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Sub-category:
Head and Neck Cancer
Category:
Head and Neck Cancer
Meeting:
2003 ASCO Annual Meeting
Session Type and Session Title:
Poster Discussion, Head and Neck Cancer
Abstract No:
2010
Citation:
Proc Am Soc Clin Oncol 22: 2003 (abstr 2010)
Author(s):
P. F. Lebowitz, C. Harkins, B. Conley, D. Headlee, K. Camphausen, D. Guis, J. Adams, Y. Elsayed, E. Sausville, C. Van Waes; National Cancer Institute, Bethesda, MD; National Institute on Deafness and Other Communication Disorders, Bethesda, MD; Millenium Pharmaceuticals, Cambridge, MA
Abstract:
The ubiquitin-proteasome pathway regulates the degradation of proteins that control cell cycle and apoptosis. Preclinically, bortezomib (formerly PS341), a potent proteasome inhibitor, demonstrates cytotoxic, radio-sensitizing, and anti-tumor activity in HNSCC models. We designed a dose-escalation trial of bortezomib with concurrent radiation therapy in patients with recurrent or metastatic HNSCC to: (1) determine the recommended bortezomib dose; (2) evaluate toxicities; and (3) evaluate antitumor activity. Patients eligible for salvage re-irradiation with good performance status and adequate organ function were entered if they had chemotherapy > 4 weeks or primary radiation > 6 months prior to entry. Bortezomib was given as an IV bolus twice weekly beginning at 0.6 mg/m2/dose with radiation at 1.8 Gy daily fractions to 60-72 Gy. To date, 7 patients have been treated at two dose levels and accrual is ongoing. At the 0.6 mg/m2 dose, the mean proteasome inhibition in peripheral blood mononuclear cells (PBMCs) at 1h, 24h and 48h was 39%, 15%, and 12% respectively (3 patients). At the 0.9 mg/m2 dose, the proteasome inhibition at 1h, 24h, and 48h was 59%, 26%, and 15% respectively (2 patients). Tumor biopsy samples obtained at 24h from 2 patients treated at 0.6 mg/m2 showed similar levels of proteasome inhibition as in PBMCs. Of the 7 patients treated, 4 have had marked reduction in tumor size, although 3 of these patients have had progressive disease at 3 months. At 0.6 mg/m2, grade 1-2 orthostatic hypotension, nausea, and fatigue were noted; no patients had dose-limiting toxicity. At 0.9 mg/m2, one patient had grade 3 orthostatic hypotension due to baroreceptor dysfunction. One patient had transient grade 3 hyponatremia. We have expanded the initial dose level with implementation of supportive measures to prevent orthostatic hypotension and hyponatremia; the data on these patients will be presented. Thus, preliminary data indicate that bortezomib and re-irradiation has promising anti-tumor activity in relapsed HNSCC; evaluation of response and tolerability at higher dose levels is ongoing.
 Associated Presentation(s):
Other Abstracts in this Sub-Category:
Abstracts by P. F. Lebowitz:
Presentations by P. F. Lebowitz:
Educational Book Manuscripts by P. F. Lebowitz:
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