Phase I-II Study of Vorinostat, Paclitaxel, and Bevacizumab in Metastatic Breast Cancer
Phase I/II Study of a Combination of Suberoylanilide Hydroxamic Acid (Vorinostat) Plus Paclitaxel and Bevacizumab in Patients With Advanced Metastatic and/or Local Chest Wall Recurrent Breast Cancer
調査の概要
詳細な説明
PRiMARY OBJECTIVES:
I. To determine the recommended phase II dose of oral suberoylanilide hydroxamic acid (vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or metastatic breast cancer. (Phase I) II. To determine the efficacy (response rate, response duration, time to disease progression, time to treatment failure, and overall survival) and toxicity of oral suberoylanilide hydroxamic acid (vorinostat) in combination with weekly paclitaxel and bevacizumab in patients with chest wall recurrent or metastatic breast cancer. (Phase II)
SECONDARY OBJECTIVES:
I. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins including histone H3 and H4, b) ubiquitylation of proteins, and c) the levels of p21 and p27 levels in the peripheral blood mononuclear cells (pre treatment vs. cycle 1 day 2 after 3 VORINOSTAT doses but prior to paclitaxel.
II. To determine whether in vivo treatment with vorinostat induces a) acetylation of proteins including histone H3 and H4, ubiquitylation of proteins, and c) the levels of Bim, Bak, tBID, p21 and p27 levels, as well as down regulate Bcl-2, Bcl-xL and survivin in chest wall recurrent or metastatic breast cancer cells (pre treatment vs. cycle 1 day 2 after 3 vorinostat doses but prior to paclitaxel).
III. To determine whether in the primary breast cancer (and metastatic cancer if available) pretreatment levels of Her-2, Estrogen Receptor (ER)-alpha, Progesterone Receptor (PR), p21, p27, p-AKT, p-ERK1/2, HDAC1, 2, 3, 4, 6, 10 and SIRT2 levels predict for the response to treatment with VORINOSTAT plus paclitaxel.
OUTLINE: This is a phase I, multicenter, dose-escalation study of vorinostat (SAHA) followed by a phase II, open-label study.
Phase I: Patients receive oral SAHA twice daily on days 1-3, 8-10, and 15-17, paclitaxel IV over 1 hour on days 2, 9, and 16, and bevacizumab IV over 30-90 minutes on days 2 and 16. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of SAHA 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. The recommended phase II dose is defined as one dose level below the MTD.
Phase II: Patients receive SAHA at the recommended phase II dose and paclitaxel and bevacizumab as in phase I.
研究の種類
入学 (実際)
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究場所
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New York
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Bronx、New York、アメリカ、10467-2490
- Montefiore Medical Center
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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
Inclusion Criteria:
- histologically or cytologically confirmed adenocarcinoma of the breast; effective with version 2.2 (1/26/09), only patients with disease that is accessible to biopsy and consent to serial biopsy are eligible
- stage IV disease, locally recurrent inoperable chest wall disease; at least one bidimensional and/or unidimensional, measurable indicator lesion must be present (patients with only non-measurable disease are eligible for the phase I trial only); all sites of disease should be noted and followed
- ECOG performance status =< 1 (Karnofsky >= 70%)
- Absolute neutrophil count >= 1,500/ul
- Platelets >= 100,000/ul
- Total bilirubin within normal institutional limits
- AST(SGOT)/ALT(SGPT) =< 2.5 x institutional upper limit of normal
- PTT and either INR or PT < 1.5 x normal
- Creatinine within normal institutional limits OR creatinine clearance >= mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- Urine protein should be screened by urine analysis for Urine Protein Creatinine (UPC) ratio; for UPC ratio > 0.5, 24-hour urine protein should be obtained and the level should be < 1000 mg for patient enrollment;
- LVEF must be at or above the lower institutional limit of the normal range (on MUGA or Echo obtained within 12 weeks of registration, or within 4 weeks of prior Herceptin)
- Not pregnant/lactating
Exclusion criteria:
- chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- may not be receiving any other investigational agents.
- history of allergic reactions attributed to compounds of similar chemical or biologic composition to vorinostat or other agents used in the study (e.g., paclitaxel, bevacizumab, quinolones)
- uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
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）
武器と介入
参加者グループ / アーム |
介入・治療 |
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実験的：vorinostat, paclitaxel, bevacizumab
Vorinostat BID on days 1-3, 8-10, and 15-17, paclitaxel IV over 1 hour on days 2, 9, and 16, bevacizumab IV over 30-90 minutes on days 2 and 16, repeat every 28 days.
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与えられた IV
他の名前：
与えられた IV
他の名前：
経口投与
他の名前：
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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 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Recommended Phase II Dose as Assessed by NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 (Phase I)
時間枠：28 days
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Dose-limiting toxcities (DLT) were defined as grade 3-4 febrile neutropenia, thrombocytopenia and non-hemtological toxicity attributed to therapy (nausea, vomiting and diarrhea would be considered dose limiting only if not adequately controlled with therapy).
Any toxicity occurring during cycle 1 that resulted in dose reduction of vorinostat or paclitaxel or failure to complete all protocol specificed doses in the first cycle was also considered a DLT
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28 days
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Objective Response Rate (CR + PR)
時間枠：Up to 12 months
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Estimated and a 95% confidence interval will be estimated via binomial proportions.
Per Response Evaluation Criteria in Solid Tumors (RECIST) for target lesions and assessed by CT scan: Complete response (CR): Disappearance of all target lesions; Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR+PR.
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Up to 12 months
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Progression-free Survival (PFS),
時間枠：From first treatment day until objective or symptomatic progression, assessed up to 12 months
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Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
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From first treatment day until objective or symptomatic progression, assessed up to 12 months
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Time to Treatment Failure (TTF)
時間枠：Time from the first treatment day until disease progression or discontinuation of treatment due to toxicity, assessed up to 12 months
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Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
Time to treatment failure was not reported for this study.
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Time from the first treatment day until disease progression or discontinuation of treatment due to toxicity, assessed up to 12 months
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Overall Survival(OS)
時間枠：Time from first treatment day until death, assessed up to 12 months
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Assessed by Kaplan-Meier survival analysis and 95% confidence intervals will be calculated using Greenwood's formulae.
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Time from first treatment day until death, assessed up to 12 months
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協力者と研究者
捜査官
- 主任研究者：Joseph Sparano、Montefiore Medical Center
出版物と役立つリンク
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
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- NCI-2012-03012 (レジストリ識別子：CTRP (Clinical Trial Reporting Program))
- N01CM62204 (米国 NIH グラント/契約)
- N01CM62207 (米国 NIH グラント/契約)
- N01CM62205 (米国 NIH グラント/契約)
- N01CM62209 (米国 NIH グラント/契約)
- 7703 (その他の識別子：CTEP)
- 06-05-291 (その他の識別子：Montefiore Medical Center)
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。
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