LOS ANGELES, CA -- October 26, 1999 -- The drug STI-571, now being tested in clinical trials, is lowering white blood cell counts and actually altering abnormal cell structure to attack a common form of adult leukemia.
"Six or eight months ago, I would have never believed this," says Charles L. Sawyers, M.D., a principal investigator in clinical trials for the drug STI-571. Dr. Sawyers is Director of the Prostate Cancer Program and Associate Chief for Basic Research at UCLA’s Jonsson Cancer Center, and an Associate Professor in the Division of Hematology-Oncology at the UCLA School of Medicine. He spoke at the AMA’s 18th Annual Science Reporters Conference, in Los Angeles, CA.
Along with Brian Druker, M.D., of Oregon Health Sciences in Portland, and Moshe Talpaz, M.D., of the M.D. Anderson Cancer Center in Houston, Dr. Sawyers has been leading clinical trials of a drug currently known as STI-571. He calls the results to date amazing.
Getting to the Root of the Disease
STI-571 was developed to treat patients with chronic myelogenous leukemia (CML), which occurs most often among middle-aged men and women. In the chronic phase of CML, patients have a high white blood cell count, but generally symptoms are minimal for three to five years, before the disease advances to the accelerated phase, when white cell growth also picks up. The end stage of the disease is known as blast crisis, and can be fatal within several months.
CML is caused by a molecular change that scientists call chromosome translocation. "That means two chromosomes switch pieces of each other," Dr. Sawyers explains. This switch produces what is known as a fusion protein. In the case of CML, it involves a class of enzymes known as tyrosine kinases.
Since a number of different cancer-causing genes identified over the past 20 years have turned out to be tyrosine kinases, scientists believe a drug designed to inhibit tyrosine kinases would also fight cancer.
One of the problems, though, is that there are several hundred tyrosine kinases in normal cells-all fairly similar to each other chemically, but each with specific functions. That means a drug designed to fight CML would have to be very selective, and attack the specific kinase known as "abl", which causes CML.
In clinical trials so far, that appears to be what the drug has done.
Although the first formal presentation of clinical trial results for STI-571 will not be delivered until early December. Dr. Sawyers says the preliminary results have been very impressive.
In the Phase 1 trial, CML patients in the chronic stage who failed to respond to conventional treatment with interferon received STI-571 in pill form once a day. At doses ranging from 25 mg to 600 mg, there has been no toxicity of any significance. And at doses starting around 200 mg, nearly every patient has had white blood cell counts come down to normal.
Perhaps most remarkable, at doses of 300 mg or more, researchers have seen the molecular cause of CML start to disappear. The fusion protein is made by the "Philadelphia chromosome", and for some patients, the "Philadelphia chromosome" was undetectable after several months of treatment with STI-571. "That is the real home run," Dr. Sawyers says.
Some Phase 1 subjects are still being treated, and Phase 2 trials are now under way for CML patients in the accelerated and blast crisis phases of the disease. The manufacturer of the drug is awaiting Phase 2 results before making a decision to seek approval from the Food and Drug Administration.
"There is definitely a very high interest level in getting this drug approved and out as fast as possible," Dr. Sawyers says.
Dr. Sawyers believes the drug will play a major role in the treatment of CML. And he is very excited about the role of molecular biology in helping researchers understand what cancer cells are, and how to fight them. "The fact that you can design a drug based on that, and have it work, bodes well for the future," he concludes.
STI-571 is being developed by Novartis Pharmaceuticals Corporation, which provided support for the clinical trials of STI-571 at UCLA and has paid consulting fees to Dr. Sawyers for providing advice in designing the structure of the clinical trials.