Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer.
OBJECTIVE
TAS-103 is an inhibitor of both topoisomerase I and II enzymes with broad antitumor activity. It is metabolized to TAS-103-glucuronide (TAS-103-G) predominantly by uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1). We conducted a phase I study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of TAS-103 when administered on a weekly schedule to patients with advanced cancer. In addition, we evaluated the influence of UGT1A1 genotype on the pharmacokinetics and toxicity of TAS-103.


METHODS
Thirty-two patients were treated with escalating doses (50 to 200 mg/m(2)) of TAS-103, administered intravenously over 1 hour each week for 3 weeks. Pharmacokinetic analysis was performed at the 130-, 160-, and 200-mg/m(2) dose levels. UGT1A1 genotypes were determined using reverse-transcription polymerase chain reaction techniques.


RESULTS
DLT (grade 3 neutropenia) was observed in 5 of 12 patients at 160 mg/m(2) and in 3 of 6 patients at 200 mg/m(2). At 160 mg/m(2), there was a significant correlation between areas under the curve (AUCs) for TAS-103 and TAS-103-G (r = 0.76, P <.05) and an apparent relationship between TAS-103 AUC and D 15 absolute neutrophil count (r = -0.63, P <.05, n = 11, one outlier excluded). UGT1A1 genotype did not influence clearance of TAS-103.


CONCLUSIONS
We recommend a dose of 130 to 160 mg/m(2), or 250 to 300 mg administered using the above weekly schedule for phase II studies. Further studies to characterize the pharmacodynamics and pharmacogenetics of TAS-103 are warranted.
Ewesuedo
R B
RB
Committee on Clinical Pharmacology, Section of Pediatric Hematology-Oncology, Department of Pediatrics, University of Chicago, IL 60637, USA.
Iyer
L
L
Das
S
S
Koenig
A
A
Mani
S
S
Vogelzang
N J
NJ
Schilsky
R L
RL
Brenckman
W
W
Ratain
M J
MJ
D000328:Adult; D000368:Aged; D000634:Aminoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007192:Indenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010597:Pharmacogenetics; D016879:Salvage Therapy / Q000379:methods*; D059005:Topoisomerase II Inhibitors; D000099148:UGT1A1 Enzyme
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D014453:Glucuronosyltransferase; D007192:Indenes; D059005:Topoisomerase II Inhibitors; D000099148:UGT1A1 Enzyme; C106647:6-((2-(dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno(2,1-c)quinolin-7-one