Abstract A101: BMS-754807, an oral dual IGF-1R/IR inhibitor: First-in-human single-dose study of safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy subjects

Abstract

Abstract Background: Type 1 insulin-like growth factor receptor (IGF-1R) signaling drives survival and proliferation in a broad range of human tumors. Insulin receptor (IR) signaling can drive tumor growth and may act as an escape mechanism for IGF-1R inhibition. BMS-754807 is a potent and selective reversible inhibitor of IGF-1R/IR family kinases (IGF-1R, IR; Ki <2nM). Inhibition of both IGF-1R and IR may be required to disrupt the malignant phenotype regulated by this receptor family; however, IR inhibition may lead to additional metabolic side effects. Methods: CA191001 was a placebo-controlled, ascending single-dose study of the safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS-754807 in healthy subjects. Eight subjects per dose panel were randomized in a 3:1 ratio to receive a single oral dose of BMS-754807 (2, 10, 20, 30, or 60 mg) or placebo after a 10 h fast. A 75 g glucose challenge was administered 2 h post-dose at the 10 and 30 mg doses; a second 30 mg panel was dosed without a glucose challenge. The 60 mg panel received a second dose of BMS-754807 or placebo with a high-fat meal after at least a 7 day washout. Results: Forty-eight male subjects received BMS-754807 (n = 36) or placebo (n = 12). Adverse events (AEs) occurred in 26 subjects, all were mild or moderate. The most frequent AE was hypoglycemia, which occurred in 10 drug-treated subjects and 1 placebo-treated subject. Most hypoglycemia AEs occurred in subjects who received a glucose challenge and occurred in these subjects with a higher frequency after the 30 mg dose than after the 10 mg dose. There was no other apparent relationship of AEs, vital signs, or clinical lab abnormalities with dose. BMS-754807 exposure was proportional to dose; mean half-life was 9 – 13 h and median Tmax was 1 – 2 h. AUC was similar when administered in the fasted and fed states, however, Cmax was lower and delayed in the fed state. All subjects receiving at least a 10 mg dose exceeded the minimal efficacious exposure predicted from mouse IGF-1R dependent xenograft tumors (RH41, IGF-Sal). Dose-related increases of insulin, C-peptide and glucose occurred in the fasted state. In dose panels without glucose challenge plasma glucose levels returned to baseline within 4 h post-dose. In subjects receiving a glucose challenge 2 h post-dose a second increase of glucose and a marked increase of insulin and C-peptide was observed, possibly explaining the observed hypoglycemia AEs in these subjects. There was no prolonged elevation of glucose after the glucose challenge. Conclusion: Current data suggest doses of BMS-754807 in humans that produce exposure predicted to be efficacious are safe and tolerable. Pharmacodynamic effects on insulin and glucose support pharmacologic activity. Dual inhibition of IGF-1R and IR is feasible and may provide differential activity from IGF-1R-specific monoclonal antibodies. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A101.