The tox didn't sound too bad at the Phase I abstract at ASCO - but of course not clear if they have an effective dose yet:
Phase I trial of 17-AAG (17-allylamino-17-demethoxygeldanamycin) in patients (pts) with advanced cancer.
Abstract No: 795
Citation: Proc Am Soc Clin Oncol 22: page 198, 2003 (abstr 795)
Author(s): D. B. Solit, M. Anana, G. Valentin, A. De La Cruz, W. Tong, K. Busam, V. Reuter, W. K. Kelly, N. Rosen, H. Scher; Memorial Sloan-Kettering Cancer Center, New York, NY
Abstract: 17-AAG is an ansamycin antibiotic that binds to a highly conserved pocket in the Hsp90 chaperone protein and inhibits its function. Hsp90 is required for the refolding of proteins during cellular stress and the conformational maturation of a subset of signaling proteins. Treatment with 17-AAG causes the proteasomal degradation of Hsp90 client proteins, which include HER2, steroid receptors, Raf and Akt. We initiated a phase I study of 17-AAG to define the MTD, toxicity profile, and pharmacodynamics of this agent in pts with advanced malignancies. Pts were treated with doses ranging between 5 and 157 mg/m2 using one of three treatment schedules: days 1-5 of a 21d cycle (5-80 mg/m2), days 1-3 of a 14d cycle (80-112 mg/m2) and most recently days 1, 4, 8, and 11 of a 21d cycle (112-157 mg/m2). To date we have enrolled 40 pts (median age 56: range 22-78) with prostate cancer (ca) (13 pts), breast ca (8), renal ca (5), lung ca (4), bladder ca (3), melanoma (3), CML (1) and others (3). Pts have received a median of 2 cycles (range: 1-12). Toxicity, in particular hepatic, was schedule dependent. Dose limiting toxicities (reversible hepatitis and diarrhea) were reached with the daily x 5 and daily x 3 schedules. No grade 3/4 toxicities have been observed with the twice-weekly schedule and dose escalation continues. Pharmacokinetic data for the 157 mg/m2 dose level showed a t1/2 of 3.8hrs with peak levels of 7.18?M for 17-AAG; and t1/2 of 9.6hrs with peak levels of 1.34?M for the active metabolite 17-AG. These concentrations exceed those associated with decreases in target protein expression in vitro and in xenograft models. No objective responses have been seen, although 9 of 34 evaluable pts had stable disease beyond 3 months. Correlative studies include collection of peripheral blood lymphocytes and pre/post treatment skin biopsies to study therapy induced changes in Hsp90 client proteins and proliferative index respectively. Tumor biopsies have been collected in selected pts. At the meeting updated enrollment, response and correlative data will be reported.
Peter |
