NEW YORKA novel taxane/fatty acid conjugate designed to increase taxane activity in tumor cells and decrease toxicity has shown promising results in a phase I trial of patients with solid tumors. Ross Donehower, MD, professor of oncology and medicine, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, presented the findings at the Chemotherapy Foundation Symposium XIX (abstract 73).
DHA-paclitaxel (Taxoprexin, Protarga, Inc) is a combination of paclitaxel(Drug information on paclitaxel) conjugated at the active site to docosahexaenoic acid(Drug information on docosahexaenoic acid) (DHA), an essential fatty acid, "which serves, in this concept, as a target vector for tumor cells," Dr. Donehower said.
Tumor cells actively take up and utilize fatty acids, both as membrane precursors and as energy sources, to a greater extent than do noncancer cells. "It’s felt that perhaps this would be a way in which taxanes could be introduced more effectively into the cell," he said.
After preclinical studies provided evidence that DHA-paclitaxel did increase paclitaxel uptake by tumor cells, a phase I trial was initiated at Johns Hopkins. The study enrolled 24 patients with a variety of solid tumors. All 13 men and 11 women had received prior chemotherapy. "We did eliminate patients who had anything more than mild peripheral neuropathy," Dr. Donehower said, "because of the desire to ascertain whether or not DHA-paclitaxel does cause peripheral neuropathy."
The drug was given in a 2-hour infusion every 21 days. Doses escalated from 200 mg/m² to 1,100 mg/m². At an evaluation after the first two cycles of treatment, Dr. Donehower reported, "roughly half the patients were stable or in one case responding." After four cycles of therapy, 6 patients continued to have stable disease. Overall, 10 of 21 evaluable patients achieved stabilization, and 1 had a complete response.
The major and dose-limiting toxicity was neutropenia, Dr. Donehower reported. Of the nine patients who received 1,100 mg/m² DHA-paclitaxel, seven had grade 3-4 febrile neutropenia, he noted. At the next lower dose of 880 mg/m², grade 4 neutropenia was seen in three of the six patients, but only one of these patients became febrile. Nonhematologic toxicity was generally mild.
Pharmacokinetic analyses showed that the volume of distribution of DHA-paclitaxel was "about 1/50th that of paclitaxel," Dr. Donehower reported, "and it circulates in this nontoxic state." The clearance rate, he added, is slow, approximately 1/300th that of paclitaxel. The half-life of the paclitaxel derived from DHA-paclitaxel was about 80 hours, compared with 8 to 10 hours for Taxol.