Clinical Trial: Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia

Study Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: 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

Brief Summary: 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

Detailed Summary:

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:

I. To determine the influence of adverse prognostic factors including interphase cytogenetics, VH mutational status, ZAP-70 expression, CD38, and p53 mutational status with response to flavopiridol treatment.

II. To determine the influence of flavopiridol treatment on serial measurements of mcl-1 (mRNA and protein), HIF-1 (mRNA and protein), NF-kappaB activity, IkappaB, IkappaB phosphorylation, GSK-beta, and IL-6 down-stream targets.

III. To assess the relationship of drug induced apoptosis and mitochondrial perturbation of Chronic Lymphocytic Leukemia (CLL) cells in vitro and subsequent relationship to clinical response and tumor lysis in vivo.

IV. To examine cytokine levels (IL-6, IFN-gamma, TNF-alpha) during treatment with flavopiridol.

V. To assess pharmacokinetics (PK) to determine the variability of PK and PD analyses between treatment administrations and correlation with specific Single Nucleotide Polymorphisms (SNPs) potentially involved in flavopiridol disposition.

VI. To assess differences in diagnosis and relapse samples to investig
Sponsor: National Cancer Institute (NCI)

Current Primary Outcome:

  • Complete Response (CR) Rate [ Time Frame: 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) [ Time Frame: 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.
  • Pharmacokinetics (PK) (AUC) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol [ Time Frame: During treatment day 1 and day 8 of cycle 1 ]
    Pharmacokinetics were performed on day 1 and day 8 of cycle 1 by plasma levels of both flavopiridol and metabolites of flavopiridol using Area Under the Curve (AUC)
  • PK (Cmax) as Assessed by Plasma Levels of Both Flavopiridol and Metabolites of Flavopiridol [ Time Frame: During treatment day 1 and day 8 of course 1 ]
    Pharmacokinetics were performed on day 1 and day 8 of cycle 1 by plasma levels of both flavopiridol and metabolites of flavopiridol
  • PK as Assessed by Levels of Both Flavopiridol and Metabolites of Flavopiridol in Urine Samples [ Time Frame: Urine collected at 4 separate times in some patients during the first 24 hours after start of infusion on day 1 of course 1. ]
    urine samples were collected in some patients during the first 24 hours after the start of the infusion on cycle 1, day 1 to isolate metabolites of flavopiridol to be used as internal standard for plasma metabolite quantification experiments.
  • Serial Levels of IL-6 as Assessed by Blood Plasma [ Time Frame: 4.5 hours, 8 hours, 12 hours, and 24 hours following the initiation of therapy during day 1 of course 1 ]
    IL-6 measures were adjusted for baseline values
  • Comparison of CLL Cell Samples Taken at Registration/Diagnosis to CLL Cell Samples Taken at Time of Relapse [ Time Frame: At baseline and at time of relapse or when patient goes off therapy due to disease progression ]
    Samples will be examined for ex vivo sensitivity to flavopiridol, expression of select anti-apoptosis proteins, BCRP mRNA and protein expression, difference in gene expression by cDNA microarray and potentially by epigenetic arrays. Comparisons will be used to evaluate mechanisms of acquired flavopiridol resistance.
  • 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 [ Time Frame: up to 8 months ]
    overall response rates (CR+PR)
  • 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) [ Time Frame: At baseline, 4.5 hours (end of continuous infusion), 8 hours, and approximately 24 hours following initiation of therapy ]
    Assessed by real time RT-PCR (mcl-1, HIF-1alpha), immunoblot analysis (mcl-1, HIF-1alpha, I-kappaB, I-kappaB phosphorylation, targets of IL-6), and electrophoretic mobility shift analysis (NF-kappaB activation)
  • Comparison of Clinical Response and Tumor Lysis in Vivo With Drug-induced Apoptosis and Mitochondrial Perturbation in Vitro as Assessed by Flow Cytometry [ Time Frame: At baseline ]
    CLL cells will be incubated with control or flavopiridol (1 or 2.8 microMolar) for 4-hours followed by a 20 hours in media with 10% heat-inactivated human serum. Assessment of apoptosis following exposure of human CLL cells will be performed using annexin/PI flow cytometry. Patient samples with greater than 50% live cells (annexin-/PI-) following exposure to 2.8 microMolar flavopiridol will be considered to have insensitive disease. Patients whose CLL cells have less than 50% live cells at 1 microMolar will be considered to have highly sensitive disease.


Original Secondary Outcome:

Information By: National Cancer Institute (NCI)

Dates:
Date Received: December 7, 2004
Date Started: April 2005
Date Completion:
Last Updated: August 31, 2016
Last Verified: August 2016