As a class, the camptothecins have been widely recognized for their therapeutic potential, which for many reasons, including the instability of the lipophilic lactone moiety, has not been fully realized. DB-67 (7-t- butyldimethylsilyl-10-hydroxycamptothecin) is a third generation analog that was engineered to be blood stable and highly potent, on the basis of structure-activity relationship studies. The camptothecins have a labile a-hydroxy-5-lactone ring, which hydrolyzes to yield the negatively charged carboxylate form. Compared to the uncharged lactone, the negatively charged carboxylate is less likely to diffuse into cells and is often considered """"""""inactive."""""""" Based on its blood stability and anti-tumor activity, DB-67 was selected by the NCI for development through three cycles of the RAID program. Data from NCI studies and from collaborative efforts revealed impressive in vitro and in vivo anti-tumor activity, particularly in glioma models, but also in melanoma and colon xenograft models. Currently DB-67 formulation and toxicology studies have been completed and clinical grade material is available through the NCI. Based on the extensive formulation, toxicology, and pharmacokinetic profile observed in preclinical models, and its potential to exert a potent anti-tumor effect in humans, we hypothesize that DB-67 will be well-tolerated and efficacious in clinical trials. This grant application outlines the clinical studies and the correlative pharmacokinetic studies that will define DB-67 disposition and toxicity in patients with refractory solid tumors. The following specific aims will be accomplished: 1.1) To estimate the maximum tolerated dose (MTD) and describe the dose limiting toxicities (DLT) of intravenous DB-67 administered once daily for 5 days every 21 days to adults with recurrent or refractory solid tumors in which standard therapies are not effective; 1.2) To characterize the plasma pharmacokinetics of DB-67 and metabolites after intravenous administration and relate DB-67 pharmacokinetics and toxicity. Ultimately, the objective is to use DB-67 as a single agent or in combination with other molecular-targeted therapies or cytotoxics in frontline therapy with the goal to improve overall patient outcome.
