title: The proteasome inhibitor bortezomib in combination with gemcitabine and carboplatin in advanced non-small cell lung cancer: a California Cancer Consortium Phase I study.
abstract: BACKGROUND
  Bortezomib is a small-molecule proteasome inhibitor with single-agent activity in patients with non-small cell lung carcinoma (NSCLC) and synergy with gemcitabine in preclinical studies. The combination of gemcitabine and carboplatin is an accepted first-line treatment for advanced NSCLC. We conducted a phase I study of gemcitabine and carboplatin in combination with bortezomib.
  
  
  METHODS
  Bortezomib was administered on days 1, 4, 8, and 11, after gemcitabine on days 1 and 8, and carboplatin on day 1 of a 21-day cycle. Three escalating dose levels were evaluated: bortezomib 1.0 mg/m2/gemcitabine 800 mg/m2, bortezomib 1.0 mg/m2/gemcitabine 1000 mg/m2, and bortezomib 1.3 mg/m2/gemcitabine 1000 mg/m2, in combination with carboplatin AUC 5.0.
  
  
  RESULTS
  Twenty-six patients with advanced NSCLC were treated; 21 were chemotherapy-naive. The median age was 59 years (range, 34-74), and 23 patients were stage IV. The Karnofsky performance score was <or=80% in 10 and >80% in 16 patients. Dose-limiting toxicities were grade 3 thrombocytopenia with bleeding and febrile neutropenia accompanied by grade 4 thrombocytopenia and grade 3 hyponatremia. The maximum-tolerated dose was defined as bortezomib 1.0 mg/m2, gemcitabine 1000 mg/m2, and carboplatin AUC 5.0. The most common grade 3/4 toxicities were thrombocytopenia (rarely associated with bleeding), and neutropenia. Nine of 26 patients (35%) achieved partial response, and eight patients had stable disease.
  
  
  CONCLUSIONS
  The combination of bortezomib 1.0 mg/m2, gemcitabine 1000 mg/m2, and carboplatin AUC 5.0 demonstrated manageable toxicities and encouraging activity in NSCLC. This regimen was used in a phase II study.
authors.affiliation: Division of Hematology and Oncology, Davis Cancer Center, University of California, Sacramento, California 95817, USA. angela.davies@ucdmc.ucdavis.edu
authors.forename: Angela M
authors.initials: AM
authors.lastname: Davies
authors.forename: Christopher
authors.initials: C
authors.lastname: Ruel
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Derick H
authors.initials: DH
authors.lastname: Lau
authors.forename: Paul H
authors.initials: PH
authors.lastname: Gumerlock
authors.forename: Richard
authors.initials: R
authors.lastname: Bold
authors.forename: Stephen
authors.initials: S
authors.lastname: Shibata
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: David P
authors.initials: DP
authors.lastname: Schenkein
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D002140:California; D016190:Carboplatin / Q000008:administration & dosage / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia / Q000139:chemically induced; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000008:administration & dosage; D013921:Thrombocytopenia / Q000139:chemically induced; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001897:Boronic Acids; D061988:Proteasome Inhibitors; D011719:Pyrazines; D003841:Deoxycytidine; D000069286:Bortezomib; D016190:Carboplatin; D000093542:Gemcitabine