Abstract
Background: Inhibiting both IGF‐1R and IR signaling may be required to disrupt the malignant phenotype regulated by the receptor family. BMS‐754807 is a potent and selective reversible inhibitor of IGF‐1R/IR family kinases (IGF‐1R, IR; Ki <2nM). In non‐clinical studies BMS‐754807 is an effective inhibitor in a broad range of human tumor types in vitro and in vivo and demonstrates synergies when combined with cytotoxic and targeted agents.
Methods: CA191002 is an ascending multiple‐dose study to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics of BMS‐754807 in subjects with solid tumors. Dosing occurs daily 2 hours after a light breakfast and is followed by a 4 hour fast. PD effects on IR are studied by assessments of plasma glucose, insulin and C‐peptide. 2‐deoxy‐2‐[18F] fluoro‐D‐glucose (FDG)‐ and 3′‐deoxy‐3′‐[18F] fluorothymidine (FLT)‐PET imaging is performed both as imaging markers for PD and to assess anti‐tumor activity.
Results: Sixteen subjects have been treated at daily doses of 4, 10, 20, 30 or 50 mg. No dose limiting toxicities have been observed and dose escalation is ongoing. Duration of dosing was between 8 and 197 days. Preliminary analysis shows dose related increases of plasma glucose, insulin and C‐peptide at 2 hours post‐dose (Table 1). The range [median] of plasma glucose at all time points was 68 –187 [95], 50 – 168 [103] and 54 –333 [124] mg/dL in subjects treated at the 4, 10 and 20, and 30 and 50 mg dose levels, respectively. 65 PET scans have been collected from 14 subjects. Preliminary analysis shows that 1 subject with osteosarcoma and 1 subject with adenoid cystic carcinoma achieved 57 and 28 % reduction of tracer uptake, respectively, on FLT‐PET by D12. Both had stable metabolic disease on FDG‐PET by D12 and D56.
Conclusion: PD effects of IR inhibition differentiate BMS‐754807 from IGF‐1R specific agents. PET results suggest anti‐tumor activity. Future analysis of PD effects, PET imaging data, safety information and response assessments will provide the basis for a rational selection of subjects and a dose or dose range to be further explored.
| Dose level (number of subjects) . | Plasma glucose [mg/dL] D1 and 8 2 h post‐dose range [median] . | Insulin [µU/mL] D1 and 8 2 h post‐dose range [median] . | C‐peptide [ng/mL] D1 and 8 2 h post‐dose range [median] . |
|---|---|---|---|
| 4 mg (3) | 77 – 101 [94] | 2 – 82 [12.5] | 0.8 – 7 [1.8] |
| 10 and 20 mg (7) | 90 – 144 [97] | 27 – 251 [58] | 3 – 18 [4.6] |
| 30 and 50 mg (6) | 110 – 200 [137] | 120 – 361 [210] | 5 – 17 [12.1] |
| Dose level (number of subjects) . | Plasma glucose [mg/dL] D1 and 8 2 h post‐dose range [median] . | Insulin [µU/mL] D1 and 8 2 h post‐dose range [median] . | C‐peptide [ng/mL] D1 and 8 2 h post‐dose range [median] . |
|---|---|---|---|
| 4 mg (3) | 77 – 101 [94] | 2 – 82 [12.5] | 0.8 – 7 [1.8] |
| 10 and 20 mg (7) | 90 – 144 [97] | 27 – 251 [58] | 3 – 18 [4.6] |
| 30 and 50 mg (6) | 110 – 200 [137] | 120 – 361 [210] | 5 – 17 [12.1] |
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A109.
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