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

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.

Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study

“…[15][16][17] Linsitinib (OSI-906) is a potent, oral, small molecule inhibitor of both IGF-1R and IR which has shown preliminary evidence of antitumor activity in a variety of solid tumors, with an acceptable tolerability profile. [18][19][20] Notably, in a dose-finding, phase 1 study, linsitinib resulted in partial responses in two of 15 patients with ACC (79 total study patients). 19 We report here the results of an international phase 3 study evaluating linsitinib in patients with advanced ACC who received at least one but not more than two prior drug regimens.…”

“…[18][19][20] Notably, in a dose-finding, phase 1 study, linsitinib resulted in partial responses in two of 15 patients with ACC (79 total study patients). 19 We report here the results of an international phase 3 study evaluating linsitinib in patients with advanced ACC who received at least one but not more than two prior drug regimens.…”

Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R

“…Initial trials with monoclonal antibodies as monotherapy were nevertheless disappointing, and further development of these therapies is in question (17,36). To further illustrate this, recent phase I trials of OSI-906 as a single agent demonstrated evidence of clinical benefit (37), and it was speculated that modest coinhibition of the insulin receptor (IR) prevents the relief of a negative feedback loop stimulating tumor growth by elevated insulin levels in vivo (38). In contrast, in a phase III study in patients with adrenocortical carcinoma, a cancer type with frequent IGF2 overexpression, no improvement of overall survival was observed with OSI-906 (39).…”

Circulating concentrations of insulin like growth factor-1 in female dogs with spontane-ous mammary tumours

“…The positive correlation has been found between a high serum level of IGF-1 and advanced stage of breast cancer (2). Numerous in vitro and in vivo studies have shown that inhibition of IGF-1 signalling decreases tumour growth and metastasis (8).…”

“…This opens the way for a search for new therapeutic methods, including anti-IGF-1R therapies in female dogs with malignant mammary tumours. Currently, in human medicine studies are being conducted on using anti--IGF-1R inhibitors for therapies of breast cancer (8).…”