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Endostatin Safety, Antitumor Activity Shown in Phase I Trials

Endostatin Safety, Antitumor Activity Shown in Phase I Trials

SAN FRANCISCO—The antiangiogenesis drug recombinant human endostatin (rHE) shows evidence of safety, biologic activity, and antitumor activity in the setting of phase I trials, Roy S. Herbst, MD, PhD, said at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO) in San Francisco.

A phase I study of recombinant human angiostatin (rHA), presented at ASCO by researchers from Thomas Jefferson University Hospital, has shown the safety of that antiangiogenesis agent in patients with advanced cancer, as well as evidence of decreased tumor vascularity. Both agents are being developed by EntreMed, Inc., of Rockville, Maryland.

Dr. Herbst, chief, Section of Thoracic Oncology, and assistant professor of medicine and cancer biology, M.D. Anderson Cancer Center, said that endostatin was well tolerated; that biopsies suggested tumor cell apoptosis increased with dose; and that imaging studies showed a significant reduction in blood flow with increasing doses, along with some evidence of decreased tumor metabolism.

"This drug is clearly safe, and, yes, we can deliver it to the blood at levels that are consistent with activity," Dr. Herbst said. "And we are seeing some interesting trends in evaluation of apoptosis induction in tumor tissue, but this needs to be pursued further in new studies."

Endostatin has previously been shown to induce tumor dormancy and complete tumor regression in animals. Possible mechanisms of action include induction of apoptosis or interference with motility of endothelial cells.

In the phase I study reported by Dr. Herbst, one of several endostatin phase I experiences reported at ASCO, the agent was given as an IV infusion over 20 minutes daily, at seven dose levels up to 600 mg/m2. Twenty-five patients with solid tumors went on study, including 31% with melanoma and 19% with sarcoma. Most patients had undergone multiple previous regimens (as many as 10).

No grade 3-4 toxicities were observed. The most common adverse event was line infection "because we are giving the IV over 20 minutes every day," he said.

Pharmacokinetic analysis showed a dose-linear response. Investigators estimated that patients on the 300 mg/m2 dose level or above reached the AUC associated with endostatin activity from preclinical studies. Terminal half-life of endostatin was 10.6 hours.

Median time on study was 69 days, with median time to progression of 49 days. One patient, a 58-year-old man with recurrent melanoma who had undergone six prior chemotherapy regimens, remained on study for 15 months. After only 2 months on endostatin, his tumor burden had grown by nearly 100%; however, his tumors then stabilized and remained stable for 1 year, with no evidence of new lesions. "This man had some evidence of activity—not a true response but certainly good, stable disease," Dr. Herbst said. "One lesion on the chin actually regressed to some extent."

Tumor regression was noted in a patient with a large mandibular synovial cell sarcoma, dosed at the 300 mg/m2 level. While the regression could have qualified as a partial response, another tumor grew during the same period, giving this patient a mixed response. Interestingly, this case pointed out the potential heterogeneity of response to antiangiogenic drugs, even among different tumors in a single patient.

Blood Flow Decreased

Positron emission tomography (PET) scans were used to measure blood flow and glucose uptake after 4 and 8 weeks of treatment in as many as three tumors per patient. Percent decrease in blood flow was higher with increasing endostatin doses (P = .002). There was also a trend toward a decrease in tumor metabolism with increasing dose, a finding that did not reach statistical significance.

In one woman with breast cancer, imaging showed that a tumor that grew in size during the study also had a 27% increase in glucose metabolism and a 36% increase in blood flow. By contrast, in the patient with synovial cell sarcoma, the mandibular lesion that responded showed a decrease in glucose metabolism of 15% and in blood flow of 28% at 56 days.

Interestingly, in another patient, a 77-year-old woman with recurrent melanoma, a tumor that grew in size actually showed a decrease in glucose metabolism and blood flow.

Investigators attempted to look at endothelial cell apoptosis in tumor tissue using laser-scanning cytometry. There was a trend in favor of increasing endothelial cell apoptosis in patients at 8-week biopsy (P = .06).

Next, investigators plan to look at continuous infusion of endostatin based on data from animal models suggesting this would be more effective. At ASCO, J. Paul Eder, MD, of Dana-Farber Cancer Institute, reported that continuous infusion is an acceptable route of administration for endostatin.

Dr. Herbst said the "best use" of endostatin would likely be in combination with radiation therapy, chemotherapy, or possibly other antiangiogenic agents "once we learn more in the laboratory about what to do."

 
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