Endostatin-Phase I Success

Endostatin Well Tolerated in Cancer Patients

NEW YORK (Reuters Health) Sept 25, 2002

The results of a phase I trial show that recombinant human endostatin is safe and well tolerated by patients with refractory solid tumors.

Furthermore, the antiangiogenesis agent conferred clinical benefit to 3 of 15 patients included in the trial. The "unprecedented interest" in endostatin resulting from media reports led to a recruitment process that was "quite different from a typical phase I clinical trial," Dr. Joseph P. Eder, Jr. of the Dana Farber Cancer Institute in Boston, and colleagues note. To ensure equitable access, a toll-free telephone number was advertised locally and nationally to recruit patients for the trial.

In vitro and animals studies have found that endostatin inhibits the migration and proliferation of endothelial cells and angiogenesis. The agent (rhEndostatin; EntreMed, Rockville, Maryland) was administered as a daily 20-minute IV infusion at dose levels ranging from 15 to 240 mg/m . Included were patients with cancer of the breast, lung, colorectum, liver, ovary, pancreas, and kidney, as well as patients with fibrosarcoma and melanoma.

One patient achieved a 17% reduction in maximum tumor volume lasting for more than 11 months, and two exhibited disease stabilization for 3 and 4 months "Toxicity was negligible, even in patients receiving the highest daily dose," the investigators report in the September 15th Journal of Clinical Oncology. The only treatment-related toxicities were two cases of self-resolving grade 1 salmon-colored rashes and two episodes of infusion-line associated sepsis.

In 10 patients who underwent MRI prior to and following treatment initiation, no consistent changes in tumor blood flow were noted. The authors observed no evidence of a dose-response or a duration-of-therapy response relationship between rhEndostatin and average changes in creatinine-normalized concentrations of basic fibroblast growth factor and vascular endothelial growth factor.

"The pharmacokinetics of rhEndostatin in humans was found to be very similar to its behavior in preclinical animal models," they write. The pharmacokinetics of the agent were also similar to those observed for other endogenous human proteins, such as interleukin 11 and interferon. However, "daily systemic exposure to rhEndostatin in patients receiving 240 mg/m /day was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies," the researchers note.

Since completion of this study, the authors have initiated another trial in which a new, more stable formulation of the protein is being administered as a continuous IV infusion. As shown in animal models, the investigators believe that the therapeutic effect will improve. "The fact that patients were given endostatin on a daily basis and had no observable side effects is a very encouraging development, and provides additional evidence that cancer may one day be treated as a chronic disease, similar to diabetes or heart disease," Dr. Eder commented in a journal statement.

In an accompanying editorial, Dr. Jan H. M. Schellens, of the Netherlands Cancer Institute in Amsterdam, and Dr. Mark J. Ratain, of the University of Chicago, remark that these results "are not what were predicted by some in 1998." They suggest that "considering the wide range of angiogenic growth factors that can be produced by tumors and the possible biologic heterogeneity of tumor-induced blood vessels, combinations of antiangiogenesis drugs may be more effective than single-agent treatment."

J Clin Oncol 2002;20:3758-3760,3772-3784.

Thanks to Reuters Health

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