A Phase I Study of Concomitant Therapy With Proteasome Inhibitor PS-341 and Radiation in Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck
- 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).
- 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.
- 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
- > 6 months since prior radiation.
- 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
- Radiation and/or drug will be given in two courses split by a two week rest to allow
recovery from combined modality therapy.
Primary Purpose: Treatment
Toxicity and maximum tolerated dose (MTD) as assessed by CTC version 2.0 during treatment and weekly for 3 months after treatment.
Brigitte C Widemann, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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