title: Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors.
abstract: Cross-talk between type I IGF receptor (IGF1R), insulin receptor (INSR), and epidermal growth factor receptor (EGFR) mediates resistance to individual receptor blockade. This study aimed to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of linsitinib, a potent oral IGF1R/INSR inhibitor, with EGFR inhibitor erlotinib.
  
  
  
  This open-label, dose-escalation study investigated linsitinib schedules S1: once daily intermittent (days 1-3 weekly); S2, once daily continuous; S3, twice-daily continuous; each with erlotinib 100-150 mg once daily; and a non-small cell lung cancer (NSCLC) expansion cohort.
  
  
  
  Ninety-five patients were enrolled (S1, 44; S2, 24; S3, 12; expansion cohort, 15) and 91 treated. Seven experienced dose-limiting toxicities: QTc prolongation (3), abnormal liver function (2), hyperglycemia (1), and anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150 mg (S1), 400/100 mg (S2). On the basis of prior monotherapy data, S3 dosing at 150 mg twice daily/150 mg once daily was the recommended phase II dose for the expansion cohort. There was no evidence of drug-drug interaction. Pharmacodynamic data showed IGF-1 elevation and reduced IGF1R/INSR phosphorylation, suggesting pathway inhibition. Across schedules, 5/75 (7%) evaluable patients experienced partial responses: spinal chordoma (268+ weeks), rectal cancer (36 weeks), three NSCLCs including 2 adenocarcinomas (16, 72 weeks), 1 squamous wild-type EGFR NSCLC (36 weeks). Disease control (CR+PR+SD) occurred in 38 of 75 (51%), and 28 of 91 (31%) patients were on study >12 weeks.
  
  
  
  The linsitinib/erlotinib combination was tolerable with preliminary evidence of activity, including durable responses in cases unlikely to respond to erlotinib monotherapy. Clin Cancer Res; 22(12); 2897-907. ©2016 AACR.
authors.affiliation: University Department of Oncology, Oxford Cancer and Haematology Centre, Headington, Oxford, United Kingdom. valentine.macaulay@oncology.ox.ac.uk.
authors.forename: Valentine M
authors.initials: VM
authors.lastname: Macaulay
authors.affiliation: University Department of Oncology, Oxford Cancer and Haematology Centre, Headington, Oxford, United Kingdom.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado.
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Juravinski Cancer Centre McMaster University, Hamilton, Ontario, Canada.
authors.forename: Rosalyn A
authors.initials: RA
authors.lastname: Juergens
authors.affiliation: Kolltan Pharmaceuticals, Inc, New Haven, Connecticut.
authors.forename: Richard
authors.initials: R
authors.lastname: Gedrich
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Sven
authors.initials: S
authors.lastname: Gogov
authors.affiliation: Finell Clinical Ltd, London, United Kingdom.
authors.forename: Sean
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: Astellas Pharma Global Development, Northbrook, Illinois.
authors.forename: Srinivasu
authors.initials: S
authors.lastname: Poondru
authors.affiliation: Piramal Imaging GmbH, Berlin, Germany.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Stephens
authors.affiliation: Karmanos Cancer Institute/Wayne State University, Detroit, Michigan.
authors.forename: Shirish M
authors.initials: SM
authors.lastname: Gadgeel
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011719:Pyrazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin / Q000037:antagonists & inhibitors; D017451:Receptors, Somatomedin / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: C551528:3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol; D015703:Antigens, CD; D000970:Antineoplastic Agents; C000597236:IGF1R protein, human; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D017451:Receptors, Somatomedin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C435941:INSR protein, human; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin
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