title: Safety and efficacy of denosumab for adults and skeletally mature adolescents with giant cell tumour of bone: interim analysis of an open-label, parallel-group, phase 2 study.
abstract: BACKGROUND
  Giant cell tumour of bone (GCTB) is a very rare, aggressive, and progressive osteolytic tumour for which no standard medicinal treatment or chemotherapy exists. We report interim safety and efficacy results from a phase 2 study of denosumab in patients with GCTB.
  
  
  METHODS
  We did an international, open-label, parallel-group, phase 2 trial of patients with histologically confirmed GCTB and radiographically measurable active disease. Eligible patients were adults or skeletally mature adolescents with radiographic evidence of at least one mature long bone who were at least 12 years old and weighed at least 45 kg. We divided patients into three cohorts--those with surgically unsalvageable GCTB (cohort 1), those with salvageable GCTB whose surgery was associated with severe morbidity (cohort 2), and those who transferred from a previous study of denosumab for GCTB (cohort 3). Patients in cohorts 1 and 2 received 120 mg of subcutaneous denosumab every 4 weeks with loading doses on days 8 and 15 of the first cycle; those in cohort 3 continued the regimen from the previous study. Investigator-determined disease status and clinical benefit were assessed every 4 weeks. Our primary endpoint was the safety profile of denosumab in terms of adverse events and laboratory abnormalities. Prespecified secondary endpoints were time to disease progression in cohort 1 and the proportion of patients without any surgery at 6 months in cohort 2. Safety analyses included all patients who received at least one dose of denosumab. Efficacy analyses included all eligible patients who received at least one dose of denosumab. This study is registered with ClinicalTrials.gov, identifier NCT00680992.
  
  
  RESULTS
  282 patients, including ten adolescents, were included between Sept 9, 2008, and March 25, 2011. Of the 281 patients analysable for safety, three (1%) had osteonecrosis of the jaw and 15 (5%) hypocalcaemia. The most common grade 3-4 adverse events were hypophosphataemia, which occurred in nine (3%) patients, and anaemia, back pain, and pain in extremities, each of which occurred in three patients (1%). Serious adverse events were reported in 25 (9%) patients. No treatment-related deaths were reported. On the basis of investigators' assessment of disease status, 163 of 169 (96%) analysable patients in cohort 1 had no disease progression after median follow-up of 13 months (IQR 5·8-21·0). In cohort 2, 74 of 100 (74%) analysable patients had no surgery and 16 of 26 (62%) patients who had surgery underwent a less morbid procedure than planned. Median follow-up in cohort 2 was 9·2 months (IQR 4·2-12·9).
  
  
  CONCLUSIONS
  Adverse events were consistent with the known safety profile of denosumab. Denosumab was associated with tumour responses and reduced the need for morbid surgery in patients with GCTB. Denosumab represents a new treatment option for patients with GCTB.
  
  
  BACKGROUND
  Amgen.
authors.affiliation: Sarcoma Oncology Center, Santa Monica, CA 90403, USA. santchawla@sarcomaoncology.com
authors.forename: Sant
authors.initials: S
authors.lastname: Chawla
authors.forename: Robert
authors.initials: R
authors.lastname: Henshaw
authors.forename: Leanne
authors.initials: L
authors.lastname: Seeger
authors.forename: Edwin
authors.initials: E
authors.lastname: Choy
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Blay
authors.forename: Stefano
authors.initials: S
authors.lastname: Ferrari
authors.forename: Judith
authors.initials: J
authors.lastname: Kroep
authors.forename: Robert
authors.initials: R
authors.lastname: Grimer
authors.forename: Peter
authors.initials: P
authors.lastname: Reichardt
authors.forename: Piotr
authors.initials: P
authors.lastname: Rutkowski
authors.forename: Scott
authors.initials: S
authors.lastname: Schuetze
authors.forename: Keith
authors.initials: K
authors.lastname: Skubitz
authors.forename: Arthur
authors.initials: A
authors.lastname: Staddon
authors.forename: David
authors.initials: D
authors.lastname: Thomas
authors.forename: Yi
authors.initials: Y
authors.lastname: Qian
authors.forename: Ira
authors.initials: I
authors.lastname: Jacobs
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy*; D015331:Cohort Studies; D000069448:Denosumab; D005260:Female; D005500:Follow-Up Studies; D018212:Giant Cell Tumor of Bone / Q000188:drug therapy*; D006801:Humans; D007390:International Agencies; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000139:chemically induced / Q000175:diagnosis*; D011379:Prognosis; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000069448:Denosumab