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Phase I Study of Intermittent Oral Dosing of the Insulin-like Growth Factor-1 and Insulin Receptors Inhibitor OSI-906 in Patients With Advanced Solid Tumors

Phase I Study of Intermittent Oral Dosing of the Insulin-like Growth Factor-1 and Insulin... Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 (schedule (S) 1, days 1–3 every 14 days; S2, days 1–5 every 14 days; S3, days 1–7 every 14 days). A fed-fasting expansion cohort was included in the study. Results: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3–4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1–2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. Conclusion: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 693–700. ©2014 AACR . See related commentary by Yee, p. 667 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Cancer Research American Association of Cancer Research

Phase I Study of Intermittent Oral Dosing of the Insulin-like Growth Factor-1 and Insulin Receptors Inhibitor OSI-906 in Patients With Advanced Solid Tumors

Phase I Study of Intermittent Oral Dosing of the Insulin-like Growth Factor-1 and Insulin Receptors Inhibitor OSI-906 in Patients With Advanced Solid Tumors

Clinical Cancer Research , Volume 21 (4): 693 – Feb 15, 2015

Abstract

Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 (schedule (S) 1, days 1–3 every 14 days; S2, days 1–5 every 14 days; S3, days 1–7 every 14 days). A fed-fasting expansion cohort was included in the study. Results: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3–4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1–2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. Conclusion: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 693–700. ©2014 AACR . See related commentary by Yee, p. 667

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References (25)

Publisher
American Association of Cancer Research
Copyright
Copyright © 2015 American Association for Cancer Research
ISSN
1078-0432
eISSN
1557-3265
DOI
10.1158/1078-0432.CCR-14-0265
pmid
25208878
Publisher site
See Article on Publisher Site

Abstract

Purpose: We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors. Experimental Design: This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 (schedule (S) 1, days 1–3 every 14 days; S2, days 1–5 every 14 days; S3, days 1–7 every 14 days). A fed-fasting expansion cohort was included in the study. Results: Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3–4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1–2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses. Conclusion: The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors. Clin Cancer Res; 21(4); 693–700. ©2014 AACR . See related commentary by Yee, p. 667

Journal

Clinical Cancer ResearchAmerican Association of Cancer Research

Published: Feb 15, 2015

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