The type 1 insulin-like growth factor receptor (IGF-1R) is an important growth factor receptor in cancer cells and is an attractive target for cancer therapy. IGF-1R is a receptor tyrosine kinase closely related to the insulin receptor (IR). BMS-754807 is a potent and reversible tyrosine kinase inhibitor of IGF-1R and IR intended for oral administration. This study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BMS-754807 in Japanese patients with advanced solid tumors.Methods
BMS-754807 was administered orally on a once-daily schedule. The dose levels were 20, 30, 50 and 100 mg/day. Dose limiting toxicity (DLT) was evaluated from the first dose to day 29 in the first cycle.Results
Fifteen patients (female/male: 11/4; median age: 59 years; ECOG PS 0/1: 3/12; tumor type: 8 sarcoma, 2 colon, 1 gastric, 1 lung and 3 others) were enrolled and treated three patients each at 20, 30 and 50 mg/day and 6 at 100 mg/day. DLT was observed in one patient at 100 mg/day. This patient required 14 days interruption of dosing due to thrombocytopenia (<100 000/μl). The most common drug-related adverse events were hyperglycemia (n = 8), nausea (n = 6), hypoglycemia, anorexia and diarrhea (n = 4, each). Hyperglycemia was reversible and manageable with drug interruption and/or oral administration of metformine. Hypoglycemia was also well managed by oral glucose and close monitoring. No objective response was observed, and four patients had stable disease (unconfirmed). BMS-754807 was rapidly absorbed with maximum drug concentration (Cmax) observed within from 1 to 4 h after dosing and the steady-state exposure was achieved in day 8 with no unexpected accumulation. The mean Cmax and AUC of BMS-754807 appeared to be dose dependent, but not proportional.Conclusions
BMS-754807 was well tolerable up to 100 mg/day in Japanese patients with solid tumors, and was warranted for further clinical evaluation.