GIST Support Wiki

 
Ponatinib


May 2014

MARINA:

The ponatinib trial for GIST is now (again) listed as recruiting. https://clinicaltrials.gov/ct2/show/NCT01874665?term=ponatinib&rank=14

A history of the changes to the protocol can be viewed at this linnk. There seems to be some tightening up of the cardiovascular exclusion criteria.

http://clinicaltrials.gov/archive/NCT01874665/2014_05_23/changes

Why is ponatinib potentially important? Ponatinib binds to KIT in a different way than the commercially available TKI's approved for GIST.

Ponatinib (and dasatinib) bind to what is called the "open" conformation of KIT/PDGFRA, so that the A loop is swung open and away from the drug binding site o nthe protein. For this reason, mutations in the A loop (exon 17 in KIT and exon 18 in PDGFRA) may not interfere with the binding of ponatinib to the degree in which they do with the bindinng of most other drugs which bind to a "closed" A loop conformation, in which A Loop loop closes over the bound drug.