title: Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors.
abstract: OBJECTIVE
  Imatinib mesylate (Gleevec; Novartis, East Hanover, NJ)is a receptor tyrosine kinase inhibitor approved previously in 2001 by the United States Food and Drug Administration for the treatment of chronic myelogenous leukemia in blast crisis, accelerated phase, or in chronic phase after failure of IFN-alpha therapy. We review herein the clinical profile of this drug and the regulatory review leading to the approval of a supplemental New Drug Application for the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors (GISTs).
  
  
  METHODS
  We discuss the efficacy and side effects of imatinib mesylate in a Phase II trial of 147 patients with metastatic and/or unresectable malignant GISTs, the basis for marketing approval, and postmarketing commitments by the drug's manufacturer.
  
  
  RESULTS
  Imatinib was assessed in a single, open-label trial involving one European center and three centers in the United States. Seventy-three patients were randomly allocated to receive 400 mg of imatinib daily, and 74 patients received 600 mg daily. At the study report cutoff date, an objective response was confirmed in 56 patients; the overall response rate for the combined study arms was 38% (95% confidence interval, 30-46%). These responses were all partial responses. There was no statistically significant difference in response rates between the two dose groups. Adverse events included edema, fluid retention, nausea, vomiting, diarrhea, myalgias, skin rash, bone marrow suppression, bleeding, and elevations in aspartate aminotransferase, alanine aminotransferase, or bilirubin. Bleeding into the gastrointestinal tract or intratumoral sites occurred in 7 patients (5%) and was not correlated with thrombocytopenia or tumor bulk. The pharmacokinetics of imatinib in GIST patients were similar to those of chronic myelogenous leukemia patients.
  
  
  CONCLUSIONS
  On February 1, 2001, imatinib mesylate was approved by the United States Food and Drug Administration for the treatment of malignant metastatic and/or unresectable GISTs. The recommended dose is 400 or 600 mg daily.
authors.affiliation: Division of Oncology Drug Products, United States Food and Drug Administration, Rockville, Maryland 20857, USA. dagherr@cder.fda.gov
authors.forename: Ramzi
authors.initials: R
authors.lastname: Dagher
authors.forename: Martin
authors.initials: M
authors.lastname: Cohen
authors.forename: Gene
authors.initials: G
authors.lastname: Williams
authors.forename: Mark
authors.initials: M
authors.lastname: Rothmann
authors.forename: Jogarao
authors.initials: J
authors.lastname: Gobburu
authors.forename: Gabriel
authors.initials: G
authors.lastname: Robbie
authors.forename: Atiqur
authors.initials: A
authors.lastname: Rahman
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Ann
authors.initials: A
authors.lastname: Staten
authors.forename: Donna
authors.initials: D
authors.lastname: Griebel
authors.forename: Richard
authors.initials: R
authors.lastname: Pazdur
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001549:Benzamides; D017277:Drug Approval; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D012074:Remission Induction; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D014018:Tissue Distribution; D016896:Treatment Outcome; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit