title: Dual blockade of epidermal growth factor receptor and insulin-like growth factor receptor-1 signaling in metastatic pancreatic cancer: phase Ib and randomized phase II trial of gemcitabine, erlotinib, and cixutumumab versus gemcitabine plus erlotinib (SWOG S0727).
abstract: BACKGROUND
  Targeting a single pathway in pancreatic adenocarcinoma (PC) is unlikely to affect its natural history. We tested the hypothesis that simulataneous targeting of the epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor-1 (IGF-1R) pathways would significantly improve progression-free survival (PFS) by abrogating reciprocal signaling that promote drug resistance
  
  
  METHODS
  This was a phase Ib/II study testing cixutumumab, combined with erlotinib and gemcitabine (G) in patients with untreated metastatic PC. The control arm was erlotinib plus G. The primary end point was PFS. Eligibility included performance status 0/1 and normal fasting blood glucose. Polymorphisms in genes involved in G metabolism and in the EGFR pathway were also studied
  
  
  RESULTS
  The phase I results (n = 10) established the safety of cixutumumab 6 mg/kg/week intravenously, erlotinib 100 mg/day orally, and G 1000 mg/m(2) intravenously on days 1, 8, and 15 of a 28-day cycle. In the RP2 portion (116 eligible patients; median age, 63), the median PFS and overall survival (OS) were 3.6 and 7.0 months, respectively, on the cixutumumab arm, and 3.6 and 6.7 months, respecively, on the control arm. Major grades 3 and 4 toxicities with cixutumumab and control were elevation of transaminases, 12% and 6%, respectively; fatigue, 16% and 12%, respectively; gastrointestinal, 35% and 28%, respectively; neutropenia, 21% and 10%, respectively; and thrombocytopenia, 16% and 7%, respecively. Grade 3/4 hyperglycemia was seen in 16% of patients on cixutumumab. Grade 3 or 4 skin toxicity was similar in both arms of the study (< 5%). No significant differences in PFS by genotype were seen for any of the polymorphisms.
  
  
  CONCLUSIONS
  Adding the IGF-1R inhibitor cixutumumab to erlotinib and G did not lead to longer PFS or OS in metastatic PC.
authors.affiliation: Wayne State University, Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Philip
authors.forename: Bryan
authors.initials: B
authors.lastname: Goldman
authors.forename: Ramesh K
authors.initials: RK
authors.lastname: Ramanathan
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.forename: Robert P
authors.initials: RP
authors.lastname: Whitehead
authors.forename: Takeru
authors.initials: T
authors.lastname: Wakatsuki
authors.forename: Syma
authors.initials: S
authors.lastname: Iqbal
authors.forename: Rakesh
authors.initials: R
authors.lastname: Gaur
authors.forename: Jacqueline K
authors.initials: JK
authors.lastname: Benedetti
authors.forename: Charles D
authors.initials: CD
authors.lastname: Blanke
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary*; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000187:drug effects / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects*; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D011799:Quinazolines; D003841:Deoxycytidine; C557414:cixutumumab; D007334:Insulin-Like Growth Factor I; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000093542:Gemcitabine
keywords: EGFR; IGF-1R; cixutumumab; erlotinib signaling; pancreatic cancer; randomized phase II; targeted treatment