title: 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.
  
  
  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.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Jimeno
authors.forename: W A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: C K
authors.initials: CK
authors.lastname: Lee
authors.forename: W W
authors.initials: WW
authors.lastname: Ma
authors.forename: D
authors.initials: D
authors.lastname: Laheru
authors.forename: R C
authors.initials: RC
authors.lastname: Donehower
authors.forename: S D
authors.initials: SD
authors.lastname: Baker
authors.forename: M
authors.initials: M
authors.lastname: Hidalgo
mesh_terms: D000328:Adult; D000368:Aged; D003596:Cytosine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004148:Dioxolanes / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007262:Infusions, Intravenous; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D011336:Probability; D018570:Risk Assessment; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine