Flavopiridol in Treating Patients With Previously Treated Chronic Lymphocytic Leukemia or Lymphocytic Lymphoma
A Dose-Escalation Study of Flavopiridol (NSC 649890) Administered as a 30 Minute Loading Dose Followed by a 4-Hour Infusion in Patients With Previously Treated B-Cell Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)
調査の概要
詳細な説明
PRIMARY OBJECTIVES:
I. To determine the toxicity profile, dose-limiting toxicity, and maximum tolerated dose of flavopiridol administered as a 30 minute loading dose followed by a 4-hour infusion once weekly for 4 consecutive weeks every 6 weeks.
II. To determine the safety and feasibility of performing dose escalation to 80 mg/m2 (30 mg/m2 30-minute IV bolus followed by 50 mg/m2 4-hour IV infusion) beginning dose 2 in patients who do not experience severe tumor lysis requiring hemodialysis during dose 1.
III. To determine the pharmacokinetics and cellular pharmacodynamics of flavopiridol administered in this schedule.
SECONDARY OBJECTIVES:
I. To determine the complete response (CR) and overall response rate (CR + PR) of flavopiridol in patients with previously-treated CLL administered as a 30 minute loading dose followed by a 4 hour infusion once weekly for 4 consecutive weeks every 6 weeks.
OUTLINE: This is a dose-escalation study.
Patients receive a loading dose of flavopiridol IV over 30 minutes followed by a 4-hour infusion on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of unacceptable toxicity or disease progression.
Cohorts of 3-6 patients receive escalating doses of flavopiridol 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. After the MTD is determined, 12 additional patients are accrued and treated as above at the recommended phase II dose.
After completion of study treatment, patients are followed at 2 months and then every 3 months for 2 years.
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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Ohio
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Columbus、Ohio、アメリカ、43210
- Ohio State University 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:
Diagnosis of B-cell chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, including Waldenstrom's macroglobulinemia, as indicated by the following:
- Massive or progressive splenomegaly and/or lymphadenopathy
- Anemia (hemoglobin less than 11 g/dL) or thrombocytopenia (platelet count less than 100,000/mm^3)
- Weight loss of more than 10% within the past 6 months
- Grade 2 or 3 fatigue
- Fevers greater than 100.5º C or night sweats for more than 2 weeks with no evidence of infection
- Progressive lymphocytosis with an increase of more than 50% over a 2-month period or anticipated doubling time of less than 6 months
- Received at least 1 prior therapy for CLL
- Performance status - ECOG (Eastern Cooperative Oncology Group) 0-2
- See Disease Characteristics
- WBC (white blood count) less than 200,000/mm^3
- Bilirubin no greater than 1.5 times normal (unless due to Gilbert's disease or any of the conditions stated below)*
- AST (aspartate aminotransferase) no greater than 2 times normal*
- Creatinine no greater than 2.0 mg/dL
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception
- No other malignancy that would limit survival to less than 2 years
- No history of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) unless inactive for more than 2 years
- No psychiatric condition that would preclude compliance with treatment or giving informed consent
- No other concurrent chemotherapy
- No concurrent chronic corticosteroids
- No concurrent hormonal therapy except steroids for new adrenal failure or hormonal agents for nondisease-related conditions (e.g., insulin for diabetes)
- No concurrent dexamethasone or other corticosteroid-based antiemetics
- No concurrent radiotherapy
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：Arm I
Patients receive a loading dose of flavopiridol IV over 30 minutes followed by a 4-hour infusion on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of unacceptable toxicity or disease progression.
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与えられた IV
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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Number of Patients With Dose Limiting Toxicities (DLTs)
時間枠：up to 7 weeks
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DLTs were defined as non-hematologic toxicity of grade 3 or greater severity (excluding transient liver function abnormalities, transient electrolyte abnormalities that are not life threatening, fatigue, or diarrhea that resolve within 4 days), or in some case grade 2 toxicity (i.e.
irreversible renal, chronic pulmonary, neurologic, or cardiac toxicity).
Hematologic toxicity were evaluated by the modified NCI criteria and followed closely.
Dose limiting only if grade 4 thrombocytopenia or neutropenia persists for 7 days or greater.
Inability to continue with cycle 2 by 7 weeks for reasons other than progression of disease will also be considered a DLT.The National Cancer Institute Common Toxicity Criteria will be used to characterize toxicity.
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up to 7 weeks
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Recommended Dose Level of Flavopiridol
時間枠：Up to 6 weeks
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Recommended dose determined by number of DLTs [non-hematologic toxicity grade 3 or greater (excluding not life-threatening transient liver function or transient electrolyte abnormalities, fatigue, or diarrhea resolving within 4 days), some grade 2 toxicity (i.e.
irreversible renal, chronic pulmonary, neurologic, or cardiac toxicity), hematologic toxicity of grade 4 thrombocytopenia/neutropenia persisting for 7 days or greater, or inability to continue cycle 2 by 7 weeks for reasons other than disease progression] and consideration of number of patients with severe tumor lysis requiring hemodialysis with dose 1.
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Up to 6 weeks
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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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Overall Response Rate (CR + PR) of Flavopiridol in Patients Evaluated Utilizing the Revised National Cancer Institute-sponsored Working Group Guidelines
時間枠：Up to 2 years
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Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: 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 2 years
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協力者と研究者
出版物と役立つリンク
一般刊行物
- Lin TS, Ruppert AS, Johnson AJ, Fischer B, Heerema NA, Andritsos LA, Blum KA, Flynn JM, Jones JA, Hu W, Moran ME, Mitchell SM, Smith LL, Wagner AJ, Raymond CA, Schaaf LJ, Phelps MA, Villalona-Calero MA, Grever MR, Byrd JC. Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol. 2009 Dec 10;27(35):6012-8. doi: 10.1200/JCO.2009.22.6944. Epub 2009 Oct 13.
- Pierceall WE, Warner SL, Lena RJ, Doykan C, Blake N, Elashoff M, Hoff DV, Bearss DJ, Cardone MH, Andritsos L, Byrd JC, Lanasa MC, Grever MR, Johnson AJ. Mitochondrial priming of chronic lymphocytic leukemia patients associates Bcl-xL dependence with alvocidib response. Leukemia. 2014 Nov;28(11):2251-4. doi: 10.1038/leu.2014.206. Epub 2014 Jul 3. No abstract available.
- Woyach JA, Lozanski G, Ruppert AS, Lozanski A, Blum KA, Jones JA, Flynn JM, Johnson AJ, Grever MR, Heerema NA, Byrd JC. Outcome of patients with relapsed or refractory chronic lymphocytic leukemia treated with flavopiridol: impact of genetic features. Leukemia. 2012 Jun;26(6):1442-4. doi: 10.1038/leu.2011.375. Epub 2012 Jan 13. No abstract available.
- Ni W, Ji J, Dai Z, Papp A, Johnson AJ, Ahn S, Farley KL, Lin TS, Dalton JT, Li X, Jarjoura D, Byrd JC, Sadee W, Grever MR, Phelps MA. Flavopiridol pharmacogenetics: clinical and functional evidence for the role of SLCO1B1/OATP1B1 in flavopiridol disposition. PLoS One. 2010 Nov 1;5(11):e13792. doi: 10.1371/journal.pone.0013792.
研究記録日
主要日程の研究
研究開始 (実際)
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 (実際)
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-2012-01435 (レジストリ識別子：CTRP (Clinical Trial Reporting Program))
- P30CA016058 (米国 NIH グラント/契約)
- U01CA076576 (米国 NIH グラント/契約)
- CDR0000287197
- NCI-5746
- OSU-0055
- OSU 0055 (その他の識別子：Ohio State University Medical Center)
- 5746 (その他の識別子：CTEP)
- R21CA112947 (米国 NIH グラント/契約)
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