Phase I dose-escalation study of daily BMS-754807, an oral, dual IGF-1R/insulin receptor (IR) inhibitor in subjects with solid tumors.

Abstract

3104 Background: BMS-754807 is a potent reversible inhibitor of IGF-1R and IR family kinases (IGF-1R, IR; Ki <2nM). Methods: CA191002 is an ascending dose study of once daily BMS-754807 in subjects with solid tumors. Study objectives include determination of maximum tolerated dose, assessment of safety, effects on metabolic parameters, pharmacokinetics, and pharmacodynamics. Antitumor activity is assessed by radiological responses and FDG- and FLT-PET imaging. Results: To date 19 subjects (12 M, 7 F, median age 59 yr) have been treated at daily doses of 4, 10, 20, 30, 50 or 70 mg. Dosing duration was 17 - 233 d. Fatigue (G1, n=3) and hyperglycemia (≤ G3, n=3) were the most frequent related adverse events (AEs). One related AE (reversible asymptomatic postprandial hyperglycemia) was G3; all other related AEs were ≤ G2. Metabolic AEs were managed by diet and/or comedication. No dose limiting toxicities have been observed and further dose escalation continues. BMS- 754807 exposure increased in relation to dose; mean accumulation index was 1.2 - 1.5. Minimum effective exposures (MEE) for Rh41 xenograft (IGF-1R dependent) tumor growth inhibition were achieved in all subjects. 15/16 subjects dosed with ≥ 10 mg achieved MEE for GEO xenografts (less IGF-1R dependent). Dose related increases of plasma glucose, insulin and C-peptide were observed at 2h post-dose and demonstrate pharmacological activity. Partial metabolic response and stable metabolic disease on FDG-PET by D56 was achieved by 1/12 and 11/12 evaluable subjects respectively. Reduction of FLT uptake by > 25% by D10 was observed in 4/16 evaluable subjects. To date stable disease (SD) > 100 d by radiological assessment was achieved in 7 subjects, including subjects with SCLC (168 d) and osteosarcoma (≥ 2 prior chemotherapy regimens, 225 d). Conclusions: Daily dosing of BMS-754807 resulting in exposures exceeding preclinical MEE is feasible and safe. Effects on blood glucose were manageable and did not lead to discontinuation of dosing. PD effects of IR inhibition were observed and differentiate BMS-754807 from IGF-1R specific agents. PET results and prolonged SD suggest anti-tumor activity. MTD has not been reached and accrual is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb