Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia.

Abstract

PURPOSE:

To investigate the toxicity profile, activity, and pharmacokinetics of a novel L-nucleoside analog, troxacitabine (BCH-4556), in patients with advanced leukemia.

PATIENTS AND METHODS:

Patients with refractory or relapsed acute myeloid (AML) or lymphocytic (ALL) leukemia, myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP). Troxacitabine was given as an intravenous infusion over 30 minutes daily for 5 days. The starting dose was 0.72 mg/m(2)/d (3.6 mg/m(2)/course). Courses were given every 3 to 4 weeks according to toxicity and antileukemic efficacy. The dose was escalated by 50% until grade 2 toxicity was observed, and then by 30% to 35% until the dose-limiting toxicity (DLT) was defined.

RESULTS:

Forty-two patients (AML: 31 patients; MDS: six patients [five MDS + one CMML]; ALL: four patients; CML-BP: one patient) were treated. Median age was 61 years (range, 23 to 79 years), and 29 patients were males. Stomatitis and hand-foot syndrome were the DLTs. The MTD was defined as 8 mg/m(2)/d. The pharmacokinetic behavior of troxacitabine is linear over the dose range of 0.72 to 10.0 m/m(2). Approximately 69% of troxacitabine was excreted as unchanged drug in the urine. Marrow hypoplasia occurred between days 14 and 28 in 73% of AML patients. Three complete remissions and one partial remission were observed in 30 assessable AML patients. One MDS patient achieved a hematologic improvement. A patient with CML-BP achieved a return to chronic phase disease.

CONCLUSION:

Troxacitabine has a unique metabolic and pharmacokinetic profile and significant antileukemic activity. DLTs were stomatitis and hand-foot syndrome. Troxacitabine merits further study in hematologic malignancies.

• Authors: F J Giles, J E Cortes, S D Baker, D A Thomas, S O'Brien, T L Smith, M Beran, C Bivins, J Jolivet, H M Kantarjian
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 19 Issue 3 Pg. 762-71 (Feb 01 2001) ISSN: 0732-183X [Print] United States
• PMID: 11157029 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article)

Chemical References

• Antineoplastic Agents
• Dioxolanes
• troxacitabine
• Cytosine

Topics

• Acute Disease
• Adult
• Aged
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Blast Crisis (drug therapy, metabolism)
• Cytosine (adverse effects, analogs & derivatives, pharmacokinetics, therapeutic use)
• Dioxolanes (adverse effects, pharmacokinetics, therapeutic use)
• Dose-Response Relationship, Drug
• Female
• Humans
• Leukemia (drug therapy, metabolism)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy, metabolism, pathology)
• Leukemia, Myeloid (drug therapy, metabolism)
• Male
• Middle Aged
• Myelodysplastic Syndromes (drug therapy, metabolism)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, metabolism)