title: Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial.
abstract: BACKGROUND
  Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry.
  
  
  METHODS
  We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015.
  
  
  RESULTS
  Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21-43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24-47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28-51) were progression free at 12 weeks. On April 6, 2011, the protocol was amended to include three additional patients in the IGF-1R-positive soft-tissue sarcoma group (total of 57 patients) and nine more in the IGF-1R-negative group (total of 63 patients). There were 2546 adverse events reported during the study, 214 (8%) of which were grade 3-4. The most common grade 3-4 toxicities in the 174 treated patients were anaemia in 16 (9%) patients, hyperglycaemia in 18 (10%), hypophosphataemia in 16 (9%), lymphopenia in 25 (14%), oral mucositis in 19 (11%), and thrombocytopenia in 19 (11%).
  
  
  CONCLUSIONS
  The combination of cixutumumab and temsirolimus shows clinical activity in patients with sarcoma and forms a basis for future trials. However, IGF-1R expression by immunohistochemistry is not predictive of clinical outcome after treatment with this combination.
  
  
  BACKGROUND
  National Cancer Institute and CycleforSurvival Fund, Memorial Sloan-Kettering Cancer Center.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. schwartg@mskcc.org
authors.forename: Gary K
authors.initials: GK
authors.lastname: Schwartz
authors.forename: William D
authors.initials: WD
authors.lastname: Tap
authors.forename: Li-Xuan
authors.initials: LX
authors.lastname: Qin
authors.forename: Michael B
authors.initials: MB
authors.lastname: Livingston
authors.forename: Samir D
authors.initials: SD
authors.lastname: Undevia
authors.forename: Bartosz
authors.initials: B
authors.lastname: Chmielowski
authors.forename: Mark
authors.initials: M
authors.lastname: Agulnik
authors.forename: Scott M
authors.initials: SM
authors.lastname: Schuetze
authors.forename: Damon R
authors.initials: DR
authors.lastname: Reed
authors.forename: Scott H
authors.initials: SH
authors.lastname: Okuno
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Ludwig
authors.forename: Vicki
authors.initials: V
authors.lastname: Keedy
authors.forename: Petra
authors.initials: P
authors.lastname: Rietschel
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Kraft
authors.forename: Douglas
authors.initials: D
authors.lastname: Adkins
authors.forename: Brian A
authors.initials: BA
authors.lastname: Van Tine
authors.forename: Bruce
authors.initials: B
authors.lastname: Brockstein
authors.forename: Vincent
authors.initials: V
authors.lastname: Yim
authors.forename: Christiana
authors.initials: C
authors.lastname: Bitas
authors.forename: Abdul
authors.initials: A
authors.lastname: Abdullah
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.forename: Mercedes
authors.initials: M
authors.lastname: Condy
authors.forename: Mark A
authors.initials: MA
authors.lastname: Dickson
authors.forename: Shyamprasad Deraje
authors.initials: SD
authors.lastname: Vasudeva
authors.forename: Alan L
authors.initials: AL
authors.lastname: Ho
authors.forename: L Austin
authors.initials: LA
authors.lastname: Doyle
authors.forename: Helen X
authors.initials: HX
authors.lastname: Chen
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000139:chemically induced / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; C557414:cixutumumab; C401859:temsirolimus; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus