A Phase II Study of Flavopiridol Administered as a 30 Minute Loading Dose Followed by a 4-Hour Continuous Infusion in Patients With Previously Treated B-Cell Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia Arising From CLL
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 64
- 试验地点
- 1
- 主要终点
- Complete Response (CR) Rate
研究概览
简要总结
This phase II trial is studying how well flavopiridol works in treating patients with chronic lymphocytic leukemia or prolymphocytic leukemia. 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. To determine the complete response (CR) and overall response rate (CR + Partial Response [PR]) of this regimen.
II. To assess the toxicity profile of this regimen. III. To examine response duration, progression-free survival and overall survival, following this treatment.
IV. To assess the pharmacokinetics of this novel schedule of administration.
SECONDARY OBJECTIVES:
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 B-cell chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) arising from CLL
- •No de novo PLL
- •Lymphocyte count > 5,000/mm^3 at some point since initial diagnosis of CLL
- •B-cells co-expressing CD5 AND CD19 or CD20
- •If no dim serum immunoglobulin or CD23 expression on leukemia cells, must be examined for cyclin D1 overexpression OR t(11;14) to rule out mantle cell lymphoma
- •Requiring therapy, defined by any of the following:
- •Massive or progressive splenomegaly and/or lymphadenopathy
- •Anemia (hemoglobin < 11 g/dL) OR thrombocytopenia (platelet count < 100,000/mm^3)
- •Weight loss > 10% within the past 6 months
- •Grade 2 or 3 fatigue
- •Fevers > 100.5°C or night sweats for > 2 weeks with no evidence of infection
- •Progressive lymphocytosis with an increase of > 50% over a 2-month period OR an anticipated doubling time < 6 months
- •Received ≥ 1 prior chemotherapy regimen that included fludarabine or nucleoside equivalent OR alternative therapy if contraindication to fludarabine exists (i.e., autoimmune hemolytic anemia)
- •Performance status - ECOG 0-2
- •More than 2 years
- •See Disease Characteristics
- •Baseline cytopenias allowed
- •WBC ≤ 200,000/mm^3
- •Bilirubin ≤ 1.5 times upper limit of normal (ULN) (unless due to Gilbert's disease, hemolysis, or disease infiltration of the liver)
- •AST ≤ 2 times ULN (unless due to hemolysis or disease infiltration of the liver)
- •Creatinine ≤ 2.0 mg/dL
- •Not pregnant or nursing
- •Negative pregnancy test
- •Fertile patients must use effective contraception
- •No other malignancy that would limit life expectancy
- •See Disease Characteristics
- •No other concurrent chemotherapy
- •No concurrent chronic corticosteroids or corticosteroids as antiemetics
- •No concurrent hormonal therapy except steroids for new adrenal failure or hormones for nondisease-related conditions (e.g., insulin for diabetes)
- •No concurrent radiotherapy
排除标准
- 未提供
研究组 & 干预措施
Treatment (alvocidib)
Patients receive flavopiridol IV over 30 minutes followed by a 4-hour infusion on days 1, 8, 15, and 22. Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients achieving at least a partial remission (PR) and whose PR lasts for > 6 months after completion of treatment may receive 6 additional courses of flavopiridol.
干预措施: alvocidib (Drug)
结局指标
主要结局
Complete Response (CR) Rate
时间窗: Up to 8 months
CR requires all of the following for at least two months from completion of therapy: Absence of lymphadenopathy in excess of 1 cm on physical exam; No hepatomegaly or splenomegaly on physical exam; Absence of constitutional symptoms; Normal CBC (complete blood count) as exhibited by polymorphonuclear leukocytes \> 1500/µL, platelets \> 100,000/µL, hemoglobin \> 11.0 g/dl (untransfused); lymphocyte count \< 5,000/µL; Bone marrow aspirate and biopsy must be normocellular for age with \< 30% of nucleated cells being lymphocytes. Lymphoid nodules must be absent.
Overall Response Rate (CR + PR)
时间窗: Up to 8 months
CR requires all of the following: Absence of lymphadenopathy in excess of 1 cm on physical exam; No hepatomegaly or splenomegaly on physical exam; Absence of constitutional symptoms; Normal CBC as exhibited by polymorphonuclear leukocytes \> 1500/µL, platelets \> 100,000/µL, hemoglobin \> 11.0 g/dl (untransfused); lymphocyte count \< 5,000/µL; Bone marrow aspirate and biopsy must be normocellular for age with \< 30% of nucleated cells being lymphocytes. Lymphoid nodules must be absent. Patients with CR after induction but wih treatment-related persistent cytopenia is a PR. PR requires a \> 50% decrease in peripheral lymphocyte count from pretreatment value, \> 50% reduction in lymphadenopathy, and/or \> 50% reduction in splenomegaly/hepatomegaly. These patients must have one of the following: polymorphonuclear leukocytes \> 1,500/μL , platelets \> 100,000/μL, hemoglobin \> 11.0 g/dl (untransfused) or any with 50% improvement from pretreatment value.
Response Duration
时间窗: Up to 8 months
Response evaluation criteria based on the Revised National Cancer Institute-sponsored Working Group Guidelines for response. Descriptive statistics will be computed (median, range, mean, standard deviation, minimum, and maximum) on response duration.
Progression-free Survival (PFS) for Responding Patients as Assessed Using Standard Kaplan-Meier Methods
时间窗: Up to 5 years
PFS was calculated from the date of study entry until time of disease progression or death, whichever came first, censoring patients alive and relapse free at last follow up. Patients who withdrew from study to undergo an allogeneic SCT (Stem cell transplantation) were censored at the time of transplantation.
Progression-free Survival for All Patients as Assessed Using Standard Kaplan-Meier Methods
时间窗: Up to 5 years
PFS was calculated from the date of study entry until time of disease progression or death, whichever came first, censoring patients alive and relapse free at last follow up. Patients who withdrew from study to undergo an allogeneic SCT were censored at the time of transplantation.
Overall Survival
时间窗: Up to 5 years
Overall survival data will be reported on a 3-month basis for 5 years
Toxicity
时间窗: Measurement prior to each infusion, at end of therapy, 2 months post-completion and post-treatment follow-up every 3 months for two years.
Toxicity determination based on NCI Common Toxicity Criteria version 3 and modified NCI Common toxicity guidelines for evaluating hematologic toxicity in leukemia.
次要结局
- Comparison of CLL Cell Samples Taken at Registration/Diagnosis to CLL Cell Samples Taken at Time of Relapse(At baseline and at time of relapse or when patient goes off therapy due to disease progression)
- Correlation of Adverse Prognostic Factors With Response to Flavopiridol Treatment as Assessed by Interphase Cytogenetics, VH Mutational Status, ZAP-70 Protein Expression, CD38, and p53(up to 8 months)
- Levels of Mcl-1 mRNA, Mcl-1 Protein, HIF-1alpha Protein, HIF-1alpha mRNA, NF-kappaB Activation, Total IkB, IkB Phosphorylation, GSK-beta Activity, and IL-6 Target Genes (i.e., STAT3)(At baseline, 4.5 hours (end of continuous infusion), 8 hours, and approximately 24 hours following initiation of therapy)
- Comparison of Clinical Response and Tumor Lysis in Vivo With Drug-induced Apoptosis and Mitochondrial Perturbation in Vitro as Assessed by Flow Cytometry(At baseline)
- Pharmacokinetics (PK) (AUC) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol(During treatment day 1 and day 8 of cycle 1)
- PK (Cmax) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol(During treatment day 1 and day 8 of course 1)
- PK as Assessed by Levels of Both Flavopiridol and Metabolites of Flavopiridol in Urine Samples(Urine collected at 4 separate times in some patients during the first 24 hours after start of infusion on day 1 of course 1.)
- Serial Levels of IL-6 as Assessed by Blood Plasma(4.5 hours, 8 hours, 12 hours, and 24 hours following the initiation of therapy during day 1 of course 1)