title: Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial.
abstract: BACKGROUND
  Results of previous study showed promising but short-lived activity of sorafenib in the treatment of patients with unresectable advanced and metastatic osteosarcoma. This treatment failure has been attributed to the mTOR pathway and might therefore be overcome with the addition of mTOR inhibitors. We aimed to investigate the activity of sorafenib in combination with everolimus in patients with inoperable high-grade osteosarcoma progressing after standard treatment.
  
  
  METHODS
  We did this non-randomised phase 2 trial in three Italian Sarcoma Group centres. We enrolled adults (≥18 years) with relapsed or unresectable osteosarcoma progressing after standard treatment (methotrexate, cisplatin, and doxorubicin, with or without ifosfamide). Patients received 800 mg sorafenib plus 5 mg everolimus once a day until disease progression or unacceptable toxic effects. The primary endpoint was 6 month progression-free survival (PFS). All analyses were intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01804374.
  
  
  RESULTS
  We enrolled 38 patients between June 16, 2011, and June 4, 2013. 17 (45%; 95% CI 28-61) of 38 patients were progression free at 6 months. Toxic effects led to dose reductions, or short interruptions, or both in 25 (66%) of 38 patients and permanent discontinuation for two (5%) patients. The most common grade 3-4 adverse events were lymphopenia and hypophosphataemia each in six (16%) patients, hand and foot syndrome in five (13%), thrombocytopenia in four (11%), and fatigue, oral mucositis, diarrhoea, and anaemia each in two (5%). One patient (3%) had a grade 3 pneumothorax that required trans-thoracic drainage, and that recurred at the time of disease progression. This was reported as a serious adverse event related to the study drugs in both instances. No other serious adverse events were reported during the trial. There were no treatment-related deaths.
  
  
  CONCLUSIONS
  Although the combination of sorafenib and everolimus showed activity as a further-line treatment for patients with advanced or unresectable osteosarcoma, it did not attain the prespecified target of 6 month PFS of 50% or greater.
  
  
  BACKGROUND
  Italian Sarcoma Group.
authors.affiliation: Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy. Electronic address: giovanni.grignani@ircc.it.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Grignani
authors.affiliation: Chemotherapy, Musculoskeletal Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Palmerini
authors.affiliation: Medical Oncology A, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: Ferraresi
authors.affiliation: Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy; Department of Oncology, University of Torino, Turin, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: D'Ambrosio
authors.affiliation: Adult Mesenchymal Tumor Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Bertulli
authors.affiliation: Pediatric Onco-Hematology, Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Sebastian Dorin
authors.initials: SD
authors.lastname: Asaftei
authors.affiliation: Paediatric Onco-Hematology, Azienda Ospedaliero Universitaria Meyer Children Hospital, Firenze, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Tamburini
authors.affiliation: Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy; Department of Oncology, University of Torino, Turin, Italy.
authors.forename: Ymera
authors.initials: Y
authors.lastname: Pignochino
authors.affiliation: Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy; Department of Oncology, University of Torino, Turin, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Sangiolo
authors.affiliation: Chemotherapy, Musculoskeletal Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Marchesi
authors.affiliation: Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy; Department of Oncology, University of Torino, Turin, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Capozzi
authors.affiliation: Oncological Orthopaedics Department, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Biagini
authors.affiliation: Department of Pathology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gambarotti
authors.affiliation: Pediatric Onco-Hematology, Città della Salute e della Scienza di Torino, Turin, Italy.
authors.forename: Franca
authors.initials: F
authors.lastname: Fagioli
authors.affiliation: Adult Mesenchymal Tumor Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Paolo Giovanni
authors.initials: PG
authors.lastname: Casali
authors.affiliation: Laboratory of Experimental Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.affiliation: Chemotherapy, Musculoskeletal Oncology, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.affiliation: Medical Oncology, Candiolo Cancer Institute-FPO, IRCCS, Candiolo, Italy; Department of Oncology, University of Torino, Turin, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
mesh_terms: D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018450:Disease Progression; D018572:Disease-Free Survival; D000068338:Everolimus; D005260:Female; D006801:Humans; D057194:Intention to Treat Analysis; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D012516:Osteosarcoma / Q000188:drug therapy* / Q000201:enzymology / Q000556:secondary; D010671:Phenylurea Compounds / Q000008:administration & dosage; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077157:Sorafenib; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D010671:Phenylurea Compounds; D009536:Niacinamide; D000068338:Everolimus; D000077157:Sorafenib; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus