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Gleevec Paired with Chemotherapy to be Further Tested in Advanced Prostate Cancer

Gleevec Paired with Chemotherapy to be Further Tested in Advanced Prostate Cancer
M. D. Anderson News Release 06/01/03

Based on results of a Phase I trial that paired Imatinib mesylate (Gleevec™) with chemotherapy to treat advanced prostate cancer, a larger Phase II/III clinical trial has just been opened at The University of Texas M. D. Anderson Cancer Center.

M. D. Anderson researchers – the first to test Imatinib with chemotherapy – say findings from a study of patients who already had multiple prior therapies indicate clear evidence of treatment benefit in some patients.

"There does not appear to be substantive single agent efficacy for Gleevec alone but the results in combination are provocative and have formed the basis for the randomized trial," says the study leader, Paul Mathew, M.D., assistant professor in the Department of Genitourinary Medical Oncology.

Imatinib, also known as STI 571, is the protein-tyrosine kinase inhibitor that has shown power in treating chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST).

It is being studied in prostate cancer because it inhibits the platelet-derived growth factor receptor (PDGFR), the cell-division signaling pathway that is targeted by Imatinib.

PDGFR is present in the majority of prostate cancers with bone metastases and may be a valid therapeutic target.
 
"The pre-clinical studies conducted here at M. D. Anderson have suggested that combination therapy is necessary for effective targeting of the PDGFR,” Mathew says.

The Phase I trial enrolled 28 patients whose androgen-independent prostate cancer had spread to their bones. The researchers treated the patients with Imatinib by itself for 30 days, and then added weekly injections of the chemotherapy drug docetaxel. To measure response, researchers tested the patients' prostate specific antigen (PSA) levels, a substance in the blood that indicates presence and severity of prostate cancer.

The investigators found that PSA levels continued to increase in 89% of patients during initial treatment with Imatinib. Measured from the start of combination therapy, 38% had declines in PSA more than 50%, 29% had PSA declines of up to 50%, and 33% had a rise in their PSA test.

"There was a slow and sustained drop in PSA in some patients over a long period of time when both drugs were used," says Mathew. While some of that response could be due to use of docetaxel in patients who had not been treated with that drug before, PSA levels usually drop more quickly in patients who show a response to chemotherapy, he says.

However, one patient whose bone disease had progressed on docetaxel alone, had full resolution of his bone pain and drop in his PSA with combination docetaxel and Imatinib, Mathew says.

Five out of 21 patients who completed at least six weeks of treatment had a partial response to the combination therapy, and two patients maintained their response for more than 18 months with good quality of life. Mathew adds that biopsies in two patients responding to combination therapy have demonstrated a decrease in tumor expression of PDGFR and adds "this may suggest successful targeting of PDGFR in these patients’ tumors."

Apart from fatigue and nausea which responded well to dose-reductions, the treatment was generally well tolerated, Mathew says.

M. D. Anderson, Memorial Sloan-Kettering and Dana-Farber Cancer Center will enroll 144 patients in a randomized, placebo-controlled Phase II/III trial that compares treatment of Imatinib and docetaxel with docetaxel alone. Mathew adds that a cross-over provision will allow all patients on the study the opportunity to receive Imatinib.

06/01/03


© 2014 The University of Texas MD Anderson Cancer Center