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

NCT ID: NCT00280176

Last Updated: 2012-02-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 11 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-04-30
• Study Completion Date: 2010-09-30

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.

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.

Conditions

Colorectal Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Interventions

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

Intervention Type: DRUG

fluorouracil

225mg/m2 given weekly, up to 6 weeks

Intervention Type: DRUG

radiation therapy

180 cGy, every 5 days, up to six weeks

Intervention Type: RADIATION

Other Intervention Names

Velcade; 5FU

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

UNC Lineberger Comprehensive Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bert H. O'Neil, MD

Role: PRINCIPAL_INVESTIGATOR

UNC Lineberger Comprehensive Cancer Center

Locations

Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill

Chapel Hill, North Carolina, United States

Vanderbilt-Ingram Cancer Center

Nashville, Tennessee, United States

Countries

United States

Other Identifiers

CDR0000549844

Identifier Type: OTHER

Identifier Source: secondary_id

LCCC 0209

Identifier Type: -

Identifier Source: org_study_id