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.
調査の概要
詳細な説明
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.
研究の種類
入学 (実際)
段階
- フェーズ 1
連絡先と場所
研究場所
-
-
North Carolina
-
Chapel Hill、North Carolina、アメリカ、27599-7295
- Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill
-
-
Tennessee
-
Nashville、Tennessee、アメリカ、37232-6838
- Vanderbilt-Ingram Cancer Center
-
-
参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
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)
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：なし
- 介入モデル：単一グループの割り当て
- マスキング：なし（オープンラベル）
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
時間枠 |
|---|---|
|
用量制限毒性
時間枠：8週間
|
8週間
|
|
Maximum tolerated dose
時間枠：6 weeks
|
6 weeks
|
二次結果の測定
結果測定 |
時間枠 |
|---|---|
|
Dose-effect relationship of bortezomib on NF-kappa B activation induced by chemoradiotherapy
時間枠：6 weeks
|
6 weeks
|
|
Downstream events induced by NF-kappa B activation
時間枠：8 weeks
|
8 weeks
|
|
Downstream events related to activation of p53 in response to treatment with chemoradiotherapy and bortezomib
時間枠：8 weeks
|
8 weeks
|
|
Rate of complete pathologic remission
時間枠：2 years
|
2 years
|
|
Gene expression pattern of tumors as assessed by cDNA microarray analysis pre- and post-treatment
時間枠：8 weeks
|
8 weeks
|
協力者と研究者
捜査官
- 主任研究者：Bert H. O'Neil, MD、UNC Lineberger Comprehensive Cancer Center
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (見積もり)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。