title: A phase 1 clinical trial of sequential pralatrexate followed by a 48-hour infusion of 5-fluorouracil given every other week in adult patients with solid tumors.
abstract: BACKGROUND
  Pralatrexate (PDX) is an inhibitor of dihydrofolate reductase that was rationally designed to improve cellular uptake and retention of the drug. Preclinical data have shown synergy with the sequential administration of a dihydrofolate reductase inhibitor followed 24 hours later by 5-fluorouracil (5-FU).
  
  
  METHODS
  Twenty-seven patients were enrolled at 1 of 5 PDX dose levels from 75 to 185 mg/m(2) on day 1 followed 24 hours later by 5-FU at a dose of 3000 mg/m(2) /48 hours every 2 weeks with folic acid and vitamin B12 supplementation. Baseline blood was collected for pharmacogenetic analysis of polymorphisms of methylenetetrahydrofolate reductase and thymidylate synthase.
  
  
  RESULTS
  Mucositis was the most common dose-limiting toxicity. When the worst toxicities across all cycles were considered, grade 3 to 4 neutropenia, anemia, and thrombocytopenia were found to have occurred in 14.8%, 14.8%, and 0% of patients, respectively. Grade 2 to 3 toxicities included mucositis (66.6%), dehydration (33.3%), fatigue (25.9%), and diarrhea (22.2%). Version 3.0 of the National Cancer Institute Common Toxicity Criteria was used to grade toxicities The median progression-free survival (PFS) was 112 days (range, 28-588 days). Seven patients (26%) had a PFS of >180 days (5 patients with colorectal cancer, 1 patient with pancreatic cancer, and 1 patient with non-small cell lung cancer). Polymorphisms in methylenetetrahydrofolate reductase and thymidylate synthase did not correlate with toxicity.
  
  
  CONCLUSIONS
  The recommended dose of PDX was 148 mg/m(2) . A subset of heavily pretreated patients had PFS durations of ≥6 months with this regimen.
authors.affiliation: Section of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Jean L
authors.initials: JL
authors.lastname: Grem
authors.affiliation: Early Clinical Trials Unit, Eppley Cancer Institute, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Kos
authors.affiliation: Section of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Ruby E
authors.initials: RE
authors.lastname: Evande
authors.affiliation: Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Meza
authors.affiliation: Section of Oncology/Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.
authors.forename: James K
authors.initials: JK
authors.lastname: Schwarz
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000630:Aminopterin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000627:therapeutic use*; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy*; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D052016:Mucositis / Q000139:chemically induced / Q000453:epidemiology; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011110:Polymorphism, Genetic / Q000235:genetics; D013762:Tetrahydrofolate Dehydrogenase / Q000097:blood / Q000235:genetics; D013940:Thymidylate Synthase / Q000097:blood / Q000235:genetics; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C418863:10-propargyl-10-deazaaminopterin; D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D013940:Thymidylate Synthase; D000630:Aminopterin; D005472:Fluorouracil
keywords: 5-fluorouracil; antineoplastic antimetabolites; clinical trials; folic acid antagonists; methylenetetrahydrofolate reductase; pharmacogenetics; phase 1; pralatrexate; thymidylate synthase