Patients on placebo can switch to real SU11248

GIST patients and their doctors may have another weapon in their arsenal in the not-too-distant future. The phase III trial of SU11248 was stopped early after proving it works, through the Pfizer drug must still win government approval before it can be prescribed.

In the meantime, patients who might benefit from SU11248 can receive the drug through a “treatment use” protocol set up by Pfizer.

SU11248 is similar to Gleevec in the way it works. It is a small molecule inhibitor of the receptor tyrosine kinases PDGFRA, VEGFR, KIT and FLT3. For patients with KIT or PDGFRA mutations, the main targets of this drug are still KIT and PDGRFA. SU11248 also inhibits VEGFR. This provides an anti-angiogenic effect in addition to the primary anti-tumor effect. All tumors need new blood vessels (angiogenesis) in order for tumor growth to occur; treatments that block the growth of these new blood vessels are called “anti-angiogenesis” treatments.

SU11248 is proving to be effective for about 65 percent of GIST patients for whom Gleevec fails, according to interim data presented by Dr. George Demetri at the 2004 American Society of Clinical Oncologists (ASCO) meeting. Demetri is the director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute in Boston.

On Jan. 29, Demetri posted the following message to the global GIST community: “… The data monitoring board (a team of experts separate from the investigators involved in a research study) met this week to evaluate the data obtained to date from the global phase III randomized study of SU11248 for patients with GIST for whom Gleevec was not able to control the disease.

“This data monitoring board … has now recommended that this trial can stop immediately due to having successfully met its efficacy endpoint. We have sent out a letter worldwide to the global team of SU11248 investigators so that they can get in touch with all of the patients on this trial and allow patients to obtain unblinded SU11248 immediately [a third of the participants were randomly assigned to a placebo].”

The trial’s early conclusion, Demetri said, “should be a very positive step towards establishing beyond any doubt another therapeutic option for patients with GIST using a novel molecularly targeted agent if Gleevec proves inadequate to control the disease.”

Demetri thanked the “selfless” patients and caregivers who supported the trial, “so that we could prove to any regulatory agency the value of this new therapy and thereby quickly make this agent available to patients and their physicians who wish to offer them the best care and the most effective options.

“I am also tremendously indebted to the global network of collaborators and the team that has made this positive study a reality. We must never stop in our quest to understand and defeat this disease, and to learn from GIST lessons that will be useful to improve the therapy of other cancers as well.”

In a Feb. 1 follow-up e-mail, Demetri answered some of the questions asked by GIST patients. Most were about how patients can get SU11248 while Pfizer is awaiting government approval.

“First, please rest assured that our global study team will be working with all due diligence and speed along with the study sponsor, Pfizer, to collect and fully analyze the study data and discuss these data with regulatory agencies worldwide,” Demetri said.

“Second, while the data are being analyzed and evaluated fully, patients with GIST for whom Gleevec is no longer effective will be able to access SU11248 through the treatment use programs that are open at sites internationally.

With several sites now open and more opening each week, “the best thing to do would be to contact either Dana-Farber’s Sarcoma Center, (617) 632-5122, or the SU11248 Information Service at (877) 416-6248 toll free,” Demetri said, to find the nearest site.

“I hope this helps to address several of the concerns I have seen in e-mails and phone calls from many concerned individuals,” said Demetri. “Please let me know if there is anything else we can do at this early stage to help allay concerns and address questions.”

The Life Raft Group contacted Emerging Med, the company selected by Pfizer to match clinical trials of SU11248 to GIST patients. Emerging Med declined to provide The Life Raft Group with the sites where SU11248 will be available. Patients must contact Emerging Med at (877) 601-8601 for the most up-to-date listing of trial sites.

The Life Raft Group has learned, however, that SU11248 will be available in Boston, Mass.; Detroit, Mich.; Minneapolis, Minn.; Park Ridge, Ill.; St. Louis, Mo.; Santa Monica, Calif.; Washington, D.C. and Montreal, Canada. The U.S. government’s Web site, www.clinicaltrials.gov, also lists Farmington Hills, Mich., East Melbourne, Australia, and Singapore.

SU11248 appears poised to move into clinical practice, possibly within the year. As more drugs become available to treat GIST both in clinical practice and in trials, it seems logical that further molecular analysis of tumors could help direct patients to the best drug for their particular molecular “fingerprint.”

The first step in developing this molecular fingerprint has been in place since the early Gleevec clinical trials. That step is “staining” tumors to see if they express the c-kit protein, also known as CD117. This helped establish that the tumors really were GIST and likely to respond to Gleevec.

The second step in developing a molecular fingerprint is already clinically available. This is the mutation testing service offered by Oregon Health Sciences University and at other locations. Patients can have their tumor samples tested to identify what type of KIT or PDGFRA mutation they have. This service is covered by insurance in many instances. This type of testing will become more important as patients and their doctors have more treatment options. It is likely to evolve even further over the coming years.