Clinical Trial: Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: A Phase II Pilot Study of Bortezomib (PS-341, Velcade) Combined With Reinduction Chemotherapy in Children and Young Adults With Recurrent, Refractory or Secondary Acute Myeloid Leukemia

Brief Summary: This phase II trial is studying the side effects and best dose of bortezomib and to see how well it works when given together with combination chemotherapy in treating younger patients with recurrent, refractory, or secondary acute myeloid leukemia (AML). Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as idarubicin, cytarabine, and etoposide, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with bortezomib may kill more cancer cells

Detailed Summary:

PRIMARY OBJECTIVES:

I. To determine the toxicities and tolerability of bortezomib in combination with standard-relapse AML therapy (idarubicin/cytarabine or etoposide/high-dose cytarabine) in pediatric and young adult patients with relapsed or primary-refractory or secondary AML.

II. To estimate the complete response rate to the Arm A and Arm B regimens.

SECONDARY OBJECTIVES:

I. To determine whether bortezomib inhibits proteasome activity, NF-kB activity and induces apoptosis pathway proteins in leukemia myeloblasts. II. To determine the feasibility of measuring AML stem cells in relapsed and recovering bone marrow.

OUTLINE: This is a multicenter, dose-escalation study of bortezomib. Patients are stratified according to anthracycline*-equivalent cumulative exposure (≤ 400 mg/m² vs > 400 mg/m²). Patients are assigned to 1 of 2 groups.

GROUP I (efficacy phase, patients with ≤ 400 mg/m² anthracycline-equivalent cumulative exposure - Closed as of 08/01/10): Patients receive idarubicin IV over 15 minutes on days 1-3, low-dose cytarabine IV continuously over days 1-7, and bortezomib IV on days 1, 4, and 8.

GROUP II (dose-finding phase (closed as of 10/10) and efficacy phase, patients with > 400 mg/m² anthracycline*-equivalent cumulative exposure): Patients receive etoposide IV over 1 hour on days 1-5, high-dose cytarabine IV over 1 hour twice daily on days 1-5, and bortezomib IV on days 1, 4, and 8.

NOTE: * Anthracycline restriction no longer required for group 2 as of 10/02/10.

  • Dose Limiting Toxicity [ Time Frame: During Course 1 ]
    Number of participants with dose limiting toxicity.
  • Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1 [ Time Frame: After course 1 ]
    Overall response (complete remission [CR] and CR with partial recovery [CRp]) during course 1.


    • Original Primary Outcome:

    • Maximum tolerated dose of bortezomib
    • Toxicity and tolerability
    • Overall response rate


    Current Secondary Outcome:

    • NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA) [ Time Frame: At baseline, prior to and up to 24 hours after bortezomib treatment ]
      NF-kB activity will be measured as a continuous variable (ng NF-kB/Mg protein). Differences in NF-κB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range. We may perform exploratory analyses to determine if single time point measurements, or the difference between time points, correlate with treatment response.
    • Proteasome Inhibition Activity [ Time Frame: At baseline, 2 hours prior to and 3 hours after first bortezomib dose ]
      Descriptive statistics will be used to determine the mean and standard deviation of proteasome inhibition.
    • Protein Expression Assessed by Western Blot [ Time Frame: At baseline, prior to and up to 24 hours after bortezomib treatment ]
      Relative expression of apoptotic and cell cycle proteins will be characterized using descriptive statistics. If differences are noted between pre and post-treatment protein expression, pairwise comparisons will be made using paired t-test or an equivalent nonparametric test if the data are non-normally distributed. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.
    • Feasibility of Stem Cell Quantitation [ Time Frame: At baseline and after completion of course 1 ]
      Descriptive statistics to assess mean +/- standard deviation for stem cell percentage before and after bortezomib treatment. If there appears to be a difference in responders vs. nonresponders, stem cell percentage differences between responders and nonresponders will be compared using a paired t-test or equivalent nonparametric test.


    Original Secondary Outcome:

    Information By: National Cancer Institute (NCI)

    Dates:
    Date Received: April 24, 2008
    Date Started: April 2008
    Date Completion:
    Last Updated: May 13, 2014
    Last Verified: December 2013