A phase I study of continuous oral dosing of OSI-906, a dual inhibitor of insulin-like growth factor-1 and insulin receptors, in patients with advanced solid tumors

OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors. This was a nonrandomiz...

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Bibliographic Details
Published in:	Clinical cancer research 2015-02, Vol.21 (4), p.701-711
Main Authors:	Puzanov, Igor, Lindsay, Colin R, Goff, Laura, Sosman, Jeff, Gilbert, Jill, Berlin, Jordan, Poondru, Srinivasu, Simantov, Ronit, Gedrich, Rich, Stephens, Andrew, Chan, Emily, Evans, T R Jeffry
Format:	Article
Language:	eng
Subjects:	Administration, Oral Adult Aged Antineoplastic Agents - administration & dosage Antineoplastic Agents - adverse effects Antineoplastic Agents - pharmacokinetics Dose-Response Relationship, Drug Female Humans Imidazoles - administration & dosage Imidazoles - adverse effects Imidazoles - pharmacokinetics Male Maximum Tolerated Dose Middle Aged Neoplasms - drug therapy Pyrazines - administration & dosage Pyrazines - adverse effects Pyrazines - pharmacokinetics
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Summary:	OSI-906 is a potent inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR). The purpose of this study was to determine the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906 in patients with advanced solid tumors. This was a nonrandomized, open-label, phase I, dose-escalation study in patients with advanced solid tumors. The study also included a diabetic expansion cohort and a biomarker expansion cohort of patients with colorectal cancer. Patients were treated with OSI-906 by once- or twice-daily continuous dosing schedules. Of 95 patients enrolled in the study, 86 received at least one dose of OSI-906. Dose-limiting toxicities included QTc prolongation, grade 2 abdominal pain and nausea, hyperglycemia, and elevation of aspartate aminotransferase and alanine aminotransferase (all grade 3). The MTDs were established to be 400 mg once daily and 150 mg twice daily. The recommended phase II dose was determined as 150 mg twice daily. OSI-906 was rapidly absorbed with a half-life of 5 hours, and steady-state plasma concentrations were achieved by day 8. Pharmacodynamic effects on IGF1R and IR phosphorylation were levels observed and correlated with plasma concentrations of OSI-906. Thirty-one patients had stable disease as their best response. One patient with melanoma had a radiographic partial response and underwent resection, during which only melanocytic debris but no viable tumor tissue was identified. At the established MTD, OSI-906 was well tolerated and antitumor activity was observed. These results support further evaluation of OSI-906 in solid tumors.
ISSN:	1078-0432 1557-3265