title: A phase I and pharmacologic study of weekly gemcitabine in combination with infusional 5-fluorodeoxyuridine and oral calcium leucovorin.
abstract: OBJECTIVE
  Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2'-deoxyuridine (FUDR), we studied this combination in a phase I trial.
  
  
  METHODS
  Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity.
  
  
  RESULTS
  During cycle 1, six of eight patients who received 150 or 100 mg/m2 over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m2 over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m2 over 1 h, 7 did not complete cycle 1 due to thrombocytopenia (n=6) or diarrhea (n=1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5-19.5 mg/m2 over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 micro M (24 h), 16.3 micro M (2 h), and 31.9 micro M (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion.
  
  
  CONCLUSIONS
  Gemcitabine 100-150 mg/m2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800-1000 mg/m2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses.
authors.affiliation: National Cancer Institute-Navy Medical Oncology, National Naval Medical Center, Bethesda, MD 20889, USA. gremj@mail.nih.gov
authors.forename: Jean L
authors.initials: JL
authors.lastname: Grem
authors.forename: Mary G
authors.initials: MG
authors.lastname: Quinn
authors.forename: Bruce
authors.initials: B
authors.lastname: Keith
authors.forename: Brian P
authors.initials: BP
authors.lastname: Monahan
authors.forename: J Michael
authors.initials: JM
authors.lastname: Hamilton
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Nancy
authors.initials: N
authors.lastname: Harold
authors.forename: Dat
authors.initials: D
authors.lastname: Nguyen
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Anthony
authors.initials: A
authors.lastname: Rowedder
authors.forename: Janet
authors.initials: J
authors.lastname: Pang
authors.forename: Geraldine
authors.initials: G
authors.lastname: Morrison
authors.forename: Alice
authors.initials: A
authors.lastname: Chen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005260:Female; D005467:Floxuridine / Q000008:administration & dosage; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009503:Neutropenia / Q000139:chemically induced; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors; D013921:Thrombocytopenia / Q000139:chemically induced; D000093542:Gemcitabine
chemical_list: D005467:Floxuridine; D003841:Deoxycytidine; D012264:Ribonucleotide Reductases; D002955:Leucovorin; D000093542:Gemcitabine