title: Angiogenesis inhibitor IM862 is ineffective against AIDS-Kaposi's sarcoma in a phase III trial, but demonstrates sustained, potent effect of highly active antiretroviral therapy: from the AIDS Malignancy Consortium and IM862 Study Team.
abstract: OBJECTIVE
  IM862 is a synthetic dipeptide (L-glutamine L-tryptophan) with in vitro and in vivo antiangiogenic properties. Phase I/II studies showed minimal toxicity and a response rate of 36% in AIDS-Kaposi's sarcoma. We report a 24-week, randomized, double-blinded, placebo-controlled phase III trial with the phase II dose, 5 mg intranasally every other day.
  
  
  METHODS
  Two hundred two HIV-positive patients were enrolled, 104 on IM862 and 98 on placebo.
  
  
  RESULTS
  Baseline characteristics were comparable except current antiretroviral therapy: 88% versus 96% (IM862 v placebo group; P = .042). The median treatment durations were 19.5 versus 24 weeks (IM862 v placebo). No significant difference was detected in response rate (IM862, 23%; 95% CI, 15% to 32% v placebo, 21%; 95% CI, 14% to 31%; P = .46), time to response (8.5 weeks v 14 weeks; P = .024), or duration of response. However, IM862 was associated with both a shorter time to response (8.5 weeks v 14 weeks; P = .024) and shorter median time to progression (16 weeks, 95% CI, 13 to 27 weeks v 35 weeks, 95% CI, 26 to 114 weeks; P = .012).
  
  
  CONCLUSIONS
  Despite promising phase I and phase II studies, IM862 5 mg every other day was not superior to placebo and may accelerate time to progression. Highly active antiretroviral therapy alone was associated with a substantial rate of sustained tumor response and may have contributed to prior estimates of IM862 response. Therapeutic trials for AIDS-Kaposi's sarcoma must account for ongoing immune reconstitution in the setting of concurrent highly active antiretroviral therapy that may confound estimates of therapeutic activity.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA. noya@mskcc.org
authors.forename: Ariela
authors.initials: A
authors.lastname: Noy
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Jeannette
authors.initials: J
authors.lastname: Lee
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Dezube
authors.forename: David
authors.initials: D
authors.lastname: Aboulafia
authors.forename: Anil
authors.initials: A
authors.lastname: Tulpule
authors.forename: Sharon
authors.initials: S
authors.lastname: Walmsley
authors.forename: Parkash
authors.initials: P
authors.lastname: Gill
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy*; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000281:Administration, Intranasal; D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004151:Dipeptides / Q000008:administration & dosage / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D012074:Remission Induction; D012514:Sarcoma, Kaposi / Q000188:drug therapy*; D012646:Self Administration; D019562:Viral Load
chemical_list: D020533:Angiogenesis Inhibitors; D019380:Anti-HIV Agents; D004151:Dipeptides; D010919:Placebos; C060736:thymogen