New Nucleoside Analog Tested in Refractory Leukemia

NEW YORK—Marrow hypoplasia was achieved within 28 days in 14 of 41 patients with refractory leukemia after a first cycle of a new nucleoside analog, troxacitabine, Francis J. Giles, MD, associate professor of medicine, M.D. Anderson Cancer Center, reported at the Chemotherapy Foundation Symposium XVII.

“Please bear in mind that many of the patients treated on this study had never previously cleared their marrow,” Dr. Giles said. In the phase I trial to determine the agent’s maximum tolerated dose, marrow hypoplasia was defined as too few cells to count or less than 5% cellularity with less than 5% blasts. “We think that, in these patients, if we see a significant incidence of this type of activity, it’s a clue that this may be an active agent,” he said.

In all, 22 of 30 evaluable patients with acute myeloid leukemia (AML) developed some marrow hypoplasia on their first cycle of therapy with troxacitabine, Dr. Giles said. “Over half of those AML patients had primary resistance,” he noted. Other patients in the trial had refractory or relapsed myelodysplastic syndromes, acute lymphocytic leukemia, or chronic myelogenous leukemia in blastic phase.

Three patients with AML had a complete response and one a partial response on their first cycle of troxacitabine, Dr. Giles reported. “The only chronic myelogenous blast phase patient on study returned to chronic phase with a single course of troxacitabine,” he said.

Troxacitabine, which was formerly known as BCH-4556, is being developed by BioChem Pharma (Laval, Quebec). The first dioxolane nucleoside analog to be investigated as an antineoplastic agent, it is a complete DNA chain terminator. “This does not contain a hydroxyl group,” Dr. Giles explained, “so you cannot extend the chain any further once the troxacitabine molecule is integrated.” The agent is also a DNA polymerase inhibitor and is not degraded by cytidine deaminase.

In addition to being tested in leukemia, troxacitabine is being studied in phase II trials in such solid tumors as pancreatic, prostate, colorectal, renal, and non-small-cell lung cancers, and malignant melanoma.

In the M.D. Anderson phase I trial in leukemia patients, the maximum tolerated dose was established at 8 mg/m² daily for 5 days. Dose-limiting adverse effects included grade 3-4 hand foot syndrome, skin rashes, and stomatitis.

Pharmacokinetic analyses in 10 patients in the study showed a biphasic elimination of the metabolite diphosphate with a half-life in the first phase of about 3.5 hours and a half-life in the second phase of more than 20 hours. The drug’s mean terminal half-life was found to be 100 hours.

Dr. Giles is moving toward phase II trials of troxacitabine as a single agent in leukemia patients in conjunction with investigators at the University of Nebraska and the University of Arkansas. “Our particular interest is to pursue combination studies,” he said. “The top three agents we wish to use in combination with troxacitabine are topotecan (Hycamtin), liposomal daunorubicin (DaunoXome), and cytarabine, particularly the latter, as nothing other than a clinical study will exactly define how troxacitabine and cytarabine will interact.”