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 Clinical Oncology.
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.