title: Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model.
abstract: Insulin-like growth factor receptor (IGF-1R) has been studied as an oncologic target in soft tissue sarcoma (STS), but its role in sarcoma biology is unclear. Anti-IGF-1R antibody cixutumumab demonstrated acceptable toxicity but limited activity as a single agent in STS. We carried out a dose-escalation study of cixutumumab with doxorubicin to evaluate safety and dosing of the combination.
  
  
  
  Eligible patients with advanced STS were treated with cixutumumab intravenously on days 1/8/15 at one of three dose levels (A: 1 mg/kg, B: 3 mg/kg, C: 6 mg/kg) with doxorubicin at 75 mg/m(2) as a 48 h infusion on day 1 of a 21 day cycle. After six cycles of the combination, patients could receive cixutumumab alone. The Time-to-Event Continual Reassessment Method was used to estimate the probability of dose-limiting toxicity (DLT) and to assign patients to the dose with an estimated probability of DLT≤20%.
  
  
  
  Between September 2008 and January 2012, 30 patients with advanced STS received a median of six cycles of therapy (range <1-22). Two DLTs were observed, grade 3 mucositis (dose level B) and grade 4 hyperglycemia (dose level C). Grade 2 and 3 reduced left ventricular ejection fraction was seen in three and two patients, respectively. Five partial responses were observed, and estimated progression-free survival was 5.3 months (95% confidence interval 3.0-6.3) in 26 response-assessable patients. Immunohistochemical staining of 11 available tumor samples for IGF-1R and phospho-IGF-1R was not significantly different among responders and non-responders, and serum analysis of select single-nucleotide polymorphisms did not predict for cardiotoxicity.
  
  
  
  The maximum tolerated dose was doxorubicin 75 mg/m(2) on day 1 and cixitumumab 6 mg/kg on days 1/8/15 of a 21 day cycle. Cardiac toxicity was observed and should be monitored in subsequent studies, which should be considered in STS only if a predictive biomarker of benefit to anti-IGF-1R therapy is identified.
  
  
  
  ClinicalTrials.gov:NCT00720174.
authors: Departments of Internal Medicine, University of Michigan, Ann Arbor.
authors: R
authors: R
authors: Chugh
authors: Biostatistics, University of Michigan, Ann Arbor.
authors: K A
authors: KA
authors: Griffith
authors: Departments of Internal Medicine, University of Michigan, Ann Arbor.
authors: E J
authors: EJ
authors: Davis
authors: Pathology, University of Michigan, Ann Arbor.
authors: D G
authors: DG
authors: Thomas
authors: Cancer Clinical Trials Office, University of Chicago, Chicago.
authors: J D
authors: JD
authors: Zavala
authors: Clinical Trials Office, University of Michigan, Ann Arbor.
authors: G
authors: G
authors: Metko
authors: NorthShore University Health System, Evanston.
authors: B
authors: B
authors: Brockstein
authors: Department of Medicine, University of Chicago, Chicago, USA.
authors: S D
authors: SD
authors: Undevia
authors: Department of Medicine, University of Chicago, Chicago, USA.
authors: W M
authors: WM
authors: Stadler
authors: Departments of Internal Medicine, University of Michigan, Ann Arbor.
authors: S M
authors: SM
authors: Schuetze
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D015233:Models, Statistical; D009367:Neoplasm Staging; D011379:Prognosis; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C557414:cixutumumab; D004317:Doxorubicin; D017526:Receptor, IGF Type 1
keywords: IGF-1R; TITE-CRM; cardiotoxicity; cixutumumab; doxorubicin; soft tissue sarcoma