Imaging with [18f]-fluorodeoxyglucose positron emission tomography (FDG-PET) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) as markers of drug effect in a phase I dose-escalation study of combined RAD 001 and cetuximab.

Abstract

3048 Background: Preclinical studies suggest that mTOR inhibitors may have both metabolic and anti-angiogenic effects. We employed FDG-PET as a pharmacodynamic marker of mTOR inhibition, and DCE-MRI as an indicator of changes in tumor blood flow in a phase 1 combination study of RAD001 and cetuximab. Methods: 29 patients with EGFR-expressing solid tumors were randomized to a 3-week run-in of single agent RAD001 (30-70 mg PO) or cetuximab (400 mg/m2 IV loading, 250 mg/m2 IV maintenance) weekly, followed by the combination weekly. The primary endpoints were phase II dose finding and toxicity characterization. FDG-PET and DCE-MRI were performed at three time points (baseline, run-in, and combination), to assess for changes in tumor metabolic activity and perfusion, and for subsequent correlation to treatment response (CT or MRI after every two cycles of combination therapy). Results: RAD 001 was tolerated at the highest dose level. Grade 3 or worse toxicity included thrombocytopenia, hypokalemia, elevation in AST and alkaline phosphatase, and skin toxicity. 10 patients were evaluable for response. 5 patients had stable disease lasting 4-19 months (colon, parotid, anal and 2 ovarian). Mean % change in SUVmax from baseline for those treated with RAD001 during run-in (n=12) was -23.4 (range +1.4 to -52.9%), and a dose relationship was evident. The SUV change in pts treated first with cetuximab (n=13) was -9.6% (-53 to +35%). In 10 pts in whom RAD001 was added after cetuximab, there was an additional 11% decrease in SUV, while in patients treated first with RAD001, the SUV change was +12.4%, suggesting that an initial inhibitory effect was being circumvented by the tumor. Mean % change in SUVmax from baseline for the group with SD was lower than in the group with PD. The Ktrans measured by DCE-MRI did not change (-0.9%, n=7), irrespective of run-in drug. Conclusions: Metabolic responses by FDG-PET compared to DCE-MRI changes reveal that the metabolic effects of RAD001 alone and in combination with cetuximab predominate, while antiangiogenic effects appear to be minimal in this patient population.