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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

Phase 1
18 Years
Not Enrolling
Colorectal Cancer

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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



- 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
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

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


- 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


- 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


- 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:


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:


Principal Investigator

Bert H. O'Neil, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UNC Lineberger Comprehensive Cancer Center


United States: Federal Government

Study ID:

LCCC 0209



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



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