Phase I Study of PS-341 in Combination With 5-Fluorouracil and External Beam Radiotherapy For The Treatment Of Locally Advanced And Metastatic Rectal Cancer
- Determine the maximum tolerated dose of bortezomib when administered in combination
with fluorouracil and external beam radiotherapy as preoperative or palliative
treatment in patients with stage II-IV rectal adenocarcinoma.
- Determine the dose-limiting toxicities of this regimen in these patients.
- Determine the dose-effect relationship of bortezomib on NF-kappa B activation induced
- Determine downstream events induced by NF-kappa B activation.
- Determine downstream events related to activation of p53 in response to treatment with
chemoradiotherapy and bortezomib.
- Determine the rate of complete pathologic remission in patients who undergo surgical
resection of their primary tumor.
- Determine the gene expression pattern of tumors by cDNA microarray analysis before and
during treatment with this regimen.
OUTLINE: This is a multicenter, dose-escalation study of bortezomib.
Patients receive bortezomib IV on days 1, 4, 8, 11, 22, 25, 29, and 32 and fluorouracil IV
continuously on days 2-38. Patients also undergo external beam radiotherapy 5 days a week
for 5½ weeks. Treatment continues in the absence of disease progression or unacceptable
Cohorts of 3-6 patients receive escalating doses of bortezomib until the maximum tolerated
dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2
of 6 patients experience dose-limiting toxicity.
Patients undergo tissue biopsy at baseline and on days 1 and 2. Samples are collected and
evaluated by tissue microarray analysis for NF-kappa B pathway activation; cDNA analysis,
RNase protection assay, and immunohistochemistry for analysis of downstream events induced
by NF-kappa B activation; and modified TdT-mediated dUTP nick-end label for analysis of
apoptosis by DNA fragmentation. NF-kappa B subunits are quantified by enzyme-linked
immunosorbent assay. Serum samples are collected at baseline and stored for future studies.
After completion of study treatment, patients are followed every 3 months for up to 2 years.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Maximum tolerated dose
Bert H. O'Neil, MD
UNC Lineberger Comprehensive Cancer Center
United States: Federal Government
|Vanderbilt-Ingram Cancer Center||Nashville, Tennessee 37232-6838|
|Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill||Chapel Hill, North Carolina 27599-7570|