Phase I study of troxacitabine administered by continuous infusion in subjects with advanced solid malignancies.

Abstract

BACKGROUND:

Troxacitabine is a novel L-nucleoside analogue. Preclinical studies showed improved activity with infusions of at least 3 days compared with bolus regimens, especially at concentrations >20 ng/ml. This phase I study tested the feasibility of achieving a troxacitabine steady-state concentration of 20 ng/ml for at least 72 h in patients with solid tumors.

PATIENTS AND METHODS:

Patients with solid tumors received troxacitabine as a progressively longer infusion on days 1-4 of a 28-day cycle. The initial length of infusion and infusion rate were 48 h and 3 mg/m(2)/day.

RESULTS:

Twenty-one patients were treated at infusion lengths that increased from 48 to 72 h and then 96 h. The infusion rate was decreased from 3 to 1.88 mg/m(2)/day due to toxicity. Dose-limiting toxicities consisted of grade 4 neutropenia (three) and grade 3 constipation (one). The maximum tolerated dose of continuous infusion troxacitabine in patients with solid tumors is 7.5 mg/m(2) administered over 96 h. This dose level resulted in steady-state drug concentration of at least 20 ng/ml for 72 h.

CONCLUSIONS:

Administration of troxacitabine by continuous infusion achieved the prospectively defined target plasma concentration. Pharmacokinetics (PK) modeling coupled with real-time PK assessment was an efficient approach to conduct hypothesis-driven phase I trials.

• Authors: A Jimeno, W A Messersmith, C K Lee, W W Ma, D Laheru, R C Donehower, S D Baker, M Hidalgo
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 19 Issue 2 Pg. 374-9 (Feb 2008) ISSN: 1569-8041 [Electronic] England
• PMID: 18245131 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Dioxolanes
• troxacitabine
• Cytosine

Topics

• Adult
• Aged
• Cytosine (administration & dosage, adverse effects, analogs & derivatives, pharmacokinetics)
• Dioxolanes (administration & dosage, adverse effects, pharmacokinetics)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug-Related Side Effects and Adverse Reactions (etiology)
• Feasibility Studies
• Female
• Follow-Up Studies
• Humans
• Immunohistochemistry
• Infusions, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Invasiveness (pathology)
• Neoplasm Staging
• Neoplasms (drug therapy, mortality, pathology)
• Predictive Value of Tests
• Probability
• Risk Assessment
• Survival Analysis
• Time Factors
• Treatment Outcome