phase I and pharmacokinetics |
Phase I study of troxacitabine administered by continuous infusion in subjects with advanced solid malignancies
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
* Correspondence to: Dr M. Hidalgo, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 1M89, Baltimore, 21231 MD, USA. Tel: +1-410-502-3543; Fax: +1-410-614-9006; E-mail: mhidalg1{at}jhmi.edu
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/m2/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/m2/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/m2 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.
Key words: continuous infusion, PK modeling, troxacitabine
Received for publication September 12, 2007. Revision received October 20, 2007. Revision received November 26, 2007. Accepted for publication November 27, 2007.