UCLA's Jonsson Cancer Center was one of three sites nationwide to conduct the first human tests on the once-a-day pill, formerly known as STI-571 and now called Glivec.

Early testing prompted such encouraging results that the U.S. Food & Drug Administration has designated Glivec for priority review for approval, said Jonsson Cancer Center researcher Dr. Charles Sawyers, one of three lead investigators who tested the experimental drug on patients with Chronic Myelogenous Leukemia (CML).

Sawyers, senior author of the journal article detailing the results of the first phase testing of Glivec, said the drug prompted dramatic responses in patients in the chronic stage of CML.

"These are the first publications documenting the remarkable activity of a pill that attacks a specific gene linked to CML," said Sawyers, who has researched CML for more than a decade. "This is confirmation of the rationale of targeted therapies in drug design."

Glivec, developed by Novartis, attacks a mutant protein in a cancer-causing gene linked to CML, which each year strikes more than 10,000 adults worldwide.

Specifically, Glivec is a signal transduction inhibitor, a new class of drugs that can interfere with cell signaling pathways implicated in tumor development. Much of the pioneering work done to link the gene and its mutant protein to CML was performed at UCLA's Jonsson Cancer Center.

In the chronic stage of CML, patients experience skyrocketing white blood cell counts, but generally exhibit no symptoms for three to five years. The disease can then advance to the accelerated stage, during which white blood cell counts increase even more. The end stage of the disease, known as blast crisis, can be fatal within several months.

Early testing of Glivec at UCLA focused on patients in the chronic stage of the disease who did not respond to standard treatments with interferon. Later, Sawyers tested the drug on patients in blast crisis. In all, about 200 patients have participated in Glivec studies at UCLA's Jonsson Cancer Center, Sawyers said.

The drug also appears to help patients in the blast crisis stage of CML, Sawyers and other investigators state in the second of the two journal articles on CML appearing in NEJM today.

UCLA patient Peter G. Barnes, 54, of Northridge, is among those with CML in blast crisis that have benefited from Glivec. Barnes lived with CML in the chronic stage for seven years, using the standard treatment of interferon to stave off the accelerated and blast crisis stages of the disease. He couldn't find a match for a bone marrow transplant, so Barnes didn't have many treatment choices.

Then, a year ago, Barnes' leukemia quickly advanced to the accelerated and then blast crisis stages. Doctors said he'd be lucky to live more than a few months. But Barnes was able to enroll in a UCLA study of Glivec under Sawyers' care, and today he works full-time and is enjoying a full life with his wife.

"This drug came along for me at just the right time," said Barnes, who writes and edits sports shows for television. "I feel great now. I'm feeling as good as I ever did. The morning after I took the first dose of Glivec, I could feel a change."

High school English teacher Virginia Garner, 55, also experienced first hand what Glivec can do. Garner was so sick in early 1999 that she'd get winded just walking down the street. Last month, Garner completed the Los Angeles marathon, and she credits Glivec for her good health.

"Miraculously, I've got my life back. This is saving my life," said Garner, who lives with her husband and two dogs in the Los Angeles suburb of Claremont. "Dr. Sawyers is my hero."

Garner was diagnosed with chronic stage CML in August of 1997. She began taking Glivec in April 1999, and saw a measurable response in her white blood cell count within five months. She said completing the marathon is a metaphor for her life philosophy: "Put one foot in front of the other and keep going."

"You can't imagine how great it feels as a doctor to see a patient come to your clinic one week after completing the L.A. Marathon, all thanks to a pill she takes once a day," Sawyers said of Garner.

In the first phase studies on CML patients in the chronic stage, Glivec was tested on 83 people in doses ranging from 25 mg to 1000 mg. Side effects were minimal, according to the article, with the most common problems being nausea and diarrhea. Complete responses -- or remissions -- were seen in 98 percent of patients treated with doses of 300 mg or greater and typically occurred within the first month of therapy.

"The data indicates that the drug is well tolerated and has significant anti-leukemic activity in patients with CML," the article states. "This trial ... demonstrates the potential for anti-cancer drug development based on the specific molecular abnormality present in a human malignancy."

In the blast crisis study, the drug was tested in 58 patients in doses ranging from 300 mg to 1000 mg. Measurable responses occurred in 55 percent of patients, including 11 percent who underwent complete remissions.

The three institutions that participated in initial testing of Glivec include UCLA's Jonsson Cancer Center, Oregon Health Sciences University and the M.D. Anderson Cancer Center in Houston. Later testing was conducted worldwide.

Novartis submitted Glivec to the FDA for approval on Feb. 27, 2001. FDA officials designated the drug for priority review on March 7, 2001. Under a priority review, the FDA is required to respond to the drug approval application within six months, meaning Glivec could receive an OK by mid-summer.

"Novartis is pleased by the FDA's decision to grant priority review of Glivec," said David Epstein, president of Novartis. "We will continue to work closely with the agency so that Glivec can get to the market and be available for patients as quickly as possible."

Glivec is now being tested on solid tumors, and data from those studies will be released at the American Society of Clinical Oncology meeting in May. In all, Glivec is being tested in more than 5,000 patients in 30 countries, Novartis officials said. - By Kim Irwin

Novartis

UCLA's Jonsson Cancer Center

[Contact: Kim Irwin, Kambra McConnel ]

05-Apr-2001