Project 1-lntraperitoneal PDT PI: Douglas Fraker Peritoneal carcinomatosis is a clinical problem which causes considerable morbidity and is uniformly fatal. Complete surgical resection is not possible, conventional radiation therapy is unable to safely treat all areas at risk, and systemic therapy with available agents is limited by drug delivery and efficacy. Intraperitoneal spread represents cancer progression on a complex surface and all areas of the abdominal cavity are at risk. During the first grant funding cycle we have demonstrated that surgical tumor debulking to minimal disease and intra-operative photodynamic therapy can be performed to treat all surfaces at risk. There were clinical responses seen in this heavily pre-treated population but the majority of patients recurred within the peritoneal cavity. This initial Phase II trial using photofrin was limited primarily by low photosensitizer retention in tumor compared to normal tissues. Other potential problems include the difficulty in delivering uniform light dose to a complex surface, and tumor hypoxia which may decrease PDT cytotoxicity. In the current proposal, Project I will address these problems by utilizing a second generation photosensitizer in combination with targeting agents to alter the signal transduction cascade in tumors. We propose to evaluate the second generation photosensitizer, benzoporphyrin derivative (BPD) in combination with the EGFR inhibitor, C225 based upon preliminary data suggesting this will increase the therapeutic index of IP PDT. Initial preclinical studies will be conducted in rabbits including peritoneal PDT at increasing doses of photosensitizer with and without bowel anastomoses. A Phase l/ll clinical trial will be performed on patients with peritoneal carcinomatosis from ovarian or gastro-intestinal cancers who have no other treatment options. The initial phase of the trial will identify and optimal dose of BPD and light energy. A second phase of the protocol will add C225 to assess response rates. In all parts of the trial malignant and normal tissue will be analyzed for sensitizer concentration, molecular markers related to PDT response, and intraoperatively for optical properties.
Showing the most recent 10 out of 127 publications
