Investigational New Drugs

, Volume 29, Issue 6, pp 1475–1481 | Cite as

A multicenter, phase II study of Bortezomib (PS-341) in patients with unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma

  • Manish A. ShahEmail author
  • Derek G. Power
  • Hedy L. Kindler
  • Kyle D. Holen
  • Margaret M. Kemeny
  • David H. Ilson
  • Laura Tang
  • Marinela Capanu
  • John J. Wright
  • David P. Kelsen


Purpose 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. Experimental Design We performed a phase II trial of bortezomib in patients with advanced gastric adenocarcinoma. Bortezomib 1.3 mg/m2 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.


Bortezomib Proteasome Gastric cancer Nuclear factor-kB (NF-KB) 



Supported by the NCI Phase II Contract–NO1-CM17105 (PI David P. Kelsen, MD), and NCI Translational Research Contract 24XS072 NCI 6003 (PI Manish A. Shah, MD)


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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Manish A. Shah
    • 1
    • 2
    Email author
  • Derek G. Power
    • 1
    • 2
  • Hedy L. Kindler
    • 4
  • Kyle D. Holen
    • 5
  • Margaret M. Kemeny
    • 6
  • David H. Ilson
    • 1
    • 2
  • Laura Tang
    • 7
  • Marinela Capanu
    • 3
  • John J. Wright
    • 8
  • David P. Kelsen
    • 1
    • 2
  1. 1.Gastrointestinal Oncology Service, Department of MedicineMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  2. 2.Department of MedicineWeill-Cornell Medical College of Cornell UniversityNew YorkUSA
  3. 3.Department of Epidemiology and BiostatisticsMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  4. 4.Section of Hematology/OncologyUniversity of Chicago Medical CenterChicagoUSA
  5. 5.Paul P. Carbone Comprehensive Cancer CenterUniversity of WisconsinMadisonUSA
  6. 6.Department of Surgical OncologyQueens Cancer Center at Queens HospitalJamaicaUSA
  7. 7.Department of PathologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  8. 8.Investigational Drug Branch, Cancer Therapy Evaluation ProgramNational Cancer InstituteRockvilleUSA

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