Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia

Refractory Chronic Lymphocytic Leukemia Clinical Trial

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 Prolymphocytic Leukemia Arising From CLL

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00098371
• Other study ID #: NCI-2009-00111
• Secondary ID: OSU 0491N01CM622
• Status: Terminated
• Phase: Phase 2
• First received: December 7, 2004
• Last updated: February 11, 2013
• Start date: April 2005

Study information

• Verified date: February 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 70
• Est. primary completion date: June 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• B-cell Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Leukemia, Prolymphocytic
• Prolymphocytic Leukemia
• Refractory Chronic Lymphocytic Leukemia

Intervention

Drug:
• alvocidib

Locations

Country	Name	City	State
United States	Ohio State University Medical Center	Columbus	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.	No
Primary	Overall response rate (CR + PR)	PR requires a > 50% decrease in peripheral lymphocyte count from pre-treatment value, > 50% reduction in lymphadenopathy, and/or > 50% reduction in splenomegaly/hepatomegaly for a period of at least two months from completion of therapy. Additionally, these patients must have one of the following: Polymorphonuclear leukocytes > 1,500/µL or 50% improvement from pre-treatment value; Platelets > 100,000/µL or 50% improvement from pre-treatment value; Hemoglobin > 11.0 g/dl (untransfused) or 50% improvement from pre-treatment value.	Evaluated after each 6 week treatment and 2 months after completion of last flavopiridol treatment.	No
Primary	Response duration	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.	Evaluated after each 6 week treatment and 2 months after completion of last flavopiridol treatment.	No
Primary	Progression-free survival as assessed using standard Kaplan-Meier methods	Response evaluation criteria based on the Revised National Cancer Institute-sponsored Working Group Guidelines for response. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). Patients in response categories 4-9 will be considered as failing to respond to treatment (disease progression).	Every 3 months for 5 years after completion of therapy	No
Primary	Overall survival		Every 3 months for 5 years after completion of therapy	No
Primary	Toxicity	Toxicity determination based on NCI Common Toxicity Criteria.	Measurement prior to each infusion, at end of therapy, 2 months post-completion and post-treatment follow-up every 3 months for two years.	Yes
Secondary	PK as assessed by plasma levels of both flavopiridol and metabolites of flavopiridol		During treatment day 1 and day 8 of course 1 and at time of progression/relapse	No
Secondary	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.	No
Secondary	Levels of cytokines (TNF-alpha, IFN-gamma, IL-6 and IL-8) as assessed by blood plasma		At baseline, 4.5 hours, 8 hours, 12 hours, and 24 hours following the initiation of therapy during day 1 and day 8 of course 1. Cytokines also measured if there is evidence of relapse or disease progression in follow-up.	No
Secondary	Comparison of CLL cell samples taken at registration/diagnosis to CLL cell samples taken at time of relapse	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.	At baseline and at time of relapse or when patient goes off therapy due to disease progression	No
Secondary	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		At baseline	No
Secondary	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)	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)	At baseline, 4.5 hours (end of continuous infusion), 8 hours, and approximately 24 hours following initiation of therapy	No
Secondary	Comparison of clinical response and tumor lysis in vivo with drug-induced apoptosis and mitochondrial perturbation in vitro as assessed by flow cytometry	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.	At baseline, 4.5 hours (end of continuous infusion), 8 hours, and approximately 24 hours following initiation of therapy	No