17-Allylaminogeldanamycin (17-AAG) is a derivative of the benzoquinone ansamycin, geldanamycin. Compounds of this class have been shown to be cytotoxic and/or cytostatic to tumor cells in vitro at concentrations that also reduce cellular levels of Raf-1, p185 erbB2, mutant p53, and other cell regulatory proteins. Downregulation of these oncoproteins is thought to be related to the ability of the geldanamycins to specifically bind the molecular chaperone protein, hsp90 and its homolog GRP94, thereby disrupting specific heteroprotein complexes in the cell. As a consequence, decreased stability and impaired cellular trafficking of these critical oncoproteins is observed. Pharmacological evaluations were initially performed with geldanamycin (GA). 17-AAG proved to be less toxic than GA and was found to be active in breast, melanoma and ovarian mouse xenograft models. 17-AAG treatment also produced a dose-dependent induction of heat shock protein expression that correlated with inihibition of tumor cell growth. It is our hypothesis that 17-AAG is a potent and effective antitumor agent. We are undertaking a phase I trial of 17-AAG in patients with solid tumors refractory to standard therapy or for whom there is no standard treatment. The objectives of the trial are: 1) to determine the maximally tolerated dose of 17-AAG when given on a weekly x 3 schedule repeated every 28 days, 2) to define the dose-limiting toxicity of 17-AAG, 3) to determine the pharmacokinetics of 17-AAG, 4) to assess the effect of 17-AAG on surrogate markers, and 5) standard therapy is curative or definitely capable of extending life expectancy; adequate bone marrow, hepatic and renal function; life expectancy > 12 weeks; no CNS metastases; seizure disorders or history of serious allergic reactions to eggs. Patients meeting the eligibility criteria will receive 17-AAG intravenously on a weekly for three weeks schedule repeated every 28 days. The starting dose will 15/mg/m2 and will be escalated in 40% increments. This study uses a Simon Accelerated Titration Design (ATD) which incorporates intrapatient dose escalation. The study uses a Simon Accelerated Titration Design (ATD) which incorporates intrapatient dose escalation. The study will utilize Simon's intrapatient modification B which allows for dose escalation on subsequent cycles for the same patient providing that the toxicity observed on the previous cycle was no greater than grade 1. The basic design involves one patient per cohort in an """"""""accelerated"""""""" phase until dose-limiting toxicity is observed or two patients experience grade 2 toxicity during their first course of treatment. The maximally tolerated dose is one dose level below that dose which causes dose-limiting toxicity. An exploratory analysis will be undertaken to relate the pharmacokinetic parameters of this treatment and clinical or hematologic toxicity. Similarly the surrogate endpoints for treatment effect, will be related to the clinical effects and the pharmacokinetic parameters.
Showing the most recent 10 out of 1267 publications
