Phase I Dose-Escalation Study of Linsitinib (OSI-906) and Erlotinib in Patients with Advanced Solid Tumors. Academic Article uri icon

Overview

abstract

  • PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

publication date

  • February 1, 2016

Research

keywords

  • Antineoplastic Agents
  • Antineoplastic Combined Chemotherapy Protocols
  • Carcinoma, Non-Small-Cell Lung
  • Erlotinib Hydrochloride
  • Imidazoles
  • Lung Neoplasms
  • Protein Kinase Inhibitors
  • Pyrazines

Identity

PubMed Central ID

  • PMC5500904

Scopus Document Identifier

  • 84975090036

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-15-2218

PubMed ID

  • 26831715

Additional Document Info

volume

  • 22

issue

  • 12