INTRODUCTION

There is currently no 2nd-line therapy available for epithelioid malignant pleural mesothelioma (MPM), with the exception of patients who have demonstrated a response to a 1st-line regimen of platinum derivatives and pemetrexed for a period of at least six months, in which case a rechallenge with the same therapy may be effective. Sarcomatoid or biphasic types of mesothelioma are usually chemotherapy-resistant, and an effective 1st-line treatment for these histotypes remains an unmet need. 
In order to overcome these problems, the Oncology Unit of S. Gerardo of Monza has initiated the first treatment program of its kind in Italy and the world with trabectedin, a natural chemotherapeutic agent of marine origin. This treatment will also shortly be available at the Medical Oncology Unit of Alessandria, the Pneumology Unit of Brescia, and the Humanitas Gavazzeni Institute of Bergamo.  

The complex chemical structure of many natural products, and natural marine products in particular, which nature has produced over millions of years of evolution, explains their ability to act on complex molecular targets and simultaneously inhibit more than one transmission pathway of the mechanisms that regulate the proliferation of neoplastic cells. 

Trabectedin is the first natural compound of marine origin that has been approved for clinical use as an antitumor agent, and is the prototype of a new class of drugs that can act directly against both neoplastic cells and the tumor micro-environment through an anti-inflammatory effect due to its ability to modulate the production of cytokines, chemokines and growth factors by the tumor macrophages. 
Preclinical data on the anti-inflammatory and anti-tumoral effects of trabectedin are of particular interest in view of the fact that inflammation is an intrinsic mechanism of resistance expressed by mesothelioma tumor cells.

Trabectedin has already been approved in Europe for the treatment of soft tissue sarcomas and pretreated advanced ovarian cancer. It will be investigated in this study after the failure of 1st-line treatment in epithelial forms of mesothelioma and as initial treatment in some particularly aggressive forms, such as sarcomatoid mesothelioma. 

The Oncology Department of the Mario Negri Institute directed by Maurizio D’Incalci will also collaborate in the study. With support from the Buzzi Unicem Foundation, the Institute will initiate a program to determine several biomolecular aspects to identify potentially useful predictive factors with the goal of improving patient selection. 

Below are the main inclusion criteria for the study:

• Cytological or histological diagnosis of advanced or metastatic MPM; 
• Performance status 0-2 (ECOG); 
• Disease measurable by CT or PET; 
• No significant biochemical changes;
• Not more than one prior treatment (pemetrexed and platinum derivatives); 
• Signed informed consent;
• No severe concomitant diseases.