A phase I, single-institution open-label, dose-escalation trial with an expansion cohort evaluating the safety and tolerability of AZD6244 and IMC-A12 in subjects with advanced solid malignancies.

Abstract

TPS156 Background: IGF-1 receptor (IGF1-R) phosphorylation leads to activation of the PI3K and Raf/MEK/ERK pathways and plays a central role in the regulation of proliferation, survival, differentiation, and apoptosis. Significant crosstalk exists between the two pathways and treatment of select cell lines with a MEK inhibitor and an IGF1-R inhibitor has been shown to cause greater inhibition of growth than either agent alone. IMC-A12 (I) is a recombinant human monoclonal antibody directed IGFI-R; it blocks interaction between IGF-1R and its ligands, IGF-I and -II. I has demonstrated tumor growth inhibition in a wide range of in vitro and in vivo human cancer. AZD6244 (A) is a highly selective, non-competitive MEK 1/2 inhibitor that has had similar success in vitro and in vivo in cancer models of various solid tumors. In vivo studies have demonstrated the most potent inhibition of cell growth in cell lines harboring RAS and BRAF mutations. Phase I/II studies have shown both agents to be tolerable as single agents and suggested modest efficacy in various cancer types. Methods: A phase I, open label, dose escalation trial with I+A is currently accruing pts with advanced malignancies. The study is a standard 3+3 design with an expansion cohort of 15 pts for correlative endpoints and PK studies. Pts will be treated with A at 50 mg po BID, then 75 mg po BID; I at 12mg/kg q2week held constant. The first 2 cohorts have accrued with a single dose-limiting toxicity in cohort 2. The expansion cohort will start accrual in February 2011. Eligibility includes advanced solid tumor, good end organ function and performance status with exclusion for poorly controlled diabetes or growth hormone abnormalities. The primary objective is to determine the safety and tolerability of the combination and to determine the MTD. Secondary objectives include assessing preliminary efficacy as defined by RECIST criteria and exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for changes in signaling in the IGF pathway, including p-ERK, p-Akt and RAS. RAS and RAF mutation sites will be sequenced in order to correlate with PD endpoints and disease response.