PS-341 and Radiation to Treat Advanced Cancer of the Head and Neck

Background: * The ubiquitin-proteasome pathway regulates the degradation of important regulatory proteins and transcription factors that control the cell cycle and cell death. Proteasome inhibition can lead to block of different phases of the cell cycle, and block expression of genes that prevent cell death induced by radiation or other cytotoxic therapeutic agents. * In preclinical studies, proteasome inhibitor PS-341 has demonstrated cytotoxic, radiosensitizing, and anti-tumor activity against squamous cell carcinomas of the head and neck (SCCHN). Objectives: * The primary objective of this phase I dose escalation clinical study is to determine the maximum tolerated dose of PS-341 to be given concomitant with radiation in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. * Secondary objectives include detection of 20S proteasome inhibition, cell cycle block, apoptosis and inhibition of transcription factor NF-kappaB activation in tumor tissue biopsies following PS-341 and radiation. Eligibility: * Persistent or recurrent SCCHN, * Eligible for local primary or re-irradiation, * ECOG performance less than or equal to 2, life expectancy \> 3 months, * Adequate organ function (PLT \> 100, 000/microL, neutrophils \> 1500/mciroL, serum creatinine \< 1.5 times the upper limits normal (ULN), serum bilirubin \< 1.5 times the ULN, serum transaminases \< 2.5 times the ULN) * No systemic chemotherapy within the past 4 weeks and recovered from chemotherapy toxicity, * \> 6 months since prior radiation. Design: * Phase I dose escalation, standard 3+3 statistical design, up to 51 subjects, * PS-341 will be given in escalating doses of 0.6, 0.9 and 1.2 mg/m(2) in cohorts of 3 or more patients by IV bolus on M, Th (or T, F), and radiation will be given in 1.8 Gy fractions M-F to 60 Gy in previously radiated or 72Gy in previously unirradiated patients. * Radiation and/or drug will be given in two courses split by a two week rest to allow recovery from combined modality therapy.