title: Phase 1/2 trial of BMS-275291 in patients with human immunodeficiency virus-related Kaposi sarcoma: a multicenter trial of the AIDS Malignancy Consortium.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) are overexpressed in Kaposi sarcoma (KS). The safety and efficacy of a novel, orally bioavailable MMP inhibitor, BMS-275291, was evaluated in patients with human immunodeficiency virus-associated KS and the correlation between changes in the percentage of apoptotic cells in tumor biopsies and response was explored.
  
  
  METHODS
  Cohorts of 6 patients were to be treated with BMS-275291. The initial cohort received 1200 mg once a day; subsequent doses were to be escalated to 600 mg twice daily and 1200 mg twice daily, or decreased to 600 mg/day. Tumor biopsies for apoptosis assays were collected pretreatment and on Day 29. Prospectively defined dose level adjustments were to be based on dose-limiting toxicity (DLT), tolerability, changes in the percentage of apoptotic cells, and treatment response.
  
  
  RESULTS
  Sixteen patients were enrolled; 15 received the study drug and could be evaluated. The median duration of treatment was 20 weeks (range, 3-54 weeks). A dose of 1200 mg once a day was well tolerated but induced only 1 response. A DLT occurred in 3 patients treated with 600 mg twice daily, and included grade 3 fatigue, grade 3 allergic reaction, and grade 3 arthralgias; 2 responses were noted at this dose level (toxicity was graded according to the National Cancer Institute Common Toxicity Criteria [version 2.0]). Based on predetermined endpoints, the trial was closed after accrual of 15 treated patients. Assessment of biologic response for dose escalation/de-escalation decisions utilizing the apoptosis assay was not feasible.
  
  
  CONCLUSIONS
  BMS-275291 given at a dose of 600 mg twice daily induced unacceptable toxicity. The better-tolerated schedule of 1200 mg once a day demonstrated inadequate efficacy in patients with human immunodeficiency virus-associated KS. The apoptosis assay was not helpful in predicting response.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University and the Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA.
authors.forename: Brett T
authors.initials: BT
authors.lastname: Brinker
authors.forename: Susan E
authors.initials: SE
authors.lastname: Krown
authors.forename: Jeannette Y
authors.initials: JY
authors.lastname: Lee
authors.forename: Ethel
authors.initials: E
authors.lastname: Cesarman
authors.forename: Amy
authors.initials: A
authors.lastname: Chadburn
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Kaplan
authors.forename: David H
authors.initials: DH
authors.lastname: Henry
authors.forename: Jamie H
authors.initials: JH
authors.lastname: Von Roenn
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000150:complications*; D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D012514:Sarcoma, Kaposi / Q000150:complications* / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; C422302:N-((2S)-2-mercapto-1-oxo-4-(3,4,4- trimethyl-2,5-dioxo-1-imidazolidinyl)butyl)-L-leucyl-N,3- dimethyl-L-Valinamide