title: Combination of the mTOR inhibitor ridaforolimus and the anti-IGF1R monoclonal antibody dalotuzumab: preclinical characterization and phase I clinical trial.
abstract: OBJECTIVE
  Mammalian target of rapamycin (mTOR) inhibition activates compensatory insulin-like growth factor receptor (IGFR) signaling. We evaluated the ridaforolimus (mTOR inhibitor) and dalotuzumab (anti-IGF1R antibody) combination.
  
  
  METHODS
  In vitro and in vivo models, and a phase I study in which patients with advanced cancer received ridaforolimus (10-40 mg/day every day × 5/week) and dalotuzumab (10 mg/kg/week or 7.5 mg/kg/every other week) were explored.
  
  
  RESULTS
  Preclinical studies demonstrated enhanced pathway inhibition with ridaforolimus and dalotuzumab. With 87 patients treated in the phase I study, main dose-limiting toxicities (DLT) of the combination were primarily mTOR-related stomatitis and asthenia at doses of ridaforolimus lower than expected, suggesting blockade of compensatory pathways in normal tissues. Six confirmed partial responses were reported (3 patients with breast cancer); 10 of 23 patients with breast cancer and 6 of 11 patients with ER(+)/high-proliferative breast cancer showed antitumor activity.
  
  
  CONCLUSIONS
  Our study provides proof-of-concept that inhibiting the IGF1R compensatory response to mTOR inhibition is feasible with promising clinical activity in heavily pretreated advanced cancer, particularly in ER(+)/high-proliferative breast cancer (ClinicalTrials.gov identifier: NCT00730379).
authors.affiliation: Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Cosimo
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Sriram
authors.initials: S
authors.lastname: Sathyanarayanan
authors.affiliation: Sarah Cannon Research Institute, Nashville, Tennessee.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.affiliation: Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Andrés
authors.initials: A
authors.lastname: Cervantes
authors.affiliation: The Cancer Institute of New Jersey, New Brunswick, New Jersey.
authors.forename: Mark N
authors.initials: MN
authors.lastname: Stein
authors.affiliation: Vall d'Hebron University Hospital, Barcelona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Braña
authors.affiliation: Institute of Health Research INCLIVA, University of Valencia, Valencia, Spain.
authors.forename: Desamparados
authors.initials: D
authors.lastname: Roda
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Brian B
authors.initials: BB
authors.lastname: Haines
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Theresa
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Winter
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Sharda
authors.initials: S
authors.lastname: Jha
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Youyuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Jason
authors.initials: J
authors.lastname: Frazier
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Klinghoffer
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Ann
authors.initials: A
authors.lastname: Leighton-Swayze
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Merck & Co., Inc., Whitehouse Station, New Jersey.
authors.forename: Scot
authors.initials: S
authors.lastname: Ebbinghaus
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, Massachusetts. baselgaj@mskcc.org.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; C515074:ridaforolimus; C569480:dalotuzumab; C546842:MTOR protein, human; D017526:Receptor, IGF Type 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus