SAN FRANCISCOThe 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
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
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 activitynot
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
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 =
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
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."