title: Phase II trial of imatinib in AIDS-associated Kaposi's sarcoma: AIDS Malignancy Consortium Protocol 042.
abstract: OBJECTIVE
  Kaposi's sarcoma (KS) is a disease of multifocal vascular proliferation that requires infection with KS herpes virus (KSHV/HHV-8). Activation of the c-kit and platelet-derived growth factor (PDGF) receptors by autocrine/paracrine mechanisms follows endothelial cell KSHV infection. In a pilot study, imatinib, a c-kit/PDGF-receptor inhibitor, induced partial regression of AIDS-associated KS (AIDS-KS) in five of 10 patients.
  
  
  METHODS
  This multicenter phase II study was designed to estimate the response rate to imatinib in AIDS-KS. Secondary objectives included investigation of predictors of response and imatinib pharmacokinetics in patients on antiretrovirals. Patients received imatinib 400 mg/day by mouth for up to 12 months with dose escalation up to 600 mg/day at 3 months if their disease was stable.
  
  
  RESULTS
  Thirty patients were treated at 12 AIDS Malignancy Consortium sites. Ten patients (33.3%) achieved partial response, six (20%) had stable disease, and seven (23.3%) exhibited KS progression. Nine patients completed 52 weeks of imatinib therapy. The median treatment duration was 22.5 weeks. Only five patients (16.7%) discontinued therapy owing to adverse events. Antiretroviral regimens did not significantly alter imatinib metabolism. Activating mutations in PDGF-R and c-kit were not found at baseline or at disease progression. We found no correlation with response with changes in any of the candidate cytokines.
  
  
  CONCLUSIONS
  Imatinib has activity in AIDS-KS. Pharmacokinetic interactions with antiretroviral drugs did not correlate with toxicity. Thirty percent of patients showed long-term clinical benefit and remained on imatinib for the entire year. These results suggest imatinib is well tolerated and may be an alternative therapy for some patients with AIDS-KS.
authors.affiliation: Henry B. Koon and Zhenghe Wang, Case Comprehensive Cancer Center, Case Western Reserve University; Kord Honda, University Hospitals; Cleveland, OH; Susan E. Krown, Ariela Noy, Memorial Sloan-Kettering Cancer Center, New York, NY; Jeannette Y. Lee, University of Arkansas for Medical Sciences, Little Rock, AR; Suthee Rapisuwon, Georgetown University Medical Center, Washington, DC; David Aboulafia, Virginia Mason Medical Center, Seattle, WA; Erin G. Reid, University of California San Diego Moores Cancer Center, San Diego, CA; Michelle A. Rudek, Johns Hopkins University, Baltimore, MD; Bruce J Dezube, Beth Israel Deaconess Medical Center, Boston, MA.
authors.forename: Henry B
authors.initials: HB
authors.lastname: Koon
authors.forename: Susan E
authors.initials: SE
authors.lastname: Krown
authors.forename: Jeannette Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Kord
authors.initials: K
authors.lastname: Honda
authors.forename: Suthee
authors.initials: S
authors.lastname: Rapisuwon
authors.forename: Zhenghe
authors.initials: Z
authors.lastname: Wang
authors.forename: David
authors.initials: D
authors.lastname: Aboulafia
authors.forename: Erin G
authors.initials: EG
authors.lastname: Reid
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Dezube
authors.forename: Ariela
authors.initials: A
authors.lastname: Noy
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D018450:Disease Progression; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D010865:Pilot Projects; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D001549:Benzamides; D016207:Cytokines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020797:Receptor, Platelet-Derived Growth Factor beta