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.
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
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.
Tipo de estudo
Inscrição (Real)
Estágio
- Fase 1
Contactos e Locais
Locais de estudo
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North Carolina
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Chapel Hill, North Carolina, Estados Unidos, 27599-7295
- Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
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Tennessee
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Nashville, Tennessee, Estados Unidos, 37232-6838
- Vanderbilt-Ingram Cancer Center
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
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)
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: N / D
- Modelo Intervencional: Atribuição de grupo único
- Mascaramento: Nenhum (rótulo aberto)
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Prazo |
|---|---|
|
Toxicidade limitante de dose
Prazo: 8 semanas
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8 semanas
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Maximum tolerated dose
Prazo: 6 weeks
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6 weeks
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Medidas de resultados secundários
Medida de resultado |
Prazo |
|---|---|
|
Dose-effect relationship of bortezomib on NF-kappa B activation induced by chemoradiotherapy
Prazo: 6 weeks
|
6 weeks
|
|
Downstream events induced by NF-kappa B activation
Prazo: 8 weeks
|
8 weeks
|
|
Downstream events related to activation of p53 in response to treatment with chemoradiotherapy and bortezomib
Prazo: 8 weeks
|
8 weeks
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|
Rate of complete pathologic remission
Prazo: 2 years
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2 years
|
|
Gene expression pattern of tumors as assessed by cDNA microarray analysis pre- and post-treatment
Prazo: 8 weeks
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8 weeks
|
Colaboradores e Investigadores
Patrocinador
Colaboradores
Investigadores
- Investigador principal: Bert H. O'Neil, MD, UNC Lineberger Comprehensive Cancer Center
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo
Conclusão Primária (Real)
Conclusão do estudo (Real)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Estimativa)
Atualizações de registro de estudo
Última Atualização Postada (Estimativa)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Doenças do aparelho digestivo
- Neoplasias
- Neoplasias por local
- Neoplasias gastrointestinais
- Neoplasias do Aparelho Digestivo
- Doenças Gastrointestinais
- Doenças Intestinais
- Neoplasias Intestinais
- Doenças retais
- Neoplasias Colorretais
- Neoplasias retais
- Efeitos Fisiológicos das Drogas
- Mecanismos Moleculares de Ação Farmacológica
- Antimetabólitos, Antineoplásicos
- Antimetabólitos
- Agentes Antineoplásicos
- Agentes imunossupressores
- Fatores imunológicos
- Fluorouracil
- Bortezomibe
Outros números de identificação do estudo
- LCCC 0209
- CDR0000549844 (Outro identificador: PDQ number)
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