title: Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.
abstract: OBJECTIVE
  To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacodynamics (PD) of the proteasome inhibitor bortezomib (previously known as PS-341) in patients with refractory hematologic malignancies.
  
  
  METHODS
  Patients received PS-341 twice weekly for 4 weeks at either 0.40, 1.04, 1.20, or 1.38 mg/m(2), followed by a 2-week rest. The PD of PS-341 was evaluated by measurement of whole blood 20S proteasome activity.
  
  
  RESULTS
  Twenty-seven patients received 293 doses of PS-341, including 24 complete cycles. DLTs at doses above the 1.04-mg/m(2) MTD attributed to PS-341 included thrombocytopenia, hyponatremia, hypokalemia, fatigue, and malaise. In three of 10 patients receiving additional therapy, serious reversible adverse events appeared during cycle 2, including one episode of postural hypotension, one systemic hypersensitivity reaction, and grade 4 transaminitis in a patient with hepatitis C and a substantial acetaminophen ingestion. PD studies revealed PS-341 induced 20S proteasome inhibition in a time-dependent manner, and this inhibition was also related to both the dose in milligrams per meter squared, and the absolute dose of PS-341. Among nine fully assessable patients with heavily pretreated plasma cell dyscrasias completing one cycle of therapy, there was one complete response and a reduction in paraprotein levels and/or marrow plasmacytosis in eight others. In addition, one patient with mantle cell lymphoma and another with follicular lymphoma had shrinkage of nodal disease.
  
  
  CONCLUSIONS
  PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations.
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Medicine, University of North Carolina at Chapel Hill, 27599-7295, USA. r_orlowski@med.unc.edu
authors.forename: Robert Z
authors.initials: RZ
authors.lastname: Orlowski
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Stinchcombe
authors.forename: Beverly S
authors.initials: BS
authors.lastname: Mitchell
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Shea
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
authors.forename: Stephanie
authors.initials: S
authors.lastname: Stahl
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Dixie-Lee
authors.initials: DL
authors.lastname: Esseltine
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Elliott
authors.forename: Christine S
authors.initials: CS
authors.lastname: Pien
authors.forename: Roberto
authors.initials: R
authors.lastname: Guerciolini
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Anderson
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Depcik-Smith
authors.forename: Rita
authors.initials: R
authors.lastname: Bhagat
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Lehman
authors.forename: Steven C
authors.initials: SC
authors.lastname: Novick
authors.forename: Owen A
authors.initials: OA
authors.lastname: O'Connor
authors.forename: Steven L
authors.initials: SL
authors.lastname: Soignet
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D016896:Treatment Outcome; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex