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

Sponsors and Collaborators:	UNC Lineberger Comprehensive Cancer Center National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00280176

Purpose

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	Intervention	Phase
Colorectal Cancer	Drug: bortezomib Drug: fluorouracil Procedure: biopsy Procedure: gene expression profiling Procedure: immunoenzyme technique Procedure: immunohistochemistry staining method Procedure: laboratory biomarker analysis Procedure: radiation therapy	Phase I

MedlinePlus related topics: Cancer Colorectal Cancer

Drug Information available for: Fluorouracil Bortezomib

U.S. FDA Resources

Study Type:	Interventional
Study Design:	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

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Maximum tolerated dose [ Designated as safety issue: Yes ]
Dose-limiting toxicity [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Dose-effect relationship of bortezomib on NF-kappa B activation induced by chemoradiotherapy [ Designated as safety issue: No ]
Downstream events induced by NF-kappa B activation [ Designated as safety issue: No ]
Downstream events related to activation of p53 in response to treatment with chemoradiotherapy and bortezomib [ Designated as safety issue: No ]
Rate of complete pathologic remission [ Designated as safety issue: No ]
Gene expression pattern of tumors as assessed by cDNA microarray analysis pre- and post-treatment [ Designated as safety issue: No ]

Estimated Enrollment:	24
Study Start Date:	April 2003
Estimated Primary Completion Date:	June 2008 (Final data collection date for primary outcome measure)

Detailed Description:

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.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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)

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00280176

Locations

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)

Investigators

Principal Investigator:

Bert H. O'Neil, MD

UNC Lineberger Comprehensive Cancer Center

More Information

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Study ID Numbers:	CDR0000549844, UNC-LCCC-0209, VU-VICC-GI-0575
Study First Received:	January 18, 2006
Last Updated:	January 7, 2009
ClinicalTrials.gov Identifier:	NCT00280176
Health Authority:	United States: Federal Government

Keywords provided by National Cancer Institute (NCI):

recurrent rectal cancer
stage II rectal cancer
stage III rectal cancer
stage IV rectal cancer
adenocarcinoma of the rectum

Study placed in the following topic categories:

Digestive System Neoplasms
Rectal Neoplasms
Gastrointestinal Diseases
Bortezomib
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Recurrence

Intestinal Neoplasms
Rectal neoplasm
Digestive System Diseases
Fluorouracil
Gastrointestinal Neoplasms
Adenocarcinoma
Rectal cancer
Colorectal Neoplasms

Additional relevant MeSH terms:

Antimetabolites
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Physiological Effects of Drugs
Enzyme Inhibitors

Immunosuppressive Agents
Pharmacologic Actions
Protease Inhibitors
Neoplasms
Neoplasms by Site
Therapeutic Uses

ClinicalTrials.gov processed this record on January 15, 2009