2551 Background: A multimodal approach based on debulking surgery is beneficial in the treatment of pleural mesothelioma (PM). In addition, hyperthermic intra-thoracic chemotherapy significantly improves patient survival. Chemotherapeutic agents such as gemcitabin (Gem) have proven their efficacy in PM. The aim of this study was to assess the feasibility, tolerability and pharmacokinetics (PK) of gemcitabine (Gem)-cisplatine (Pt) both administered using this new intra-thoracic hyperthermic schedule. Methods: A phase II study was conducted in patients with T<3, N<2, M0 epithelioid mesothelioma. After neoadjuvant chemotherapy (Gem-Pt), extra-pleural pneumonectomy with diaphragmatic and pericardic reconstruction was performed, followed by a 1-hour intra-thoracic hyperthermic infusion of Pt (100 mg/m²) + Gem (1250 mg/m²). Pleural and blood samples were analyzed for Gem and its active metabolite difluorodeoxyuridine (dFdU, HPLC assay) and for total and free Pt concentrations (atomic absorption spectrophotometry). Five patients were analyzed for PK. Results: No major chemotherapy-related side effect was reported. Main PK data are the following: the maximum dFdU concentration was reached between 1.25 and 1.5 h in pleura, and between 1.25 and 4 h in plasma. For free Pt, maximum concentrations were observed between 0.25 and 1 h in pleura and between 1 and 1.25 h in plasma. Large inter-patient variability was observed for both dFdU and free Pt PK. Importantly, the local exposure to dFdU was 2.5 to 9-fold that of plasma exposure. For free Pt, pleural exposure was 8.7 to 30-fold greater than plasma exposure. Conclusions: These data indicate a markedly higher pleural exposure as compared to systemic exposure for dFdU and Pt. Along with satisfactory tolerance, these results support the potential benefit offered by this new intra-thoracic hyperthermic schedule in the management of PM. Patient AUC0–48h dFdU (μM.h) AUC0–48h free Pt (mg/l.h) Plasma Pleura Pleura/plasma Plasma Pleura Pleura/plasma 1 913 2,350 2.57 6.96 60.65 8.71 2 304 1,396 4.59 5.44 not done - 3 379 953 2.51 1.87 56.68 30.31 4 537 4,856 9.04 4.26 100.87 23.68 5 386 1,453 3.76 1.82 29.72 16.29 No significant financial relationships to disclose.