title: Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer.
abstract: OBJECTIVE
  To determine the dose-limiting toxicity and maximum-tolerated dose of the proteasome inhibitor bortezomib administered intravenously weekly for 4 every 5 weeks; to determine the bortezomib pharmacokinetics and pharmacodynamics using plasma levels and an assay for 20S proteasome inhibition (PI) in whole blood; to correlate toxicity with bortezomib dose and degree of 20S PI; and to conduct a preliminary determination of the antitumor activity of bortezomib in patients with androgen independent prostate cancer (AIPCa).
  
  
  METHODS
  Fifty-three patients (48 with AIPCa) received 128 cycles of bortezomib in doses ranging from 0.13 to 2.0 mg/m(2)/dose, utilizing a careful escalation scheme with a continuous reassessment method. Pharmacokinetic and pharmacodynamic studies were performed in 24 patients (at 1.45 to 2.0 mg/m(2)).
  
  
  RESULTS
  A dose-related 20S PI was seen, with dose-limiting toxicity at 2.0 mg/m(2) (diarrhea, hypotension) occurring at an average 1-hour post-dose of >/= 75% 20S PI. Other side effects were fatigue, hypertension, constipation, nausea, and vomiting. No relationship was seen between body-surface area and bortezomib clearance over the narrow dose range tested. There was evidence of biologic activity (decline in serum prostate-specific antigen and interleukin-6 levels) at >/= 50% 20S PI. Two patients with AIPCa had prostate-specific antigen response and two patients had partial response in lymph nodes.
  
  
  CONCLUSIONS
  The maximum-tolerated dose and recommended phase II dose of bortezomib in this schedule is 1.6 mg/m(2). Biologic activity (inhibition of nuclear factor-kappa B-related markers) and antitumor activity is seen in AIPCa at tolerated doses of bortezomib. This agent should be further explored with chemotherapy agents in advanced prostate cancer.
authors.affiliation: The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 0427, Houston, TX 77030, USA.
authors.forename: Christos N
authors.initials: CN
authors.lastname: Papandreou
authors.forename: Danai D
authors.initials: DD
authors.lastname: Daliani
authors.forename: Darrell
authors.initials: D
authors.lastname: Nix
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.forename: Timothy
authors.initials: T
authors.lastname: Madden
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.forename: Christine S
authors.initials: CS
authors.lastname: Pien
authors.forename: Randall E
authors.initials: RE
authors.lastname: Millikan
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Tu
authors.forename: Lance
authors.initials: L
authors.lastname: Pagliaro
authors.forename: Jeri
authors.initials: J
authors.lastname: Kim
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Peter
authors.initials: P
authors.lastname: Elliott
authors.forename: Dixie
authors.initials: D
authors.lastname: Esseltine
authors.forename: Alexandria
authors.initials: A
authors.lastname: Petrusich
authors.forename: Pauline
authors.initials: P
authors.lastname: Dieringer
authors.forename: Cherie
authors.initials: C
authors.lastname: Perez
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Logothetis
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001897:Boronic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000069286:Bortezomib; D003546:Cysteine Endopeptidases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000097:blood; D009369:Neoplasms / Q000188:drug therapy*; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex; D011719:Pyrazines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D018709:Statistics, Nonparametric
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex