) The overall objective of Project 4 is to design and initiate the first hypothesis-driven clinical trial(s) of the silicon phthalocyanine photosensitizer PC 4 in photodynamic therapy (PDT) of human cancers. The project is based on extensive in vitro and in vivo testing performed at CWRU during the last funding period. The National Cancer Institute's (NCI) Drug Decision Network (DN) has also contributed significantly to the pre-clinical testing of Pc 4-PDT, including pharmacokinetic studies in mice and IND-directed toxicology studies in two animal species. Based on CWRU and NCI DN data, we hypothesize that Pc 4-PDT will be effective in the treatment of primary and metastatic skin cancers without severe local or systematic toxicity including cutaneous photosensitivity. We also hypothesize that a mechanism of Pc 4-PDT-related tumor response in humans involves cell death by apoptosis. To test these hypotheses, we have designed a Phase I and translational study of Pc 4-PDT in selected patients with primary and metastatic skin cancers, which will be completed in years 1-3 of this project.
The specific aims are: (1) To conduct a two-part Phase I dose escalation trial to determine the maximum tolerated dose and dose-limiting toxicities of PDT with intravenously administered Pc 4; (2) To determine the pharmacokinetics of Pc 4 following a two-hour i.v. infusion in humans; (3) To monitor normal and tumor tissues in patients for clinical, histological, and biochemical endpoints of PC 4-PDT-related toxicity and cell death mechanisms; (4) To observe patients for a clinical anti-tumor response to Pc 4-PDT; and (5) Based upon the results of the first Phase I study described in Specific Aims 1-4, to design for years 3-5 of this program: (a) a Phase II trial of Pc 4-PDT in patients with recurrent and locally invasive basal and squamous cell skin carcinomas using the recommended dose schedule of Pc 4 and light determined in the Phase I trial; and (b) a Phase III trial of Pc 4-PDT for locally recurrent esophageal cancers. In the clinical trials of Specific Aim 5, in addition to cleavage of poly(ADP-ribose) polymerase, other biochemical markers of Pc 4-PDT tumor responses will be tested for clinical relevance based on promising experimental data from Projects 2 and 3.
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