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Naturally-Occurring Angiogenesis Inhibitor Safe to Administer Subcutaneously: Presented at EORTC-NCI-AACR

By Paula Moyer
Special to DG News

FRANKFURT, GERMANY -- November 25, 2002 -- An agent that mimics a naturally occurring angiogenesis inhibitor is safe to administer subcutaneously and appears to prolong disease stabilisation in several types of advanced solid tumours.

Dr. Ronald Hoekstra, a medical oncologist at Erasmus University in Rotterdam, The Netherlands, presented the finding here November 22 at the 14^th joint meeting of the European Organisation for the Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AARC): Symposium on Molecular Targets and Cancer Therapeutics.

"This agent, known for now as ABT-510, is safe to give in once or twice daily injections and has very low toxicity," said Dr. Hoekstra.

The investigators were interested in the therapeutic potential of thrombospondin-1 because of its natural origin. ABT-510 is a thrombospondin-mimetic peptide that exhibited antiangiogenic activity and inhibited tumour growth in animal studies at concentrations of 200 ng/mL for three hours daily.

Dr. Hoekstra and colleagues studied the substances' effects on 32 patients. Four patients received continuous infusion of 100 mg daily. The remaining patients received either two bolus injections of 50 mg, or daily injections consisting of 100 mg, 200 mg, or 260 mg. Patients were switched from continuous infusions to once- or twice-daily injections after two of the four patients on continuous infusion had grade 2 skin infiltrations.

Among these patients, 23 were men and nine were women. The median age was 57 years. Seven of the patients had colorectal cancer and seven had lung tumours of various types. Six had sarcoma, and three each had renal cell carcinoma and oesophageal cancer. The remaining six had advanced tumours of miscellaneous origins.

The investigators obtained plasma samples for pharmacokinetic analysis on days 1 and 22. In selected patients, positron emission tomography (PET) scans with H2¹⁵O and ¹⁸F-FDG were performed at days 1 and 22. Dr. Hoekstra and colleagues assessed responses after every two cycles that were each 28 days in duration.

The most commonly observed adverse events consisted of grade 1 and 2 fatigue, anorexia, insomnia, headache, and nausea, he said. One patient with non-small cell lung cancer who had progressive disease developed a haemorrhage in a cerebellar metastasis after 32 days of treatment at a dose of 100 mg daily. The metastasis had not been diagnosed previously, Dr. Hoekstra said. He noted that another patient with leiomyosarcoma had a transient ischaemic attack after 21 days at 260 mg daily. Both of these severe adverse events were possibly related to the treatment drug, although they could also be tumour-related, he said.

The investigators have documented no other clinically significant, treatment-related toxicities or cumulative toxicities. The pharmacokinetic analysis on day 1 showed rapid absorption of ABT-510, with a half-life of approximately one hour, a mean cumulative level of 955 ± 350 mg for the 50 mg twice-daily dose, of 1793 ± 549 mg for the 100 mg daily dose, and 3293 ± 1105 ng/mL for the 200 mg daily dose.

Area-under-the-curve levels were 2,734 ± 728 ng/h/mL for the 50 mg twice-daily dose, 4,168 ± 1,335 ng/h/mL for the 100 mg daily dose, and 8,636 ± 1,331 ng/h/mL for the 200 mg dose. The pharmacokinetic data on day 22 showed similar results.

Serial positron emission tomography scans performed on four patients to date showed that ABT-510 was biologically active, Dr. Hoekstra said. Stable disease was seen in nine of the 23 evaluable patients for more than two cycles or eight weeks. Five patients had stable disease for more than 16 weeks across various tumour types.

The findings show that ABT-510 can be administered safely subcutaneously at a dose of 200 mg daily, he said. The plasma concentrations they documented exceed those found to be efficacious in earlier animal studies, he said.

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