NEW YORKA potential chemopreventive agent against melanoma
stopped metastatic spread in some patients in a phase I clinical trial,
according to a report presented at the Chemotherapy Foundation Symposium XIX
(abstract 69). The agent, Apomine (SR-45023A), is being developed by Ilex
Oncology, San Antonio, reported David S. Alberts, MD, professor of medicine,
pharmacology and public health and director of Prevention & Control,
Arizona Cancer Center.
Initial studies of the agent, he said, were directed toward preventing
breast cancer metastases. "It’s active in preclinical models by the oral
route against a wide variety of human cancers in vivo," he said. The agent
is also active if applied topically, he noted.
A bisphosphonate ester, Apomine activates the farnesoid X receptor (FXR) to
induce apoptosis, in addition to downreg-ulating the mevelo-nate isoprenoid
cholesterol (MIC) pathway, Dr. Alberts explained. "It is extremely well
tolerated in animal models using single- and chronic-dose administration,"
In the phase I clinical trials of oral Apomine at the Arizona Cancer Center
and University of Texas San Antonio Cancer Center, three different dosing
schedules were used: a 14-day schedule in 19 patients, a continuous schedule in
23 patients, and a weekly schedule in 11 patients, Dr. Alberts reported. Doses
ranged from 100 to 700 mg/d orally on the 14-day and continuous schedules, and
from 400 to 2,100 mg/wk orally on the weekly schedule.
Of the nine patients in the trial with melanoma, three achieved stable
disease. In one 63-year-old man, stabilization of pulmonary metastases has
continued for 33 months and 41 cycles of Apomine (see Figure for two views).
Before entering the Apomine trial, the patient had undergone five chemotherapy
regimens for his melanoma. He continues to receive Apomine on a schedule of 50
mg twice daily for 14 days every 21 days.
A woman, age 32, with a large anterior abdominal wall mass had stable
disease for 6 months with nine cycles of Apomine therapy. She previously
progressed on three other regimens. A man, age 43, treated with five prior
regimens had stable disease for 3 months with four cycles of Apomine.
The study, Dr. Alberts reported, showed that the maximum area under the
Apomine plasma disappearance curve was reached at a dose of 100 mg twice daily
and fell off thereafter. The reason, he suggested, is probably bile "sludging"
that occurs because the FX receptors are also bile acid receptors. "When
you get to a certain concentration of Apomine," he said, "you’re
really sludging bile so it’s counterproductive."