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

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

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.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: bortezomib; Drug: fluorouracil; Radiation: radiation therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7295
      • Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
  • Tennessee
    • Nashville, Tennessee, United States, 37232-6838
      • Vanderbilt-Ingram Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: UNC Lineberger Comprehensive Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Bert H. O'Neil, MD, UNC Lineberger Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start: April 1, 2003
• Primary Completion (Actual): November 1, 2008
• Study Completion (Actual): September 1, 2010

Study Registration Dates

• First Submitted: January 18, 2006
• First Submitted That Met QC Criteria: January 19, 2006
• First Posted (Estimate): January 20, 2006

Study Record Updates

• Last Update Posted (Estimate): February 14, 2012
• Last Update Submitted That Met QC Criteria: February 12, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Keywords: adenocarcinoma of the rectum; stage IV rectal cancer; recurrent rectal cancer; stage II rectal cancer; stage III rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Fluorouracil; Bortezomib
• Other Study ID Numbers: LCCC 0209; CDR0000549844 (Other Identifier: PDQ number)