NEW YORKMarrow 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 agents 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, its 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,
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
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 drugs 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.