title: Imatinib mesylate for targeting the platelet-derived growth factor beta receptor in combination with fluorouracil and leucovorin in patients with refractory pancreatic, bile duct, colorectal, or gastric cancer--a dose-escalation Phase I trial.
abstract: BACKGROUND
  In previous experimental models, because of its ability to inhibit the activity of platelet-derived growth factor beta receptor, imatinib decreased the interstitial fluid pressure and improved the delivery and efficacy of anticancer drugs, including fluorouracil. The objective of this Phase I study was to define the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of imatinib in combination with fluorouracil and leucovorin in patients with chemotherapy-refractory gastrointestinal cancer.
  
  
  METHODS
  A 3-patient cohort dose-escalating study design was used. Patients received leucovorin 200 mg/m2 followed by fluorouracil 2000 mg/m2 as a 24-hour infusion on Days 1 and 2 combined with imatinib on Days -4, -3, -2, -1, 1, 2, 3, and 4. Cycles were repeated every 2 weeks, and the imatinib dose was escalated from 300 mg daily to 700 mg daily in 100-mg steps.
  
  
  RESULTS
  Thirty patients were enrolled at 5 dose levels. Frequent and dose-dependant National Cancer Institute Common Toxicity Criteria grade 1-4 adverse events with suspected relation to the treatment were anemia (43%), nausea (33%), fluid retention (27%), elevated serum gamma-glutamyl-transpeptidase (20%), and diarrhea. DLTs were severe neutropenia, central fluid retention, and severe nausea observed in 1 patient each, resulting in an MTD for imatinib of 600 mg per day. There were no differences in imatinib pharmacokinetics before or during chemotherapy. A minor response was observed; and signs of clinical activity, including the resolution of ascites and improvement in performance status, were noted in some patients.
  
  
  CONCLUSIONS
  The combination of biweekly fluorouracil/leucovorin and imatinib 600 mg daily given in a week-on/week-off schedule was feasible and safe. Nausea and fluid retention represented the DLTs.
authors: Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt am Main, Germany. albatran@aol.com
authors: Salah-Eddin
authors: SE
authors: Al-Batran
authors: Akin
authors: A
authors: Atmaca
authors: Eberhard
authors: E
authors: Schleyer
authors: Claudia
authors: C
authors: Pauligk
authors: Christian
authors: C
authors: Hosius
authors: Gerhard
authors: G
authors: Ehninger
authors: Elke
authors: E
authors: Jäger
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001549:Benzamides; D004067:Digestive System Neoplasms / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D000068877:Imatinib Mesylate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D001549:Benzamides; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D002955:Leucovorin; D005472:Fluorouracil