HDAC Inhibitors the gemcitabine free combination chemotherapy regimen FOLFIRINOX as compared with gemcitabine. Although patients were highly selected and toxicity was considerable, this trial opens the way to new treatment strategies in advanced pancreatic cancer.Significant improvements in our knowledge of the molecular mechanisms involved in cancer development and progression, and the availability of drugs interfering with aberrant activity in various signaling pathways, have subsequently resulted in numerous clinical trials combining conventional chemotherapy with various targeted drugs. The EGFR/ MAPK and PI3K/Akt/mTOR pathways are often dysregulated and considerable evidence supports the important role of these pathways in the biology of pancreatic cancer.

Several targets in these pathways are potential candidates to achieve inhibition of aberrant signaling. Erlotinib, a tyrosine kinase EGFR inhibitor, was one of the first FDA approved tyrosine kinase inhibitors. In a randomized clinical trial in pancreatic cancer patients, erlotinib in combination with gemcitabine induced a statistically significant improvement in survival, although the two weeks survival benefit was considered clinically not meaningful. Targeting EGFR with the monoclonal antibody cetuximab in combination with gemcitabine failed to demonstrate a survival advantage. mTOR is an important signaling molecule in the PI3K pathway and inhibition of mTOR could inhibit tumor growth in pancreatic cancer xenograft models. However, in a clinical study no benefit was demonstrated using the  tovok  everolimus as a single agent in second line. Possible explanations for the relative insensitivity to drugs targeting only one aberrant molecule is the heterogeneous molecular pathogenesis of pancreatic cancer leading to deviant activation of multiple signaling pathways and the intensive crosstalk between these pathways.

Although some tumors with specific crucialmutations are sensitive to mono-targeted therapies, such as gastrointestinal stromal tumor and imatinib, for most cancer types  lordships including pancreatic cancer this is not the case. Exploration of drug combinations targeting multiple pathways is therefore an interesting strategy to overcome drug resistance. Rational targets for this combined approach in pancreatic cancer are EGFR and mTOR, leading to synergistic anticancer activity as has been demonstrated in pre-clinical models. Therefore we explored in the present study the feasibility and efficacy of a triple drug combination consisting of cetuximab, everolimus and capecitabine in patients with advanced pancreatic cancer. In an earlier phase I study we demonstrated that everolimus in combination with capecitabine was a safe and tolerable regimen.In the present study gemcitabine was replaced by capecitabine because gemcitabine in combination with everolimus induced severe bone-marrow toxicity already at the gemcitabine dose level of 600 mg/m. The failure of gemcitabine based combination regimens was also taken in to account. The monoclonal antibody cetuximab instead of erlotinib was chosen because of potential pharmacokinetic interactions between erlotinib and mTOR inhibitors.