title: Combination mTOR and IGF-1R inhibition: phase I trial of everolimus and figitumumab in patients with advanced sarcomas and other solid tumors.
abstract: OBJECTIVE
  Preclinical models demonstrate synergistic antitumor activity with combination blockade of mTOR and IGF-1R signaling. We aimed to determine the safety, tolerability, and recommended phase II dose (RP2D) of the combination of figitumumab, a fully human IgG(2) anti-insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (Pfizer) and the mTOR inhibitor, everolimus (Novartis). Pharmacokinetics and preliminary antitumor effects of the combination were evaluated.
  
  
  METHODS
  Phase I trial in patients with advanced sarcomas and other solid tumors. Initial cohort combined full phase 2 dose figitumumab (20 mg/kg IV every 21 days) with full dose everolimus (10 mg orally once daily). Intercohort dose de-escalation was planned for unacceptable toxicities. Dose modifications were allowed beyond cycle 1.
  
  
  RESULTS
  No DLTs were observed in the initial cohort during cycle one, therefore full dose figitumumab and everolimus was declared the RP2D. In total, 21 patients were enrolled on study. Most toxicities were grade 1 or 2, and were similar to reported toxicities of the single agents. Mucositis was the most frequently observed grade 3 toxicity. Median time on study was 104 days (range 17-300). Of 18 patients evaluable for response, best response was partial response in 1 patient with malignant solitary fibrous tumor and, stable disease in 15 patients. There were no apparent pharmacokinetic interactions between everolimus and figitumumab.
  
  
  CONCLUSIONS
  Combination figitumumab plus everolimus at full doses appears safe and well tolerated with no unexpected toxicities. Dose reductions in everolimus may be required after prolonged drug administration. This regimen exhibits interesting antitumor activity warranting further investigation.
authors.affiliation: Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,
authors.forename: Richard
authors.initials: R
authors.lastname: Quek
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Morgan
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: Shapiro
authors.forename: James E
authors.initials: JE
authors.lastname: Butrynski
authors.forename: Nikhil
authors.initials: N
authors.lastname: Ramaiya
authors.forename: Tarsha
authors.initials: T
authors.lastname: Huftalen
authors.forename: Nicole
authors.initials: N
authors.lastname: Jederlinic
authors.forename: Judith
authors.initials: J
authors.lastname: Manola
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wagner
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.forename: Suzanne
authors.initials: S
authors.lastname: George
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000068338:Everolimus; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D012509:Sarcoma / Q000188:drug therapy* / Q000473:pathology; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D016756:Immunoglobulins, Intravenous; D000068338:Everolimus; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; C525021:figitumumab; D020123:Sirolimus