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
18 Years
N/A
Both
Colorectal Cancer
Trial Information
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
OBJECTIVES:
Primary
- 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.
Secondary
- Determine the dose-effect relationship of bortezomib on NF-kappa B activation induced
by chemoradiotherapy.
- 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
toxicity.
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.
Inclusion Criteria
DISEASE CHARACTERISTICS:
- Biopsy confirmed diagnosis of adenocarcinoma of the rectum meeting 1 of the following
clinical staging criteria:
- T3-T4, N0, M0 (stage II disease)
- T4 disease defined as tumor fixed on examination or involving adjacent
pelvic structures, such as the sidewall, bladder, uterus, prostate, or
small bowel by ultrasound or CT scan
- Any T, N1-2, M0 (stage III disease)
- Any T, any N, M1 (stage IV disease)
- Recurrent disease (any prior stage)
- Candidate for local palliative therapy or curative resection of metastatic disease
- Previously treated CNS disease allowed provided it is stable for > 3 months
PATIENT CHARACTERISTICS:
- ECOG performance status 0-2
- Life expectancy > 3 months
- Adequate nutrition
- WBC ≥ 4,000/mm³
- ANC > 2,000/mm³
- Platelet count ≥ 100,000/mm³
- Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min
- Bilirubin ≤ 1.5 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No serious medical or psychiatric illness that would limit study compliance or limit
survival to < 2 years
- No history of refractory congestive heart failure or cardiomyopathy
- No active coronary artery disease, myocardial infarction within the past 3 months, or
cerebrovascular accident within the past 3 months
- No peripheral neuropathy ≥ grade 2
- No hypersensitivity to bortezomib, boron, or mannitol
PRIOR CONCURRENT THERAPY:
- More than 1 week since prior major surgery
- More than 28 days since prior investigational agents
- Prior chemotherapy allowed
- No prior pelvic radiotherapy (for treatment of any pelvic malignancy)
- No concurrent herbal medication (excluding vitamin and mineral supplements)
- No concurrent filgrastim (G-CSF) or sargramostim (GM-CSF)
Type of Study:
Interventional
Study Design:
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Maximum tolerated dose
Outcome Time Frame:
6 weeks
Safety Issue:
Yes
Principal Investigator
Bert H. O'Neil, MD
Investigator Role:
Principal Investigator
Investigator Affiliation:
UNC Lineberger Comprehensive Cancer Center
Authority:
United States: Federal Government
Study ID:
LCCC 0209
NCT ID:
NCT00280176
Start Date:
April 2003
Completion Date:
September 2010
Related Keywords:
- Colorectal Cancer
- recurrent rectal cancer
- stage II rectal cancer
- stage III rectal cancer
- stage IV rectal cancer
- adenocarcinoma of the rectum
- Rectal Neoplasms
- Colorectal Neoplasms
Name | Location |
|---|---|
| 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 |
