title: A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors.
abstract: BACKGROUND
  The nucleoside 3'-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors.
  
  
  METHODS
  Patients were enrolled in cohorts of three, starting at 0.22 mg/m(2)/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level.
  
  
  RESULTS
  In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m(2)/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m(2)/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet.
  
  
  CONCLUSIONS
  Due to neurotoxicity the MTD was the 2.64 mg/m(2)/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m(2)/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.
authors.affiliation: College of Medicine, Medical University of South Carolina, Charleston, 20 Cape Flattery Ct, Irmo, SC 29063, USA. fridaybs@gmail.com
authors.forename: Benjamin
authors.initials: B
authors.lastname: Friday
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lassere
authors.forename: Christina A
authors.initials: CA
authors.lastname: Meyers
authors.forename: Akira
authors.initials: A
authors.lastname: Mita
authors.forename: James L
authors.initials: JL
authors.lastname: Abbruzzese
authors.forename: Melanie B
authors.initials: MB
authors.lastname: Thomas
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003562:Cytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*
chemical_list: C103084:1-(3-C-ethynylribopentofuranosyl)cytosine; D000970:Antineoplastic Agents; D003562:Cytidine