Sugen

Researchers at ASCO say SU11248 worked in 11 of 18 trial patients

CHICAGO — Patients with the rare digestive-tract cancer known as gastrointestinal stromal tumor (GIST) who develop resistance to the frontline drug Gleevec may benefit from a novel compound that targets specific genetic mutations in GIST cells.

At the American Society of Clinical Oncology’s annual meeting in Chicago, scientists from Dana-Farber Cancer Institute presented data from an early stage clinical trial of a new drug called SU11248 in patients with Gleevecresistant GIST. The study, headed by Dr. George Demetri, demonstrated that 11 of the 18 patients (61 percent) with progressive metastatic GIST experienced disease shrinkage or stabilization with no further progression when treated with SU11248. Like Gleevec, SU11248 target specific enzyme switches, called kinases, that keep cancer cells growing. The findings were presented June 1.

An estimated 5,000-10,000 cases of GIST are diagnosed in the United States each year. Surgery has been effective in treating some patients when the disease has not spread, but there are few treatment options for those patients in whom the tumor spread beyond the original site of surgery. Last year, the FDA approved the use of Gleevec as the first effective treatment for GIST. Gleevec has proven to be highly beneficial therapy for metastatic GIST, but not all patients can tolerate it and some develop resistance to the drug over time.

“Approximately 85 percent of GIST patients benefit from treatment with Gleevec, but, over time, they tend to develop resistance to it and the disease once again begins to grow,” says Demetri. “Two-and-a-half years after starting treatment with Gleevec, approximately three-quarters of patients will show some level of resistance to Gleevec. There is no other effective treatment for these patients, and that is why we need new treatment options for them.”

Last year, Demetri and his colleagues, including Dr. Jonathan Fletcher of Dana-Farber and Dr. Michael Heinrich of Oregon Health & Science University, sought to identify what those additional mutations are and to design a counterattack with a new targeting strategy. They screened a variety of compounds known to act against abnormal enzymes. The results with SU11248, which is now made by Pfizer Oncology of La Jolla, CA, were particularly promising.

“SU11248 is a small molecule that inhibits the production of four enzyme switches: KIT, PDGF-R, VEGF-R, and FLT-3,” explains Demetri, who is also an associate professor of medicine at Harvard Medical School. “Laboratory and animal studies showed it could be effective in GIST cells that had become resistant to Gleevec. The VEGF-R blockage is particularly interesting, too, since this drug is a powerful anti-angiogenesis drug, blocking the growth of new blood vessels to feed tumors, as well as shutting down other overactive enzyme switches inside the cancer cells.”

Based on the results of those preclinical studies, Demetri and his colleagues began a Phase I clinical trial of SU11248 in patients with Gleevecresistant GIST. (The main purpose of a Phase I trial is to determine the safe dose for administration of new medications.) Successive groups of patients were treated with SU11248 at starting daily doses of 25, 50, or 75 mg. for 14 days, followed by a 14-day rest period per cycle. The maximum safe dose was determined to be 50 mg. after some patients at the 75-mg. dose level experienced unpleasant, but temporary, side effects (fatigue, nausea and vomiting).

The development of SU11248 as a potential treatment for Gleevecresistant GIST “is an exciting example of the new world of targeted therapy,” Demetri remarks. “We can analyze cancer cells to identify mutations, then screen drugs in the laboratory that target those specific mutations. The resulting therapies should be more effective and less toxic than traditional chemotherapy, which tends to attack normal cells as well as cancerous ones.” In addition to Fletcher and Heinrich, the study’s other contributor were Dr. Annick Van den Abbeele of Dana- Farber, Dr. Christopher Fletcher of Brigham and Women’s Hospital, and collaborators at Pfizer Oncology (the biotechnology company formerly known as Sugen).