A Phase I Clinical, Pharmacokinetic and Pharmacodynamic Study of Flavopiridol in Patients With Refractory Solid Tumors and Hematologic Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 100
- 试验地点
- 1
- 主要终点
- Dose-limiting toxicity (DLT)
研究概览
简要总结
This phase I trial is studying the side effects and best dose of alvocidib in treating patients with metastatic or unresectable refractory solid tumors or hematologic malignancies. Drugs used in chemotherapy, such as alvocidib, work in different ways to stop cancer cells from dividing so they stop growing or die.
详细描述
PRIMARY OBJECTIVE:
I. Determine the maximum tolerated dose of flavopiridol in patients with metastatic or unresectable refractory solid tumors or hematologic malignancies. (Accrual for patients with hematologic malignancies temporarily closed as of 11/30/04)
SECONDARY OBJECTIVES:
I. Determine the safety profile and toxic effects of this drug in these patients.
II. Determine the pharmacokinetics of this drug in these patients. III. Determine, by pharmacodynamic assays, the ability of this drug to inhibit cyclin-dependent kinase activity in tumor tissue, normal proliferating tissues, circulating tumor cells, and in plasma in these patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed malignancy, including the following types:
- •Hematologic malignancy, including any of the following: (Accrual for patients with hematologic malignancies temporarily closed as of 11/30/04)
- •Mantle cell lymphoma
- •Morphologically confirmed disease
- •CD20 and CD5 positive
- •Any other refractory lymphoma
- •Chronic lymphocytic leukemia
- •Rai stage III or IV and meeting at least 1 of the following criteria for active disease:
- •Weight loss > 10% in the last 6 months
- •Fever or night sweats with no evidence of infection
- •Progressive anemia or thrombocytopenia
- •Progressive lymphocytosis with a lymphocyte doubling time of < 6 months
- •Marked hypogammaglobulinemia or paraproteinemia
- •Progressive splenomegaly and/or lymphadenopathy
- •Multiple myeloma
- •Disease confirmed by bone marrow aspirate and/or biopsy
- •Relapsed or refractory disease after the most recent treatment regimen
- •Quantifiable monoclonal immunoglobulin in serum and/or urine
- •Solid tumor, including but not limited to any of the following:
- •Breast cancer
- •Histologically or cytologically confirmed stage IV invasive disease
- •HER-2 positivity not required for study enrollment
- •Tumor overexpressing HER-2 should be confirmed by immunohistochemistry OR fluorescence in situ hybridization
- •Small cell lung cancer
- •Extensive stage or limited stage disease in relapse
- •Extrapulmonary small cell carcinoma allowed
- •Squamous cell carcinoma of the head and neck
- •Metastatic, recurrent, or refractory disease
- •Renal cell carcinoma
- •Mesothelioma
- •Pleural or peritoneal disease of epithelial, sarcomatoid, or mixed subtype
- •Kaposi's sarcoma
- •Metastatic or unresectable disease for which standard therapy does not exist or is no longer effective
- •Measurable or nonmeasurable disease (solid tumor patients)
- •Measurable disease defined as at least 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or 10 mm by spiral CT scan
- •Nonmeasurable disease includes any of the following:
- •All other lesions, including lesions < 20 mm by conventional techniques or 10 mm by spiral CT scan
- •Bone lesions
- •Cytologically positive pleural or peritoneal disease
- •Elevated tumor marker (e.g., CEA, CA 125, CA 19-9, or other tumor marker)
- •Multinodular or confluent nonmeasurable pulmonary, hepatic, adrenal, intra-abdominal, or skin metastases
- •Previously treated with at least 1 chemotherapy regimen*
- •Prior therapy may have included combined modality treatment (e.g., full-dose chemotherapy and radiotherapy with radiosensitizing chemotherapy)
- •Prior therapy with flavopiridol allowed provided the patient was enrolled in a flavopiridol clinical trial employing a different schedule NOTE: *Except in cases where chemotherapy is not known to be effective (e.g., renal cell carcinoma, chondrosarcoma, or gastrointestinal stromal tumor)
- •No active CNS metastases
- •History of CNS metastases allowed provided all of the following criteria are met:
- •Previously treated and stable and asymptomatic for at least 4 weeks since the completion of treatment
- •Image documentation required
- •Off steroids or on a stable dose of steroids for at least 1 week
- •Hormone receptor status:
- 另有 39 项未显示
排除标准
- 未提供
研究组 & 干预措施
Treatment
PART 1 (closed to accrual as of 8/2005): Patients receive alvocidib IV over 1 hour on days 1, 8, and 15.
Cohorts of 3-6 patients receive escalating doses of alvocidib until the MTD* is determined.
PART 2: Patients receive alvocidib IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of alvocidib IV over 1-6 hours on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating durations of the maintenance dose of alvocidib until the MTD* is determined. An additional cohort of 10-20 patients receives alvocidib over 1 hour on days 1 and 15 at the MTD.
NOTE: *The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
In both parts, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: alvocidib (Drug)
Treatment
PART 1 (closed to accrual as of 8/2005): Patients receive alvocidib IV over 1 hour on days 1, 8, and 15.
Cohorts of 3-6 patients receive escalating doses of alvocidib until the MTD* is determined.
PART 2: Patients receive alvocidib IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of alvocidib IV over 1-6 hours on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating durations of the maintenance dose of alvocidib until the MTD* is determined. An additional cohort of 10-20 patients receives alvocidib over 1 hour on days 1 and 15 at the MTD.
NOTE: *The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
In both parts, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
Treatment
PART 1 (closed to accrual as of 8/2005): Patients receive alvocidib IV over 1 hour on days 1, 8, and 15.
Cohorts of 3-6 patients receive escalating doses of alvocidib until the MTD* is determined.
PART 2: Patients receive alvocidib IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of alvocidib IV over 1-6 hours on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating durations of the maintenance dose of alvocidib until the MTD* is determined. An additional cohort of 10-20 patients receives alvocidib over 1 hour on days 1 and 15 at the MTD.
NOTE: *The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
In both parts, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: fludeoxyglucose F 18 (Radiation)
Treatment
PART 1 (closed to accrual as of 8/2005): Patients receive alvocidib IV over 1 hour on days 1, 8, and 15.
Cohorts of 3-6 patients receive escalating doses of alvocidib until the MTD* is determined.
PART 2: Patients receive alvocidib IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of alvocidib IV over 1-6 hours on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating durations of the maintenance dose of alvocidib until the MTD* is determined. An additional cohort of 10-20 patients receives alvocidib over 1 hour on days 1 and 15 at the MTD.
NOTE: *The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
In both parts, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: fluorine F 18 fluorothymidine (Other)
Treatment
PART 1 (closed to accrual as of 8/2005): Patients receive alvocidib IV over 1 hour on days 1, 8, and 15.
Cohorts of 3-6 patients receive escalating doses of alvocidib until the MTD* is determined.
PART 2: Patients receive alvocidib IV over 1 hour at or below the MTD determined in part 1 and then receive a maintenance dose of alvocidib IV over 1-6 hours on days 1, 8, and 15. Cohorts of 3-6 patients receive escalating durations of the maintenance dose of alvocidib until the MTD* is determined. An additional cohort of 10-20 patients receives alvocidib over 1 hour on days 1 and 15 at the MTD.
NOTE: *The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.
In both parts, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: positron emission tomography (Procedure)
结局指标
主要结局
Dose-limiting toxicity (DLT)
时间窗: 28 days
MTD (or recommended phase II dose), defined as one dose level below that which produces two instances of DLT during the first 28-day course and the level at which no more than one of six patients experiences DLT during course 1
时间窗: 28 days
次要结局
- Pharmacokinetic parameters, including maximum concentration (Cmax), half-life, area under the curve (AUC), clearance, and volume of distribution(24 hours, 48 hours, 72 hours, and 8 weeks)
- Potency of alvocidib in plasma based on change in proliferation of stimulated peripheral blood mononuclear cells (PBMCs)(Baseline to up to 72 hours of day 1 course 1)
- Change in tumor metabolism and proliferation assessed by fludeoxyglucose F 18 (FDG) and fluorine F 18 fluorothymidine (FLT) positron emission tomography (PET)(Baseline to up to day 19 of course 2)