Embargoed for Release: 9:00a.m. Pacific Time May 13, 2001 Contact: Janet Haley Dubow [email protected](617) 632-4090
International Collaboration Announces Results of Gleevec(tm) Trial For Rare Form Of Abdominal Cancer known as GIST
Information from Phase II trial to be reported at major cancer conference in San Francisco
SAN FRANCISCO -- An international team of researchers will report on Monday that a drug approved by the U.S. Food and Drug Administration last week for its striking success against chronic myelogenous leukemia (CML) can also benefit the majority of patients with a rare and otherwise incurable form of gastrointestinal cancer.
At the plenary presentation of the annual meeting of the American Society of Clinical Oncologists here, investigators will report preliminary findings from the first large-scale clinical study of Gleevec(tm) in patients with a condition known as Gastrointestinal Stromal Tumor (GIST). The researchers -- from Dana-Farber Cancer Institute, Oregon Health Sciences University (OHSU), Fox Chase Cancer Center, and Helsinki University Central Hospital -- found that well over three quarters of patients had some shrinkage of their tumors, and that in more than half the patients, tumors shrank by at least 50 percent.
"This work is based on an understanding of the genetic mechanisms that characterize this type of cancer," says George Demetri, M.D., of Dana-Farber, who is the senior author of the study. "Laboratory experiments predicted this medication might work in GIST, and we have been tremendously pleased with the clinical benefits which the majority of patients achieved in this trial."
Gleevec (formerly known as STI 571) was initially developed as an anti-CML medicine by Brian Druker, M.D., of OHSU, based on research he had conducted in collaboration with Novartis Pharmaceuticals of Switzerland. In a clinical trial that gained widespread publicity last year, the drug produced remissions in all 31 CML patients who took it.
Gleevec works by blocking the action of a select group of enzymes known as tyrosine kinases. In patients with CML, an abnormality in the DNA of leukemia cells causes the action of a specific kinase enzyme, called "ABL", to be switched on in an uncontrolled manner. This over-activity of ABL triggers the runaway growth of the cancerous white blood cells. Importantly, previous research in Boston, Japan, Finland, Washington, and other labs has shown that GISTs possess a defective version of a distinct tyrosine kinase enzyme called KIT. The defect, or mutation, causes the KIT enzyme in GIST cells to be switched on in an uncontrolled manner, analogous to the problem of ABL in CML.
"Dr. Druker's laboratory had previously shown that Gleevec is able to inhibit the enzymatic action of KIT," Demetri says. "We reasoned that since Gleevec can block tyrosine kinase activity in CML, and since this fights the cancer effectively, this drug could very well do the same for GIST by its inhibition of the KIT enzyme."
Malignant GIST occurs in an estimated 5,000 Americans each year, usually originating in the stomach or small intestine in cells that form the connective tissue supporting the structure of the gastrointestinal tract. For patients in whom the malignant GIST cannot be completely removed by surgery, the outlook to date has been distressingly bleak. Less than 5 percent of such tumors respond to any type of conventional chemotherapy, and in those rare cases that do respond, progression of the disease usually occurs within weeks. Patients with this disease that cannot be managed by surgery have generally died within a year or two of diagnosis.
In collaboration with laboratory investigators including Drs. David Tuveson and Jonathan Fletcher at the Dana-Farber/Harvard Cancer Center, Demetri showed that Gleevec could block the KIT enzyme in GIST cells and that this enzyme blockade would kill the tumor cells. Last month, in a separate collaboration between DFCI, OHSU and Helsinki University Central Hospital the first patient with GIST to receive Gleevec was reported in the New England Journal of Medicine to have had dramatic benefit, with significant and sustained tumor shrinkage. The positive results in that single patient, as well as the powerful scientific rationale for this new drug, provided the impetus to mount an international effort to study the drug in this otherwise fatal disease.
The study presented today is the first report of that large-scale effort. One hundred forty eight patients with GIST were randomly assigned to receive either a 400- or 600 mg. daily dose of Gleevec for as long as the tumors were controlled. Of these 148 patients, 86 have been treated with Gleevec long enough so that the response to the drug could be evaluated.
The early results from this study show that 59 percent of the patients had a partial response to the medication, meaning their tumors shrank by 50 percent or more. Twenty-six percent of the patients had shrinkage of less than 50 percent. Only 13 percent had progression of their disease. Patients who received Gleevec at the higher dose of 600 mg./day had a slightly higher response rate than those who received 400 mg./day. The side effects of the medication were relatively mild and very tolerable overall. No patient whose tumor shrank in response to Gleevec treatment has yet had the disease regrow.
The results of this US/Finnish collaborative group have been corroborated by a separate European study of Gleevec in GIST patients that is being presented by Dr. Allan van Oosterum of Belgium.
"The excitement surrounding Gleevec for GIST goes well beyond the dramatic benefits for a small group of patients with an inevitably fatal disease," said Demetri. "This drug provides proof of the concept that the understanding of cancer at a molecular level can generate truly effective and well tolerated medications to treat human disease. Additionally, the speed with which PET (Positron Emission Tomography) scans can detect the effects of this drug on tumors in some patients - within one day - should help to accelerate the pace of rational drug development." Demetri said that he and others would expand their studies of Gleevec to determine its effectiveness against other types of tumors. Demetri is also the principal investigator of a clinical trial, sponsored by the United States National Cancer Institute in collaboration with the National Cancer Institute of Canada, which will attempt to determine whether a higher dose of Gleevec is in fact more effective than a lower dose.
Dana-Farber Cancer Institute (www.danafarber.org) is a principal teaching affiliate of the Harvard Medical School. It is a founding member of the Dana-Farber/Harvard Cancer Center (DF/HCC), designated a comprehensive cancer center by the National Cancer Institute.
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