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
18 Years
N/A
Both
B-cell Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Refractory Chronic Lymphocytic Leukemia
Trial Information
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
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 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.
Inclusion Criteria:
- 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
Type of Study:
Interventional
Study Design:
Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Outcome Measure:
Complete response rate
Outcome Description:
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.
Outcome Time Frame:
Evaluated after each 6 week treatment and 2 months after completion of last flavopiridol treatment.
Safety Issue:
No
Principal Investigator
John Byrd
Investigator Role:
Principal Investigator
Investigator Affiliation:
Ohio State University
Authority:
United States: Food and Drug Administration
Study ID:
NCI-2009-00111
NCT ID:
NCT00098371
Start Date:
April 2005
Completion Date:
Related Keywords:
- B-cell Chronic Lymphocytic Leukemia
- Prolymphocytic Leukemia
- Refractory Chronic Lymphocytic Leukemia
- Leukemia
- Leukemia, Lymphocytic, Chronic, B-Cell
- Leukemia, Lymphoid
- Leukemia, Prolymphocytic
Name | Location |
|---|---|
| Ohio State University Medical Center | Columbus, Ohio 43210 |
