K. Harlacker

Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer

Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed.

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.

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.