancer.
abstract: OBJECTIVE
  Based on the pivotal role of Ras-Raf-MAP-ERK signaling and vascular endothelial growth factor (VEGF) in papillary thyroid cancer (PTC), we conducted a phase II clinical trial of sorafenib targeting RAF and VEGF receptor kinases in PTC.
  
  
  METHODS
  The primary end point was the objective response rate. Secondary end points included response correlation with serum thyroglobulin (Tg); functional imaging; tumor genotype; and signaling inhibition in tumor biopsies. Using a Simon minimax two-stage design, 16 or 25 chemotherapy-naïve metastatic PTC patients were to be enrolled in arm A (accessible tumor for biopsy). Arm B patients had other subtypes of thyroid carcinoma or prior chemotherapy, and did not require tumor biopsies. Patients received 400 mg orally twice per day of sorafenib. Response was assessed every 2 months using RECIST (Response Evaluation Criteria in Solid Tumors).
  
  
  RESULTS
  Of 41 PTC patients, six patients had a partial response (PR; 15%; 95% CI, 6 to 29) and 23 patients (56%; 95% CI, 40 to 72) had stable disease longer than 6 months. Median duration of PR was 7.5 months (range, 6 to 14). Median progression-free survival was 15 months (95% CI, 10 to 27.5). In 14 (78%) of 18 Tg-assessable PTC patients, Tg declined more than 25%. Common grade 3 adverse events included hand-foot skin reaction, musculoskeletal pain, and fatigue. BRAF mutation was detected in 17 (77%) of 22 PTCs analyzed. Four of 10 paired tumor biopsies from PTC patients showed a reduction in levels of vascular endothelial growth factor receptor phosphorylation, ERK phosphorylation, and in VEGF expression during sorafenib therapy. No PRs were noted among non-PTC patients.
  
  
  CONCLUSIONS
  Sorafenib is reasonably well-tolerated therapy with clinical and biologic antitumor activity in metastatic PTC.
authors.affiliation: Ohio State University, Department of Internal Medicine, Molecular Virology, Immunology, and Genetics, Pathology, Radiology, Center for Biostatistics, Ohio State University, Columbus, OH 43210, USA.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Kloos
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Ringel
authors.forename: Michael V
authors.initials: MV
authors.lastname: Knopp
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Hall
authors.forename: Mark
authors.initials: M
authors.lastname: King
authors.forename: Robert
authors.initials: R
authors.lastname: Stevens
authors.forename: Jiachao
authors.initials: J
authors.lastname: Liang
authors.forename: Paul E
authors.initials: PE
authors.lastname: Wakely
authors.forename: Vasyl V
authors.initials: VV
authors.lastname: Vasko
authors.forename: Motoyasu
authors.initials: M
authors.lastname: Saji
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rittenberry
authors.forename: Lai
authors.initials: L
authors.lastname: Wei
authors.forename: Daria
authors.initials: D
authors.lastname: Arbogast
authors.forename: Minden
authors.initials: M
authors.lastname: Collamore
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Michael
authors.initials: M
authors.lastname: Grever
authors.forename: Manisha H
authors.initials: MH
authors.lastname: Shah
mesh_terms: D000231:Adenocarcinoma, Papillary / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001557:Benzenesulfonates / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use*; D000077157:Sorafenib; D013954:Thyroglobulin / Q000097:blood / Q000187:drug effects; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D013954:Thyroglobulin; D000077157:Sorafenib