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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: bortezomib
* Drug: fluorouracil
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|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|
|Drug: fluorouracil|225mg/m2 given weekly, up to 6 weeks|
|Radiation: radiation therapy|180 cGy, every 5 days, up to six weeks|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose |  | 6 weeks | 
| Dose-limiting toxicity |  | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-effect relationship of bortezomib on NF-kappa B activation induced by chemoradiotherapy |  | 6 weeks | 
| Downstream events induced by NF-kappa B activation |  | 8 weeks | 
| Downstream events related to activation of p53 in response to treatment with chemoradiotherapy and bortezomib |  | 8 weeks | 
| Rate of complete pathologic remission |  | 2 years | 
| Gene expression pattern of tumors as assessed by cDNA microarray analysis pre- and post-treatment |  | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent rectal cancer, stage II rectal cancer, stage III rectal cancer, stage IV rectal cancer, adenocarcinoma of the rectum