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Chapter 6110study EGFR signaling was examined by assessing phosphorylated EGFR and AKT protein levels in pancreatic cancer cell lines and tumor xenografts. The addition of an EGFR inhibitor to gemcitabine based CRT showed a reduction in EGFR and AKT protein levels and impaired tumor growth in tumor tissue compared to CRT with gemcitabine alone, indicating that the radiosensitizing effect of gemcitabine may be improved by EGFR inhibition. Several studies demonstrated that EGFR pathway inhibition in PDAC can improve the antitumor efficacy of RT independent of the KRAS mutation status of a tumor (9). This is relevant because KRAS mutations are common and associated with a worse prognosis in PDAC (10). Suggested mechanisms for EGFR inhibition regardless of downstream activating KRAS mutations are inhibition through the EGFR-PI3K-AKT pathway or HRAS signaling pathway (9, 11). Based on these preclinical data we investigated the safety, tolerability, and potential clinical efficacy of the human monoclonal anti-EGFR monoclonal antibody panitumumab (12) when added to CRT with gemcitabine in patients with LAPC. This phase I study is described in chapter 2. Patients diagnosed with LAPC and a WHO performance status of 0 to 1 were treated with panitumumab once a week at four different dose levels (1 to 2.5 mg/kg). This was combined with gemcitabine at a dose of 300 mg/m2 once a week along with radiotherapy (50.4 Gy in 28 fractions) during 6 weeks. Subsequently, patients received gemcitabine at a dose of 1,000 mg/m2 weekly for 3 weeks every 4 weeks, until either disease progression or unacceptable toxicity occurred. Each dose cohort was closely monitored during combination therapy to identify dose-limiting toxicity. Tumor assessment was carried out after CRT and during gemcitabine monotherapy. Fourteen patients were enrolled, with 14 being assessable for toxicity and 13 for response. The Maximum Tolerated Dose (MTD) for panitumumab in this combination was determined to be 1.5 mg/kg. Partial response was observed in 3 patients (23%), one in each dose cohort. Major toxicities potentially related to the combination of panitumumab and gemcitabine were nausea, vomiting, neutropenia, fatigue, and anorexia, whereas acneiform rash was considered to be definitively related to panitumumab. We concluded that adding panitumumab to gemcitabine-based CRT is feasible with considerable, but manageable toxicity. The median progression free survival (PFS) and OS of respectively 11.8 and 17.0 months in the MTD cohort and median PFS of 8.9 months for the three cohorts combined suggest some efficacy, although this cannot be established in a phase I study design with small numbers of patients.