Flavopiridol in Treating Patients With Chronic Lymphocytic Leukemia or Prolymphocytic Leukemia

Brief Summary

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”

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

  • Study Type: Interventional
  • Study Design: Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
  • Study Primary Completion Date: June 2009

Detailed Clinical Trial 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.

Interventions Used in this Clinical Trial

  • Drug: alvocidib

Arms, Groups and Cohorts in this Clinical Trial

  • Experimental: 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.

Outcome Measures for this Clinical Trial

Primary Measures

  • Complete response rate
    • Time Frame: Evaluated after each 6 week treatment and 2 months after completion of last flavopiridol treatment.
      Safety Issue?: No
  • Overall response rate (CR + PR)
    • Time Frame: Evaluated after each 6 week treatment and 2 months after completion of last flavopiridol treatment.
      Safety Issue?: No
  • Response duration
    • Time Frame: Evaluated after each 6 week treatment and 2 months after completion of last flavopiridol treatment.
      Safety Issue?: No
  • Progression-free survival as assessed using standard Kaplan-Meier methods
    • Time Frame: Every 3 months for 5 years after completion of therapy
      Safety Issue?: No
  • Overall survival
    • Time Frame: Every 3 months for 5 years after completion of therapy
      Safety Issue?: No
  • Toxicity
    • Time Frame: Measurement prior to each infusion, at end of therapy, 2 months post-completion and post-treatment follow-up every 3 months for two years.
      Safety Issue?: Yes

Secondary Measures

  • PK as assessed by plasma levels of both flavopiridol and metabolites of flavopiridol
    • Time Frame: During treatment day 1 and day 8 of course 1 and at time of progression/relapse
      Safety Issue?: No
  • 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.
      Safety Issue?: No
  • Levels of cytokines (TNF-alpha, IFN-gamma, IL-6 and IL-8) as assessed by blood plasma
    • Time Frame: 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.
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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: At baseline
      Safety Issue?: No
  • 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
      Safety Issue?: No
  • 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, 4.5 hours (end of continuous infusion), 8 hours, and approximately 24 hours following initiation of therapy
      Safety Issue?: No

Criteria for Participation in this Clinical Trial

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial: No

Clinical Trial Investigator Information

  • Lead Sponsor
    • National Cancer Institute (NCI)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • John Byrd, Principal Investigator, Ohio State University

Source

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The URL of this page is:
http://clinicaltrialsfeeds.org/clinical-trials/show/NCT00098371