title: A phase I pharmacodynamic trial of bortezomib in combination with doxorubicin in patients with advanced cancer.
abstract: OBJECTIVE
  This phase I trial sought to define the toxicity, maximally tolerated dose (MTD) and pharmacodynamics of a combination of bortezomib and doxorubicin in patients with advanced malignancies.
  
  
  METHODS
  Twenty-six patients were treated with bortezomib intravenously on days 1, 4, 8 and 11, with doxorubicin also administered intravenously on days 1 and 8, both in a 21-day cycle. Dosing ranged from 1.0 mg/m(2) of bortezomib with 15 mg/m(2) of doxorubicin to 1.5 mg/m(2) of bortezomib with 20 mg/m(2) of doxorubicin. Pharmacodynamic studies performed included assessment of levels of 20S proteasome activity and ubiquitin-protein conjugates.
  
  
  RESULTS
  The combination of bortezomib and doxorubicin was generally well tolerated. There were two dose limiting toxicities (DLT) at dose cohort 3 (1.3 mg/m(2) bortezomib, 20 mg/m(2) doxorubicin) and 2 DLT at dose cohort 3a (1.5 mg/m(2) bortezomib, 15 mg/m(2) doxorubicin). DLT seen included neutropenia, thrombocytopenia, and neuropathy. In addition, one patient developed grade 3 central nervous system toxicity in cycle 2 (not a DLT). One patient with hormone refractory prostate cancer had a partial response. Proteasome inhibition in whole blood was demonstrated and an increase in ubiquitin-protein conjugates was observed in peripheral blood mononuclear cells of most patients.
  
  
  CONCLUSIONS
  Bortezomib and doxorubicin can be administered safely. The recommended phase II dose for this 21-day cycle is bortezomib 1.3 mg/m(2 )intravenously on days 1, 4, 8 and 11, and doxorubicin 20 mg/m(2) intravenously on days 1 and 8. This combination may be of special interest in multiple myeloma, given the activity of both drugs in that disease.
authors.affiliation: University of Wisconsin Paul P Carbone Comprehensive Cancer Center, K4/548 CSC, Madison, WI 53792, USA. ns3@medicine.wisc.edu
authors.forename: Noelle K
authors.initials: NK
authors.lastname: LoConte
authors.forename: James P
authors.initials: JP
authors.lastname: Thomas
authors.forename: Dona
authors.initials: D
authors.lastname: Alberti
authors.forename: Jennifer
authors.initials: J
authors.lastname: Heideman
authors.forename: Kimberly
authors.initials: K
authors.lastname: Binger
authors.forename: Rebecca
authors.initials: R
authors.lastname: Marnocha
authors.forename: Kyle
authors.initials: K
authors.lastname: Utecht
authors.forename: Peter
authors.initials: P
authors.lastname: Geiger
authors.forename: Jens
authors.initials: J
authors.lastname: Eickhoff
authors.forename: George
authors.initials: G
authors.lastname: Wilding
authors.forename: Jill
authors.initials: J
authors.lastname: Kolesar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000069286:Bortezomib; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D016879:Salvage Therapy; D016896:Treatment Outcome; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D001897:Boronic Acids; D009363:Neoplasm Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D004317:Doxorubicin