title: A study of paclitaxel, carboplatin, and bortezomib in the treatment of metastatic malignant melanoma: a phase 2 consortium study.
abstract: BACKGROUND
  Chemotherapy has not been reported to have a significant impact on survival for patients with metastatic melanoma. Bortezomib was shown to have additive/synergistic effects with several chemotherapeutic agents, including paclitaxel and platinum. A phase 1 trial of this 3-drug combination reported that 6 of 28 patients treated with bortezomib followed by paclitaxel and carboplatin achieved a partial response (including 2 of 5 patients with metastatic melanoma).
  
  
  METHODS
  A 2-stage phase 2 clinical trial was conducted to assess the antitumor activity of this 3-agent combination in patients with metastatic melanoma who had received at most 1 prior chemotherapy for metastatic disease. Treatment included bortezomib at a dose of 1.3 mg/m2 intravenously on Days 1, 4, and 8; paclitaxel at a dose of 175 mg/m2; and carboplatin at an area under the concentration (AUC) of 6 on Day 2 of a 21-day cycle. The primary endpoint of this trial was tumor response rate (TRR).
  
  
  RESULTS
  Seventeen eligible patients were enrolled. A median of 4 cycles were administered (range, 1-7 cycles). Three patients discontinued treatment due to persistent grade 4 (based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]) neutropenia with grade 3 leukopenia (2 patients) or grade 4 pulmonary embolism (1 patient). Grade>or=3 toxicities included neutropenia (71%), leukopenia (41%), thrombocytopenia (29%), and arthralgia (12%). Two partial responses were observed (TRR, 11.8%). Four patients had stable disease at >12 weeks. The median progression-free survival was 3.2 months, and the median overall survival was 7.0 months.
  
  
  CONCLUSIONS
  Due to insufficient clinical efficacy, this trial did not proceed to second-stage accrual. The combination of paclitaxel, carboplatin, and bortezomib demonstrated limited clinical benefit and was associated with significant toxicity.
authors.affiliation: Department of Medical Oncology, Melanoma Study Group, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. croghan.gary@mayo.edu
authors.forename: Gary A
authors.initials: GA
authors.lastname: Croghan
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: William J
authors.initials: WJ
authors.lastname: Maples
authors.forename: Mark
authors.initials: M
authors.lastname: Albertini
authors.forename: Gerald
authors.initials: G
authors.lastname: Linette
authors.forename: Lawrence
authors.initials: L
authors.lastname: Flaherty
authors.forename: John
authors.initials: J
authors.lastname: Eckardt
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ma
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D016190:Carboplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000008:administration & dosage; D011719:Pyrazines / Q000008:administration & dosage; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib; D016190:Carboplatin; D017239:Paclitaxel