title: Phase I study of intermittent and chronomodulated oral therapy with capecitabine in patients with advanced and/or metastatic cancer.
abstract: BACKGROUND
  The combination of capecitabine and gemcitabine at Fixed Dose Rate (FDR) has been demonstrated to be well tolerated, with apparent efficacy in patients with advanced cancers. FDR gemcitabine infusion leads to enhanced intracellular accumulation of drug and possible augmented clinical effect. The goals of this phase I study were to determine the maximum-tolerated dose (MTD) of chronomodulated capecitabine in patients with advanced cancer and to describe the dose-limiting toxicities (DLT), the safety profile of this way of administration.
  
  
  METHODS
  Patients with advanced solid tumours who had failed to response to standard therapy or for whom no standard therapy was available were eligible for this study. Capecitabine was administered orally according to following schedule: 1/4 of dose at 8:00 a.m.; 1/4 of dose at 6:00 p.m. and 1/2 of dose at 11:00 p.m. each day for 14 consecutive days, followed by a 7-day rest period.
  
  
  RESULTS
  All 27 patients enrolled onto the study were assessable for toxicity. The most common toxicities during the first two cycles of chemotherapy were fatigue, diarrhoea and hand foot syndrome (HFS). Only one out of the nine patients treated at capecitabine dose of 2,750 mg/m2 met protocol-specified DLT criteria (fatigue grade 4). However, at these doses the majority of cycles of therapy were delivered without dose reduction or delay. No other episodes of DLT were observed at the same dose steps and at the lower dose steps of capecitabine (1,500/1,750/2,000/2,250/2,500 mg/m2). The dose of 2,750 mg/m2 is recommended for further study. Tumor responses were observed in patients with metastatic breast and colorectal cancer.
  
  
  CONCLUSIONS
  High doses of chronomodulated capecitabine can be administered with acceptable toxicity. The evidence of antitumor activity deserves further investigation in phase II combination chemotherapy studies.
authors.affiliation: Medical Oncology, University Campus Bio-Medico, Rome, Italy. d.santini@unicampus.it
authors.forename: Daniele
authors.initials: D
authors.lastname: Santini
authors.forename: Bruno
authors.initials: B
authors.lastname: Vincenzi
authors.forename: Gaia
authors.initials: G
authors.lastname: Schiavon
authors.forename: Annalisa
authors.initials: A
authors.lastname: La Cesa
authors.forename: Simona
authors.initials: S
authors.lastname: Gasparro
authors.forename: Angelo
authors.initials: A
authors.lastname: Vincenzi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tonini
mesh_terms: D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms / Q000188:drug therapy*; D000069287:Capecitabine; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000031:analogs & derivatives; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism; D013997:Time Factors; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil; D000093542:Gemcitabine