title: Phase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced solid tumors.
abstract: BACKGROUND
  Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on proteasome inhibition by bortezomib in whole blood was also investigated.
  
  
  METHODS
  Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30-minute infusion) on Days 1 and 8 of a 21-day cycle. Groups of > or =3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/m(2) to 1000 mg/m(2) with bortezomib 1.0 mg/m(2) to 1.5 mg/m(2) were planned.
  
  
  RESULTS
  There were no DLTs in patients receiving bortezomib 1.0 mg/m(2) and gemcitabine 500 mg/m(2) to 1000 mg/m(2) in the first 3 dose levels. Dose-limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose level 4 (bortezomib 1.3 mg/m(2), gemcitabine 800 mg/m(2)), establishing bortezomib 1.0 mg/m(2) and gemcitabine 1000 mg/m(2) as the MTD. Most common Grade > or =3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients), and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7 achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration.
  
  
  CONCLUSIONS
  Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA. dpryan@partners.org
authors.forename: David P
authors.initials: DP
authors.lastname: Ryan
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Appleman
authors.forename: Thomas
authors.initials: T
authors.lastname: Lynch
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Fidias
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Clark
authors.forename: Mayer
authors.initials: M
authors.lastname: Fishman
authors.forename: Andrew X
authors.initials: AX
authors.lastname: Zhu
authors.forename: Peter C
authors.initials: PC
authors.lastname: Enzinger
authors.forename: Oscar
authors.initials: O
authors.lastname: Kashala
authors.forename: James
authors.initials: J
authors.lastname: Cusack
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Eder
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D003841:Deoxycytidine; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D000093542:Gemcitabine