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One of the benefits of using targeted therapies such as imatinib (Gleevec, Novartis) in treating cancer is that they seem to be fairly well tolerated. Indeed, it may be beneficial to investigate combining them with cytotoxic chemotherapy, or even other targeted therapies, to see if patients' clinical outcomes can be improved, said B. Douglas Smith, M.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine in Baltimore.
Smith addressed a session at the First Annual National Comprehensive Cancer Network (NCCN) Hematologic Malignancies Congress, held last month in New York City. He focused his discussion on the need for new, novel combinations of drugs to improve clinical outcomes in patients in whom standard treatments are either ineffective or poorly tolerated. He also discussed the importance of implementing well-designed clinical trials to identify such combination therapies.
The best clinical trials interweave biological correlates and laboratory studies with the clinical work, Smith said. "I'd like to share with you one example of a study that is moving forward as much on the biological correlative work that is being done as it is on the clinical results of the therapy itself," he added.
Smith said he and his group found that monotherapy with an FLT-3 inhibitor, CEP-701 (lestaurtinib, Cephalon), resulted in moderate biological and clinical activity in those with FLT-3 mutation, but not in a sustained response. So they decided to combine CEP-701 with cytotoxic chemotherapy.
Smith said he and his colleagues randomized patients to receive cytotoxic chemotherapy plus or minus CEP-701. They found that patients who could achieve a sufficiently high plasma concentration of CEP-701, and whose cells were sensitive to CEP-701, went into complete remission. They also found that patients who achieved only significant plasma concentrations of CEP-701 went into remission. However, the investigators did not see a remission in those who were either resistant to CEP-701 or who could not achieve a significant plasma concentration of the drug. So, Smith said, the correlative studies perfectly mirrored the clinical responses they were seeing.
Another area that Smith and other investigators are focusing on is the treatment of older persons with AML. As he explained, "Among those over the age of 70, one in 70,000 is likely to have or develop AML. As the U.S. population ages, this problem is only going to grow.
"Unfortunately, older persons do not tolerate the standard treatments for acute leukemia very well," Smith continued. "So we need to look at alternatives. One class of compounds we have been looking at is the farnesyltransferase inhibitors [FTIs]."
Smith went on to say that "one way to activate a protein is to add a farnesyl group to it post-transcriptionally. Farnesyltransferase catalyzes this reaction. Farnesylated proteins are very important for cell growth and apoptosis, transformation, mitosis, proliferation, and angiogenesis-all of the important things that we consider when we target leukemia cells."