title: A phase I trial of the novel proteasome inhibitor PS341 in advanced solid tumor malignancies.
abstract: OBJECTIVE
  The purpose of this study was to evaluate the toxicity and pharmacodynamic behavior of the novel proteasome inhibitor PS341 administered as a twice weekly i.v. bolus for 2 weeks, followed by a 1-week recovery period in patients with advanced solid tumor malignancies.
  
  
  METHODS
  In this Phase I trial, 43 patients were treated with PS341 in doses ranging from 0.13 to 1.56 mg/m2/dose. A standard Phase I design was used. Pharmacodynamic studies were performed to access 20S proteasome activity.
  
  
  RESULTS
  Forty-three patients were treated with 89 cycles of PS341. Patients were heavily pretreated. Dose-limiting toxicities on this schedule were diarrhea and sensory neurotoxicity. Other side effects seen were fatigue, fever, anorexia, nausea, vomiting, rash, pruritus, and headache. There was no dose-limiting hematological toxicity. A dose-related inhibition of 20S proteasome activity with increasing dose of PS341 was seen. There was one major response in a patient with refractory non-small cell lung carcinoma.
  
  
  CONCLUSIONS
  Given the results of this trial, it is safe and reasonable to recommend treatment with PS341 on the schedule used in this trial at 1.56 mg/m2/dose in Phase II trials. Particular care should be taken with patients with preexisting neuropathy. Further testing in Phase II trials is warranted.
authors.affiliation: The Developmental Chemotherapy Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. aghajanc@mskcc.org
authors.forename: Carol
authors.initials: C
authors.lastname: Aghajanian
authors.forename: Steven
authors.initials: S
authors.lastname: Soignet
authors.forename: Don S
authors.initials: DS
authors.lastname: Dizon
authors.forename: Christine S
authors.initials: CS
authors.lastname: Pien
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Elliott
authors.forename: Paul
authors.initials: P
authors.lastname: Sabbatini
authors.forename: Vincent
authors.initials: V
authors.lastname: Miller
authors.forename: Martee L
authors.initials: ML
authors.lastname: Hensley
authors.forename: Sandra
authors.initials: S
authors.lastname: Pezzulli
authors.forename: Christina
authors.initials: C
authors.lastname: Canales
authors.forename: Adil
authors.initials: A
authors.lastname: Daud
authors.forename: David R
authors.initials: DR
authors.lastname: Spriggs
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D001897:Boronic Acids / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D000069286:Bortezomib; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000493:pharmacokinetics* / Q000627:therapeutic use* / Q000633:toxicity; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D009097:Multienzyme Complexes; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex