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

3020 Background: Significant crosstalk exists between the PI3K and Raf/MEK/ERK 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. AZD6244 (A) is a highly selective, non-competitive MEK ½ inhibitor. Methods: The study is a phase I, dose-escalation with a standard 3+3 design. Eligible patients had advanced solid tumor, good end organ function and performance status with exclusion for poorly controlled diabetes or growth hormone abnormalities. Part 1: open label, dose escalation. Pts were treated with A at 50 mg BID, then 75 mg BID; I at 12mg/kg q2wk held constant. DLTs were defined as grade (G) 3 or 4 toxicities during cycle 1. Part 2: expansion cohort of 15 pts for correlative endpoints and PK studies; serial tumor biopsies will be evaluated for changes in signaling in the IGF pathway, including p-ERK, p-Akt and RAS. Mutational analysis of RAS and RAF will be done to correlate with PD endpoints and disease response. Results: Part 1: 16 patients accrued with 6 treated at DL1 and 10 treated at DL2. Multiple tumor types were represented, including 4 colon, 2 thyroid, 2 pancreatic, and 1 breast. At 75 mg of A, there was 1 DLT of visual changes. G3 AEs included nausea/vomiting (n=2, 12%), visual changes/retinopathy (n=2, 12%), MRSA skin infection (n=1, 6%), (n=1, 6%), hyperglycemia (n=1, 6%), and stroke (n=1, 6%). Other common AEs included acneform rash (n=10, 63%), nausea/vomiting (n=6, 37%), anorexia (n=4, 25%), and diarrhea (n=3, 19%). Of 10 evaluable patients in Part 1, 1 had a partial response and 4 patients had stable disease (40%). Sustained responses of 10 and 14 months were seen in the DTC patients. 3 patients are currently enrolled in the expansion cohort. The RP2D is 50 mg of A, due to the visual changes seen with 75 mg, and 12mg/kg of I. Conclusions: A at 50 mg QD combines safely with I 12mg/kg. An expansion cohort is underway to determine if this combination warrants further investigation.