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
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. All patients receive intrathecal cytarabine prior to courses 1 and 2. In both arms, treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed periodically for at least 5 years.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
52
Given IV
Given IV or IT
Given IV
Given IV
Correlative studies
University of Alabama at Birmingham
Birmingham, Alabama, United States
Phoenix Childrens Hospital
Phoenix, Arizona, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Southern California Permanente Medical Group
Downey, California, United States
Miller Children's Hospital
Long Beach, California, United States
Dose Limiting Toxicity
Number of participants with dose limiting toxicity.
Time frame: During Course 1
Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1
Overall response (complete remission \[CR\] and CR with partial recovery \[CRp\]) during course 1.
Time frame: After course 1
NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)
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.
Time frame: At baseline, prior to and up to 24 hours after bortezomib treatment
Proteasome Inhibition Activity
Mean and standard deviation of β1 and β5- Results are ratios (proteasome subunit/β-actin based on loading of 15 µg total protein, normalized to CEM).
Time frame: At baseline
Protein Expression Assessed by Western Blot
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.
Time frame: At baseline, prior to and up to 24 hours after bortezomib treatment
Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion
Descriptive statistics to assess mean +/- standard deviation for the percentage leukemia initiation cells (LIC) depletion.
Time frame: At baseline and after completion of course 1
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Children's Hospital and Research Center at Oakland
Oakland, California, United States
Childrens Hospital of Orange County
Orange, California, United States
Packard Children's Hospital Stanford University
Palo Alto, California, United States
University of California San Francisco Medical Center
San Francisco, California, United States
Connecticut Children's Medical Center
Hartford, Connecticut, United States
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