Inhibition of heat shock protein 90 (Hsp90) with the novel agent IPI-504 in metastatic GIST following failure of tyrosine kinase inhibitors (TKIs) or other sarcomas: Clinical results from phase I trial

10503 Background: Laboratory studies have demonstrated that inhibition of the Hsp90 chaperone protein results in selective destruction of the mutated KIT kinase in human GIST cell lines across multiple genotypes which confer TKI resistance. Other histopathologic subtypes of soft tissue sarcoma (STS) are also sensitive in vitro. To test this clinically, we conducted a phase I trial of IPI-504, a water-soluble Hsp90 inhibitor, for patients (pts) with metastatic, TKI-resistant GIST or metastatic STS. Methods: Pts with metastatic, TKI-resistant GIST or advanced/metastatic STS received IPI-504 in 21 day cycles (IV in 250 cc of normal saline over 30 min) either twice weekly for 2 weeks followed by 1 week off treatment (Schedule A) or twice weekly continuously for 3 weeks (Schedule B). Serial monitoring with 18FDG-PET imaging at baseline, day 11, and day 21, as well as PK profiling of IPI-504 and its major active metabolites (17-AAG and 17-AG) were performed. Results: 54 pts (38 GIST; 16 STS) have been entered a...