title: Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies.
abstract: BACKGROUND
  TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships.
  
  
  RESULTS
  Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity.
  
  
  CONCLUSIONS
  The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Hammond-Thelin
authors.forename: Melanie B
authors.initials: MB
authors.lastname: Thomas
authors.forename: Michiko
authors.initials: M
authors.lastname: Iwasaki
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lassere
authors.forename: Christina A
authors.initials: CA
authors.lastname: Meyers
authors.forename: Paulo
authors.initials: P
authors.lastname: Hoff
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.forename: Jody
authors.initials: J
authors.lastname: Norris
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Matsushita
authors.forename: Akira
authors.initials: A
authors.lastname: Mita
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D001711:Biotransformation; D003562:Cytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D005240:Feasibility Studies; D005260:Female; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D020714:Maximum Tolerated Dose; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D012318:RNA Polymerase I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012320:RNA Polymerase III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013781:Texas; D016896:Treatment Outcome
chemical_list: C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D003562:Cytidine; D012319:RNA Polymerase II; D012318:RNA Polymerase I; D012320:RNA Polymerase III