UPDATE – January 6th, 2011 by Jerry Call, LRG Science Coordinator

The first ever clinical trial specifically for the PDGFRA D842V mutation has been announced by Arog pharmaceuticals. The phase II trial is scheduled to open in April, 2011 at Fox Chase Cancer Center in Philadelphia Pennsylvania and at Oregon Health Sciences University in Portland Oregon. The trial will test CP-868,596 (Crenolanib), a new, very potent inhibitor of the D842V mutation. This trial is listed at Clinicaltrials.gov as NCT01243346. Please see the link for more information.

NOTE: The text below this line represents the original article as published in the November, 2008 LRG newsletter. The text above represents the most recent information as of January, 2010, which includes the new option for the CP-868,596 trial.

Effective treatments for metastatic GIST were born in 2000 when Gleevec transformed the management of GIST. Treatment with Gleevec resulted in substantial benefit for 85 percent of GIST patients, up dramatically from the historical benefit rate of about 5 percent.

The 15 percent of patients that do not respond to Gleevec (primary resistance) are made up of several groups, including some with wildtype GIST (no detectable mutation in KIT or PDGFRA, the two genes most commonly mutated in GIST). The other major group of patients that tend to not respond to Gleevec are patients with the most common PDGFRA mutation, a PDGFRA D842V mutation in exon 18. This mutation is also insensitive to treatment with Sutent. Patients with PDGFRA D842V mutations make up about five percent of all GIST patients.

What patients need to know about D842V mutations

  • D842V mutations do not respond to currently approved therapies, Gleevec and Sutent
  • D842V mutations may be less likely to spread to other locations, but the data on this is incomplete
  • Much of the information that is readily available about GIST does not apply to patients with D842V mutations (risk assessment, response to drugs, clinical trials options, etc).
  • PDGFRA mutations, including the D842V mutation occurs mostly in the stomach, although some occur in the omentum
  • D842V mutations are rare; about 5% of GIST patients
  • Testing to detect mutations in GIST patients is rare in the United States, with less than 10% of patients having this test done. The percentage of patients having mutational testing is higher in some countries in Europe.
  • A new clinical trial for patients with D842V and other D842 mutations with measurable disease is open for patients.
  • Finding enough patients with D842V mutations to conduct a clinical trial is very difficult. Only patients with measurable disease are eligible for such trials and only a few patients fit into this category at any one time.
  • Developing therapies and running clinical trials for such a small population will be very difficult and require the active participation and cooperation of patients, clinicians, researchers, pharmaceutical companies and regulatory agencies.

Click here to view clinical trial options.