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

Abstract

BACKGROUND: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. METHODS: A total of 29 patients were randomized to a run-in of oral everolimus (30, 50, or 70 mg) or cetuximab (400 mg/m 2 loading, 250 mg/m 2 maintenance) weekly, followed by the combination in this dose-escalation study. Primary endpoints were phase 2 dose and toxicity characterization. [ 18 F]Fluorodeoxyglucose positron emission tomography (FDG-PET) was performed as a pharmacodynamic marker of mTOR inhibition, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed as an indicator of tumor perfusion changes, at 3 time points. RESULTS: Everolimus and cetuximab were tolerable at full doses, with an expected toxicity profile. Dose-limiting toxicities in the everolimus 70 mg group included grade 3 skin toxicity in 2 patients, and mucositis in 1 patient. Of 16 patients evaluable for response, 5 had stable disease lasting 4 to 19 months. Mean change in maximum standardized uptake value (SUV max ) for those treated initially with everolimus was 224% (2% to 254%), and with cetuximab was 25% (223 to 36%). The K trans measured by DCE-MRI did not decrease, regardless of run-in drug. CONCLUSIONS: Everolimus and cetuximab can be safely administered at standard doses, and are associated with prolonged disease control. The recommended phase 2 dose of oral weekly everolimus is 70 mg in combination with standard cetuximab. Imaging studies reveal that metabolic inhibition by everolimus alone and in combination with cetuximab predominates over changes in tumor perfusion in this patient population. Cancer 2014;120:77-85.

Oral stomatitis and mTOR inhibitors: A review of current evidence in 20,915 patients

“…(), Ciunci et al. () reported the incidence rates limited to grades 2, 3, and 4 treatment‐related toxicities; for this reason, data about cases of stomatitis and stomatitis grade 1 are lower than real.…”

Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck

“…Recently, the results of a phase 1 trial combining everolimus with cetuximab were reported . This trial dose‐escalated everolimus to 30, 50, or 70 mg weekly with a standard fixed dose of cetuximab.…”

“…Model convergence was achieved (to >3 decimal places) with the conditional Laplace method, which allowed for η‐ω interactions (preference = COND LAP‐LACE INTER SLOW (computer commands to implement the conditions mentioned in the beginning of sentence)). The model diagnostics for the goodness of fit included the NONMEM objective function (OFV; −2 × log‐likelihood) and a visual inspection of graphics, such as the correlation/symmetry of observations versus predictions (population and post hoc) and conditional weighted residuals versus time and predictions . Statistical support for using a 2‐compartment model versus a 1‐compartment model (2 extra parameters) was obtained through comparisons of changes in OFV (ΔOFV); ΔOFV > 3.84 or 5.99 in nested models represented a statistical improvement for 1 or 2 additional estimated parameters, respectively ( P < .05, χ 2 ) .…”

“…All protein markers were stained with immunohistochemistry as described previously . Tissues were obtained upon the initial diagnosis of SCCHN.…”

“…The intensity of immunohistochemistry staining was measured with a numerical scale (0 = no expression, 1 = weak expression, 2 = moderate expression, and 3 = strong expression). The staining data were quantified as a weighted index (WI; percentage of positive staining in the tumor × intensity score) as previously described . The WI was determined by 2 individuals, and the final values were the average of the 2 readings.…”