title: Phase I and pharmacokinetic study of the oral fluoropyrimidine capecitabine in combination with paclitaxel in patients with advanced solid malignancies.
abstract: OBJECTIVE
  To evaluate the feasibility of administering the oral fluoropyrimidine capecitabine in combination with paclitaxel, to characterize the principal toxicities of the combination, to recommend doses for subsequent disease-directed studies, and to determine whether significant pharmacokinetic interactions occur between these agents when combined.
  
  
  METHODS
  Sixty-six courses of capecitabine and paclitaxel were administered to 17 patients in a two-stage dose-escalation study. Paclitaxel was administered as a 3-hour intravenous (IV) infusion every 3 weeks, and capecitabine was administered continuously as two divided daily doses. During stage I, capecitabine was escalated to a target dose of 1,657 mg/m(2)/d, whereas the paclitaxel dose was fixed at 135 mg/m(2). In stage II, paclitaxel was increased to a target dose of 175 mg/m(2), and the capecitabine dose was the maximum established in stage I. Pharmacokinetics were characterized for each drug when given alone and concurrently.
  
  
  RESULTS
  Myelosuppression, predominately neutropenia, was the principal dose-limiting toxicity (DLT). Other toxicities included hand-foot syndrome, diarrhea, hyperbilirubinemia, skin rash, myalgia, and arthralgia. Two patients treated with capecitabine 1,657 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs, whereas none of six patients treated with capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2) developed DLTs during course 1. Pharmacokinetic studies indicated that capecitabine and paclitaxel did not affect the pharmacokinetic behavior of each other. No major antitumor responses were noted.
  
  
  CONCLUSIONS
  Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2)/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.
authors.affiliation: Institute for Drug Development, Cancer Therapy and Research Center, and The University of Texas Health Science Center at San Antonio, TX, USA. villanova-1@medctr.osu.edu
authors.forename: M A
authors.initials: MA
authors.lastname: Villalona-Calero
authors.forename: G R
authors.initials: GR
authors.lastname: Weiss
authors.forename: H A
authors.initials: HA
authors.lastname: Burris
authors.forename: M
authors.initials: M
authors.lastname: Kraynak
authors.forename: G
authors.initials: G
authors.lastname: Rodrigues
authors.forename: R L
authors.initials: RL
authors.lastname: Drengler
authors.forename: S G
authors.initials: SG
authors.lastname: Eckhardt
authors.forename: B
authors.initials: B
authors.lastname: Reigner
authors.forename: J
authors.initials: J
authors.lastname: Moczygemba
authors.forename: H U
authors.initials: HU
authors.lastname: Burger
authors.forename: T
authors.initials: T
authors.lastname: Griffin
authors.forename: D D
authors.initials: DD
authors.lastname: Von Hoff
authors.forename: E K
authors.initials: EK
authors.lastname: Rowinsky
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019540:Area Under Curve; D001663:Bilirubin / Q000097:blood; D000069287:Capecitabine; D015331:Cohort Studies; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced
chemical_list: D003841:Deoxycytidine; D000069287:Capecitabine; D017239:Paclitaxel; D001663:Bilirubin; D005472:Fluorouracil