Phase I study of troxacitabine administered by continuous infusion in subjects with advanced solid malignancies.
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.
Jimeno
A
A
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Messersmith
W A
WA
Lee
C K
CK
Ma
W W
WW
Laheru
D
D
Donehower
R C
RC
Baker
S D
SD
Hidalgo
M
M
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
D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine