Memorial Sloan-Kettering Cancer Center (MSKCC) is preparing for what it calls “a breakthrough clinical trial” that will test a new drug that uses a MEK inhibitor to target ETV1 in combination with imatinib on a small group of newly diagnosed GIST patients with advanced disease.
We hope to begin recruitment in August, said Dr. William Tap, Section Chief of Sarcoma Oncology at MSKCC. The Phase II trial will be small, with only about 45 participants, and will only have one site at MSKCC in New York City, he said. That’s because “we just want to show that this approach works,” before recruiting for a larger scale trial, Dr. Tap said. There will be a Phase I portion of the trial to define the Phase II doses of the combination regimen.
The trial is unique because most new GIST clinical trials recruit patients that already have taken imatinib, sunitinib or other drugs and have already developed resistance to those drugs. This trial will try to show that treatment with a combination of imatinib and the MEK inhibitor from the start will be even more effective in combating GIST and will reduce the likelihood of secondary mutations that cause resistance.
Novartis Pharmaceuticals is co-developing the MEK inhibitor, MEK162, with Array Biopharma. MEK162 has been through Phase I trials and recently completed a Phase II trial in NRAS-mutant melanoma.
Dr. Tap said the research that opened the way to this new approach was led by his colleague at MSKCC, Dr. Ping Chi. She was able to show that ETV1, a transcription factor, was essential to the survival of GIST; while it was hard to target ETV1 because it didn’t have molecule-binding pockets that could be blocked by drugs, she found a way around this problem by discovering that MEK inhibitors could do that job.
“MEK inhibitors alone doesn’t seem to be great, but by doing combination therapy with imatinib we get a dramatic response,” Dr. Chi said. ETV1 is a master regulator that is highly expressed in all GISTS.
“Ping’s discovery is one of the major discoveries that we have seen in GIST research since the discovery of KIT,” Dr. Tap said.
ETV1 inhibitor takes lead in combination approach to clinical trials
Posted by Phil Avila – May 20, 2013 – News, Research
In 2010, Dr. Chi published a study she led, “ETV1 is a lineage survival factor that cooperates with KIT in gastrointestinal stromal tumours,” in Nature.