Purpose: Cross-talk between type 1 IGF receptor (IGF-1R), 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 IGF-1R/INSR inhibitor, with EGFR inhibitor erlotinib. Experimental Design: This open-label, dose-escalation study investigated linsitinib schedules S1: once-daily (QD) intermittent (days 1-3 weekly); S2, QD continuous; S3, twice-daily (BID) continuous; each with erlotinib 100-150mg QD; 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), anorexia (1). Common adverse events included drug eruption (84%), diarrhea (73%), fatigue (68%), nausea (58%), vomiting (40%). MTDs for linsitinib/erlotinib were 450/150mg (S1), 400/100mg (S2). Based on prior monotherapy data, S3 dosing at 150mg BID/150mg QD 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 IGF-1R/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 38/75 (51%), and 28/91 (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.
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