title: Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors.
abstract: OBJECTIVE
  Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy.
  
  
  METHODS
  Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m(2) on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m(2), given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses).
  
  
  RESULTS
  The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m(2) for group I and 1,250/500 mg/m(2) for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA.
  
  
  CONCLUSIONS
  The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m(2).
authors.affiliation: Department of Oncology, Mayo Clinic and Foundation, Rochester, MN 55905, USA. adjei.alex@mayo.edu
authors.forename: A A
authors.initials: AA
authors.lastname: Adjei
authors.forename: C
authors.initials: C
authors.lastname: Erlichman
authors.forename: J A
authors.initials: JA
authors.lastname: Sloan
authors.forename: J M
authors.initials: JM
authors.lastname: Reid
authors.forename: H C
authors.initials: HC
authors.lastname: Pitot
authors.forename: R M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: P
authors.initials: P
authors.lastname: Peethambaram
authors.forename: P
authors.initials: P
authors.lastname: Atherton
authors.forename: L J
authors.initials: LJ
authors.lastname: Hanson
authors.forename: S R
authors.initials: SR
authors.lastname: Alberts
authors.forename: J
authors.initials: J
authors.lastname: Jett
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D005260:Female; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005971:Glutamates / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006147:Guanine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000068437:Pemetrexed; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D005493:Folic Acid Antagonists; D005971:Glutamates; D000068437:Pemetrexed; D003841:Deoxycytidine; D006147:Guanine; D000093542:Gemcitabine