A Phase I/II Study of Flavopiridol Administered as a 30-Minute Bolus Followed by a 4-Hour Infusion in Lymphomas and Multiple Myeloma
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- Disease-specific Dose-limiting Toxicity and Maximum Tolerated Dose of Flavopiridol Graded According to the CTCAE (Common Toxicity Criteria for Adverse Effects) Version 4.0 (Phase I)
研究概览
简要总结
This phase I/II trial is studying the side effects and best dose of flavopiridol and to see how well it works in treating patients with lymphoma or multiple myeloma. Drugs used in chemotherapy, such as flavopiridol, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.
详细描述
PRIMARY OBJECTIVES:
I. Determine the disease-specific dose-limiting toxicity and maximum tolerated dose of flavopiridol in patients with relapsed or refractory lymphoma or multiple myeloma.
II. Determine the complete and partial response rate in patients with selected non-Hodgkin's lymphoma (e.g., indolent B-cell, mantle cell, intermediate grade B-cell, and T/NK-cell), Hodgkin's lymphoma, or multiple myeloma treated with this drug.
III. Determine the qualitative and quantitative toxic effects or this drug, in terms of organ specificity, time course, predictability, and reversibility in these patients.
IV. Determine subsets of lymphoid/plasma cell malignancies that are suitable for larger phase II studies designed to further evaluate the efficacy and toxicity of this drug 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
- •Diagnosis of 1 of the following hematologic malignancies:
- •Hodgkin's lymphoma
- •Non-Hodgkin's lymphoma (NHL)
- •Multiple myeloma
- •Patients in the phase II portion of the study are enrolled in 1 of the following strata according to diagnosis*
- •Stratum 1: Indolent B-cell NHL (non-Hodgkin's lymphoma), follicle center B-cell NHL (grade 1, 2, or 3), marginal zone lymphoma, Waldenstrom's macroglobulinemia, or small lymphocytic lymphoma (without blood lymphocytosis at any point in the disease process)
- •Must have progressive lymphadenopathy, worsening cytopenias, or progressive symptoms attributed to lymphoma
- •Must require therapy, as determined by progressive anemia, thrombocytopenia, symptoms (e.g., fever, night sweats, weight loss, or fatigue), or progressive lymphadenopathy that causes discomfort
- •Received ≥ 2 prior therapies, including rituximab
- •Stratum 1a: Hairy cell leukemia
- •Must require therapy, as determined by progressive cytopenias or symptoms (fever, night sweats, weight loss, or fatigue)
- •Must have received ≥ 2 therapies
- •Stratum 2: Mantle cell lymphoma, as determined by the presence of cyclin D1 staining OR t(11;14)
- •Stratum 3: Intermediate grade B-cell NHL, including diffuse large B-cell NHL and T-cell rich B-cell NHL
- •Diffuse large B-cell NHL arising from an indolent NHL (i.e., transformed lymphoma) allowed
- •Ineligible for potentially curative autologous stem cell transplantation
- •Stratum 4: T-cell and natural killer-cell NHL, including anaplastic large cell lymphoma and peripheral T-cell NHL
- •Primary cutaneous lymphoma or Sezary syndrome allowed provided criteria for measurable disease are met
- •Received ≥ 1 prior systemic therapy
- •Stratum 5: Hodgkin's lymphoma
- •Any of the following subtypes are allowed:
- •Nodular sclerosing
- •Mixed cellularity
- •Lymphocyte predominant
- •Lymphocyte depleted
- •Ineligible for potentially curative autologous stem cell transplantation
- •Stratum 6: Progressive stage I or stage II or IIIA multiple myeloma meeting ≥ 1 major and 1 minor criterion OR ≥ 3 minor criteria as follows:
- •Major criteria
- •Plasmacytoma on tissue biopsy
- •Bone marrow plasmacytosis ≥ 30% of marrow cellularity
- •Monoclonal paraprotein ≥ 3,500 mg/dL (IgG), or ≥ 2,000 mg/dL (IgA), OR monoclonal protein (Bence-Jones protein) ≥ 1,000 mg by 24-hour urine collection
- •Minor criteria
- •Bone marrow plasmacytosis 10-29% of marrow cellularity
- •Monoclonal paraprotein < 3,500 mg/dL (IgG) or < 2,000 mg/dL (IgA)
- •Lytic bone lesions by x-ray or CT scan
- •Decrease in normal IgM (< 50 mg/dL), IgA (< 100 mg/dL), or IgG (< 600 mg/dL)
- •Relapsed or refractory disease
- •Measurable disease, defined by 1 of the following:
- •At least 1 node > 2 cm by CT scan
- •Measurable disease in a lymphoid structure (i.e., spleen) by CT scan
- •Bone marrow involvement (> 20% of marrow cellularity)
- •Patients with multiple myeloma must have detectable serum or urinary paraprotein
- •Patients with only cutaneous or subcutaneous disease (i.e., no measurable lymph node or bone marrow disease) are eligible if the extent of rash or skin involvement OR the size of the nodules are measurable
- •Must have received ≥ 1 prior therapy
- •Steroids alone are not considered prior therapy for patients with NHL or Hodgkin's lymphoma
- •High-dose dexamethasone is considered 1 prior therapy for patients with multiple myeloma
- •No standard effective therapy exists
- •No HIV-associated lymphoma
- •No nonsecretory multiple myeloma
- •Performance status - ECOG (Eastern Cooperative Oncology Group) 0-2
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排除标准
- 未提供
研究组 & 干预措施
Treatment (alvocidib)
PHASE I: Patients receive flavopiridol IV over 4½ hours on days 1, 8, 15, and 22. Treatment repeats every 6 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. 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.
PHASE II: Patients receive flavopiridol* as in phase I at the MTD determined in phase I.
干预措施: alvocidib (Drug)
结局指标
主要结局
Disease-specific Dose-limiting Toxicity and Maximum Tolerated Dose of Flavopiridol Graded According to the CTCAE (Common Toxicity Criteria for Adverse Effects) Version 4.0 (Phase I)
时间窗: 28 days
Dose limiting toxicity (DLT) for an individual disease group is defined as 1) any grade 3-4 non-hematologic toxicity (except leukopenia or neutropenia) that does not resolve or decrease to grade 1-2 within 2 weeks, or 2) any grade 4 hematologic toxicity that causes more than a 1 week delay in administration of therapy.
Maximum Tolerated Dose (MTD)
时间窗: 28 days
The maximum tolerated dose (MTD) is defined as that dose level beneath the dose at which 2 or more of 6 patients experience DLT.
Complete and Partial Response Rate (Phase II)
时间窗: Up to 2 years
Patients were assessed for clinical response after two , four and six cycle with laboratory studies, physical exam, and CT scans. Response was evaluated using the modified NCI-sponsored Working Group Lymphoma Response Criteria.
Qualitative and Quantitative Toxicities in Regard to Organ Specificity
时间窗: Up to 30 days after completion of study treatment
The NCI Common Toxicity Criteria for Adverse Events (version 3.0) were used to define and grade toxicity for patients.
Lymphoid/Plasma Cell Malignancies
时间窗: Up to 2 years
Identify subsets, based on levels of response (PR and SD), of lymphoid / plasma cell malignancies that are suitable for larger phase II studies designed to further evaluate the efficacy and toxicity of flavopiridol.
次要结局
- Induced Response in Patients Independent of p53 Mutational Status(Up to 2 years)
- Pharmacodynamic Effects of Flavopiridol on Normal Peripheral Blood Mononuclear Cells (PBMCs).(Day 1)
- Number of Patients Reporting Acute Infusion Toxicity (e.g., Fever, Hypotension, Tumor Pain, and Dyspnea)(Up to 30 days after completion of study treatment)
- Pharmacokinetics (Area Under the Curve; AUC) of Flavopiridol(0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1)
- Pharmacokinetics (Cmax) of Flavopiridol(0, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96 hours post-dose on Days 1 and 22 of Cycle 1)