title: A multicenter, phase II study of bortezomib (PS-341) in patients with unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma.
abstract: OBJECTIVE
  The transcription factor nuclear factor-kB (NFkB) is implicated in gastric cancer carcinogenesis and survival, and its inhibition by proteosome inhibition is associated with preclinical gastric cancer anti-tumor activity. We examined the single agent efficacy of bortezomib, a selective proteasome inhibitor, in gastric adenocarcinoma.
  
  
  METHODS
  We performed a phase II trial of bortezomib in patients with advanced gastric adenocarcinoma. Bortezomib 1.3 mg/m(2) was administered on days 1, 4, 8, and 11 every 21 days. The primary endpoint was objective response rate(RR); the null hypothesis was RR <1% versus the alternative ≥15%. One response in the first stage(15 patients) was required before proceeding with an additional 18 patients. If at least 2 or more responses out of 33 were observed, further study with bortezomib was warranted. Correlative studies evaluated pre-treatment tumor expression of NFkB, IkB, p53, p21, and cyclin D1.
  
  
  RESULTS
  We enrolled 16 patients (15 evaluable for response) from four institutions. No patients demonstrated an objective response(95% CI, 0-22%); one patient achieved stable disease. Fourteen out of 16 patients experienced ≥ grade 2 toxicity. The most common toxicity was fatigue in six patients (n = 4 grade 2, n = 2 grade 3). Seven patients experienced neuropathy (n = 5 grade 1, and 1 each grade 2 and 3). Seven (60%) had high cytoplasmic staining for NFkB.
  
  
  CONCLUSIONS
  Single agent bortezomib is inactive in metastatic gastric adenocarcinoma and should not be pursued. Future study of proteasome inhibition in gastric adenocarcinoma should be considered in combination with targeted inhibition of other non-overlapping oncogenic pathways as a potential rational approach.
authors.affiliation: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA. shah1@mskcc.org
authors.forename: Manish A
authors.initials: MA
authors.lastname: Shah
authors.forename: Derek G
authors.initials: DG
authors.lastname: Power
authors.forename: Hedy L
authors.initials: HL
authors.lastname: Kindler
authors.forename: Kyle D
authors.initials: KD
authors.lastname: Holen
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Kemeny
authors.forename: David H
authors.initials: DH
authors.lastname: Ilson
authors.forename: Laura
authors.initials: L
authors.lastname: Tang
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsen
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001897:Boronic Acids / Q000009:adverse effects / Q000627:therapeutic use*; D000069286:Bortezomib; D004943:Esophagogastric Junction / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D009362:Neoplasm Metastasis; D011480:Protease Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D011719:Pyrazines / Q000009:adverse effects / Q000627:therapeutic use*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D016328:NF-kappa B; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib