title: Phase I/II study of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer.
abstract: OBJECTIVE
  To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent prostate cancer.
  
  
  METHODS
  Two bortezomib doses (1.3 and 1.6 mg/m(2)/dose) in combination with four docetaxel doses (25-40 mg/m(2)/dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in Solid Tumors guidelines.
  
  
  RESULTS
  Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (>or=50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for >or=4 weeks in 14 patients (21%). According to Response Evaluation Criteria in Solid Tumors guidelines, 11% achieved a partial response, and an additional 67% had stable disease. The degree of proteasome inhibition was similar to that reported with single-agent bortezomib. Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred.
  
  
  CONCLUSIONS
  The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m(2) bortezomib plus 40 mg/m(2) docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.
authors.affiliation: Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA. Dreicer@ccf.org
authors.forename: Robert
authors.initials: R
authors.lastname: Dreicer
authors.forename: Daniel
authors.initials: D
authors.lastname: Petrylak
authors.forename: David
authors.initials: D
authors.lastname: Agus
authors.forename: Iain
authors.initials: I
authors.lastname: Webb
authors.forename: Bruce
authors.initials: B
authors.lastname: Roth
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy*; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000097:blood / Q000188:drug therapy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000728:Androgens; D001897:Boronic Acids; D015850:Interleukin-6; D011719:Pyrazines; D043823:Taxoids; D000077143:Docetaxel; D000069286:Bortezomib; D017430:Prostate-Specific Antigen