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
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.
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
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 investigate mechanisms of
acquired flavopiridol resistance in primary CLL cells.
OUTLINE: This is an open-label study. 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.Patients are followed at 2 months and then every 3 months for 5 years.
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Complete response rate
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 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.
Evaluated after each 6 week treatment and 2 months after completion of last flavopiridol treatment.
Ohio State University
United States: Food and Drug Administration
|Ohio State University Medical Center||Columbus, Ohio 43210|