Bortezomib, Fluorouracil, and External-Beam Radiation Therapy in Treating Patients With Stage II, Stage III, or Stage IV Rectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00280176
Recruitment Status : Completed
First Posted : January 20, 2006
Last Update Posted : February 14, 2012
National Cancer Institute (NCI)
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:

RATIONALE: Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving bortezomib and fluorouracil together with radiation therapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of bortezomib when given together with fluorouracil and external-beam radiation therapy in treating patients with stage II, stage III, or stage IV rectal cancer.

Condition or disease Intervention/treatment Phase
Colorectal Cancer Drug: bortezomib Drug: fluorouracil Radiation: radiation therapy Phase 1

Detailed Description:



  • 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 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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : April 2003
Actual Primary Completion Date : November 2008
Actual Study Completion Date : September 2010

Resource links provided by the National Library of Medicine

Intervention Details:
  • Drug: bortezomib
    0.7mg/m2 - 1.5mg.m2 given during Weeks 1, 2, 4 and 5 on a Monday/Thursday or Tuesday/Friday schedule, up to six weeks
    Other Name: Velcade
  • Drug: fluorouracil
    225mg/m2 given weekly, up to 6 weeks
    Other Name: 5FU
  • Radiation: radiation therapy
    180 cGy, every 5 days, up to six weeks

Primary Outcome Measures :
  1. Maximum tolerated dose [ Time Frame: 6 weeks ]
  2. Dose-limiting toxicity [ Time Frame: 8 weeks ]

Secondary Outcome Measures :
  1. Dose-effect relationship of bortezomib on NF-kappa B activation induced by chemoradiotherapy [ Time Frame: 6 weeks ]
  2. Downstream events induced by NF-kappa B activation [ Time Frame: 8 weeks ]
  3. Downstream events related to activation of p53 in response to treatment with chemoradiotherapy and bortezomib [ Time Frame: 8 weeks ]
  4. Rate of complete pathologic remission [ Time Frame: 2 years ]
  5. Gene expression pattern of tumors as assessed by cDNA microarray analysis pre- and post-treatment [ Time Frame: 8 weeks ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00280176

United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
Chapel Hill, North Carolina, United States, 27599-7295
United States, Tennessee
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232-6838
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
National Cancer Institute (NCI)
Principal Investigator: Bert H. O'Neil, MD UNC Lineberger Comprehensive Cancer Center

Responsible Party: UNC Lineberger Comprehensive Cancer Center Identifier: NCT00280176     History of Changes
Other Study ID Numbers: LCCC 0209
CDR0000549844 ( Other Identifier: PDQ number )
First Posted: January 20, 2006    Key Record Dates
Last Update Posted: February 14, 2012
Last Verified: February 2012

Keywords provided by UNC Lineberger Comprehensive Cancer Center:
recurrent rectal cancer
stage II rectal cancer
stage III rectal cancer
stage IV rectal cancer
adenocarcinoma of the rectum

Additional relevant MeSH terms:
Colorectal Neoplasms
Rectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs