title: Phase I and pharmacokinetic study of cisplatin and troxacitabine administered intravenously every 28 days in patients with advanced solid malignancies.
abstract: OBJECTIVE
  To assess the feasibility of administering troxacitabine, an L-nucleoside analog that is not a substrate for deoxycytidine deaminase, in combination with cisplatin, to identify pharmacokinetic interactions, and to seek preliminary evidence of antitumor activity.
  
  
  METHODS
  Patients with advanced solid malignancies were treated with cisplatin intravenously over an hour followed by troxacitabine intravenously over 30 min on day 1 every 28 days at the following cisplatin/troxacitabine (mg/m(2)) dose levels 50/4.8, 75/4.8, 50/6.4, 75/6.4, and 75/8.0. Plasma and urine sampling were performed to characterize the pharmacokinetic parameters of troxacitabine in combination with cisplatin.
  
  
  RESULTS
  Thirty-one patients received 77 courses of cisplatin/troxacitabine at five dose levels. Grade 4 neutropenia lasting more than 5 days and/or grade 4 thrombocytopenia were consistently experienced by minimally pretreated (MP) and heavily pretreated (HP) patients at doses exceeding 75/6.4 and 50/4.8 mg/m(2), respectively. Mean values for the volume of distribution at steady state and clearance of troxacitabine were 196-396 L and 7.2-9.8 L/h, respectively. A patient with metastatic non-small cell lung cancer experienced a 42% reduction in extent of disease for 6 months.
  
  
  CONCLUSIONS
  The combination of cisplatin and troxacitabine produces dose-limiting myelosuppression at lower doses of troxacitabine than single agent doses. The recommended phase II doses of cisplatin/troxacitabine are 75/6.4 and 50/4.8 mg/m(2), every 4 weeks, for MP and HP patients, respectively. The addition of cisplatin did not substantially alter the pharmacokinetic behavior of troxacitabine.
authors.affiliation: The Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, TX, USA.
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Lin
authors.forename: Muralidhar
authors.initials: M
authors.lastname: Beeram
authors.forename: Eric K
authors.initials: EK
authors.lastname: Rowinsky
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Chee M
authors.initials: CM
authors.lastname: Ng
authors.forename: Charles E
authors.initials: CE
authors.lastname: Geyer
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Denis
authors.forename: Johann S
authors.initials: JS
authors.lastname: De Bono
authors.forename: Desiree
authors.initials: D
authors.lastname: Hao
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Tolcher
authors.forename: Sun-Young
authors.initials: SY
authors.lastname: Rha
authors.forename: Jacques
authors.initials: J
authors.lastname: Jolivet
authors.forename: Amita
authors.initials: A
authors.lastname: Patnaik
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002945:Cisplatin / Q000008:administration & dosage; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004148:Dioxolanes / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced*; D013921:Thrombocytopenia / Q000139:chemically induced*; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004148:Dioxolanes; C074908:troxacitabine; D003596:Cytosine; D002945:Cisplatin