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

  • PHASE II STUDIES
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Summary

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.

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Acknowledgements

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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Authors and Affiliations

  1. Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, H910, New York, NY, 10021, USA

    Manish A. Shah, Derek G. Power, David H. Ilson & David P. Kelsen

  2. Department of Medicine, Weill-Cornell Medical College of Cornell University, 300 York Avenue, New York, NY, 10065, USA

    Manish A. Shah, Derek G. Power, David H. Ilson & David P. Kelsen

  3. Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, H910, New York, NY, 10021, USA

    Marinela Capanu

  4. Section of Hematology/Oncology, University of Chicago Medical Center, Chicago, IL, USA

    Hedy L. Kindler

  5. Paul P. Carbone Comprehensive Cancer Center, University of Wisconsin, Madison, WI, USA

    Kyle D. Holen

  6. Department of Surgical Oncology, Queens Cancer Center at Queens Hospital, Jamaica, NY, USA

    Margaret M. Kemeny

  7. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Laura Tang

  8. Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Rockville, MD, USA

    John J. Wright

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  1. Manish A. Shah
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Correspondence to Manish A. Shah.

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Shah, M.A., Power, D.G., Kindler, H.L. et al. A multicenter, phase II study of Bortezomib (PS-341) in patients with unresectable or metastatic gastric and gastroesophageal junction adenocarcinoma. Invest New Drugs 29, 1475–1481 (2011). https://doi.org/10.1007/s10637-010-9474-7

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  • DOI: https://doi.org/10.1007/s10637-010-9474-7

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