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.

• Authors: Robin L Jones, Edward S Kim, Pilar Nava-Parada, Salma Alam, Faye M Johnson, Andrew W Stephens, Ronit Simantov, Srinivasu Poondru, Rich Gedrich, Scott M Lippman, Stan B Kaye, Craig P Carden
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 4 Pg. 693-700 (Feb 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25208878 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• 3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
• Antineoplastic Agents
• Imidazoles
• Pyrazines

Topics

• Administration, Oral
• Adolescent
• Adult
• Aged
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Female
• Humans
• Imidazoles (administration & dosage, adverse effects, pharmacokinetics)
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasms (drug therapy)
• Pyrazines (administration & dosage, adverse effects, pharmacokinetics)
• Young Adult