SAN FRANCISCOAberrant responses to growth signals lead to the
development of several types of cancer. The mammalian target of rapamycin
(mTOR) is a protein kinase involved in the signal transduction pathway that
links growth stimuli and cell cycle progression. It has emerged as a promising
new target for intervening in the cancer process.
Rapamycin, a macrolide fungicide, blocks mTOR activity but has toxicity
problems due to its potent immunosuppressive actions. The rapamycin derivative
CCI-779 (Wyeth-Ayerst) has produced particularly promising results in treatment
of solid tumors, Manuel Hidalgo, MD, PhD, said at an industry-supported
educational symposium of the 37th Annual Meeting of the American Society of
Dr. Hidalgo is assistant professor of medicine, University of Texas Health
Science Center at San Antonio.
Dr. Hidalgo said that two single-agent phase I trials of CCI-779 have been
completed and preliminary data are available: a European trial of weekly
CCI-779 that included 18 patients, and a US trial of CCI-779 given daily for 5
days and repeating every 2 weeks that included 63 patients. The maximum
tolerated dose was 15 to 20 mg/m²/d on the daily schedule and had not yet been
reached at 220 mg/m²/wk on the weekly schedule.
Preliminary pharmacokinetics analysis showed little or no accumulation with
either the daily or weekly dosing schedule. Dr. Hidalgo said the elimination
half-life was 30 hours in the US trial and 17 to 20 hours in the European
trial. "There is a long elimination half-life, but much of the drug is
bound to red blood cells and so is not available for distribution to the
tumor," he said.
In general, Dr. Hidalgo said, "this was a very well-tolerated
regimen." The most common toxicities included a variety of cutaneous
reactions, asymptomatic hypocalcemia, reversible elevations in liver function
tests, and thrombocytopenia.
There was one partial response on the daily regimen (a patient with
previously treated non-small-cell lung cancer). On the weekly schedule, three
patients had a partial response (patients with previously treated renal cell,
breast, and neuroendocrine cancer). "This is encouraging preliminary
evidence of antitumor activity," he said.