Phase I dose-escalation study of continuous oral dosing of OSI-906, a dual tyrosine kinase inhibitor of insulin-like growth factor-1 receptor (IGF-1R) and insulin receptor (IR), in patients with advanced solid tumors.

Abstract

2531 Background: OSI-906 is a potent inhibitor of IGF-1R and IR tyrosine kinase activity. Increased IGF-1R activity is observed in human malignancies and implicated in resistance to chemotherapy. Methods: Patients with advanced cancer received escalating doses of OSI-906. Study objectives included determination of MTD and evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and tumor response. Results: 57 pts have been treated (37M/20F, median age 59 yrs) at 10–450 mg QD and at 20–200 mg BID. Median number of weeks on trial was 6 (range 0–44). Six DLTs were observed: 2 DLTs at 450 mg QD (grade 3 hyperglycemia and inability to complete treatment period 1), 1 DLT at 400 mg QD (grade 3 elevated QTc), 2 DLTs at 200 mg BID (grade 3 hyperglycemia and grade 4 elevated ALT/AST), and 1 DLT at 150 mg BID (grade 3 elevated AST). Hyperglycemia (6/54 pts) related to OSI-906 was grade 1–2 (4 pts) and grade 3 (2 pts). Other related adverse events were grade 1–2: nausea (20%), vomiting (20%), lethargy (19%), and fatigue (15%). Preliminary PK analysis indicates the exposure of OSI-906 was dose proportional. The median of both Tmax and t3/4 was 2–4 hours. Steady-state plasma concentrations were achieved by day 8 after BID dosing. Stable disease > 12 weeks was seen in 18/43 pts (range 12–44 weeks), including 1 pt each with thymic cancer (27w), adrenocortical carcinoma (28w), colorectal cancer (34w), and melanoma (44w+). PD effects on the GH-IGF1 and IGF- 1R/IR axes were observed and correlated with plasma OSI-906 concentrations. Conclusions: MTD has been reached for the two dosing schedules: 400 mg QD and 150 mg BID. OSI 906 is well tolerated with linear PK characteristics and no unexpected toxicities. Steady-state plasma concentrations above 1 μ M (predicted efficacious concentration) were reached at doses ≥ 75 mg BID. PD data indicate sufficient exposure can be achieved in some patients for target modulation. Preliminary antitumor activity has been observed. Separate expansion cohorts in colorectal cancer (biomarker focus) and non-insulin-dependent diabetes mellitus will be enrolled at the recommended phase II dose of 150 mg BID. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration OSI OSI OSI