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

Primary Purpose

Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2)

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
idarubicin
cytarabine
bortezomib
etoposide
laboratory biomarker analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Acute Monoblastic Leukemia (M5a)

Eligibility Criteria

1 Year - 21 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diagnosis of acute myeloid leukemia (AML) according to WHO classification

    • At least 5% blasts in the bone marrow
    • With or without extramedullary disease
  • To be eligible for the dose-finding phase (closed as of 10/10) :

    • Relapsed patients must meet the following criteria:

      • Must have had a prior diagnosis of AML, but may NOT have inv(16) or t(8;21) cytogenetics
      • May be in first or any subsequent relapse
      • If in first relapse, remission duration must be less than one year
    • Refractory patients must meet the following criteria:

      • Must have had a prior diagnosis of AML
      • May have received one or more attempt at remission induction
    • Patients with treatment-related AML may be previously treated or untreated for secondary AML
  • To be eligible for the efficacy phase:

    • Relapsed patients must meet the following criteria:

      • Must have had a prior diagnosis of AML, with no restriction on prior cytogenetics
      • Must be in first relapse
      • Must not have received prior reinduction therapy
    • Refractory patients must meet the following criteria:

      • Must have had a prior diagnosis of AML
      • Must not have received more than one attempt at remission induction (which may consist of up to two therapy courses)
    • Patients with treatment-related AML must be previously untreated for secondary AML
  • No juvenile myelomonocytic leukemia or acute promyelocytic leukemia (APL; FAB M3)
  • Patients with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy:

    • CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs
    • CNS 2, defined as presence of < 5/μL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm:

      • CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts
      • CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts
      • CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm
  • Patients with CNS3 disease (presence of ≥ 5/μL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia) are not eligible
  • CNS toxicity ≤ grade 2
  • Lansky (patients ≤ 16 years of age) or Karnofsky (patients > 16 years of age) performance status (PS) 50-100%
  • ECOG PS 0-2
  • No Down syndrome
  • No Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome
  • No evidence of active graft-vs-host disease
  • Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age/gender as follows:

    • 0.4 mg/dL for patients 1 month to < 6 months of age
    • 0.5 mg/dL for patients 6 months to < 1 year of age
    • 0.6 mg/dL for patients 1 to < 2 years of age
    • 0.8 mg/dL for patients 2 to < 6 years of age
    • 1 mg/dL for patients 6 to < 10 years of age
    • 1.2 mg/dL for patients 10 to < 13 years of age
    • 1.5 mg/dL (male) or 1.4 mg/dL (female) for patients 13 to < 16 years of age
    • 1.7 mg/dL (male) or 1.4 mg/dL (female) for patients ≥ 16 years of age
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
  • ALT < 3.0 times ULN for age (unless elevation due to leukemia involvement)
  • Shortening fraction ≥ 27% by ECHO OR LVEF ≥ 50% by gated radionuclide
  • Normal respiratory rate and pulse oximetry > 94% on room air
  • FEV_1 ≥ 80% of predicted
  • FVC and DLCO > 50% (corrected for hemoglobin)

    • Patients who are unable to perform pulmonary function tests (PFTs) (e.g., because of young age) will be excluded provided they have a medical history of significant prior pulmonary events or chronic pulmonary disease (e.g., pneumonia requiring mechanical ventilation support, pulmonary GVHD, pneumonectomy, or pulmonary toxin exposure)
    • Children with histories of resolved bronchiolitis, resolved viral pneumonias and well-controlled asthma are eligible, even if they are unable to perform PFTs
  • Patients with seizure disorder may be enrolled if on a non-enzyme-inducing anticonvulsant and if seizures are well-controlled
  • No uncontrolled infection
  • No known allergy to idarubicin, cytarabine, etoposide, boron, mannitol or bortezomib
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Concurrent radiotherapy allowed for patients who present with a chloroma that is producing or threatens to produce an irreversible neurologic deficit
  • Recovered from all prior chemotherapy, immunotherapy, or radiotherapy
  • More than 2 weeks since prior cytotoxic chemotherapy (4 weeks for nitrosoureas), except for hydroxyurea, which is allowed up to 24 hours prior to first dose of study drug, and intrathecal chemotherapy, which is allowed immediately up to administration of study drug
  • Prior steroid allowed as clinically indicated for patients with asthma

    • Hydrocortisone and methylprednisolone allowed as premedication in patients with a history of severe allergic reactions
  • At least 7 days since prior biologic agents, such as steroids, retinoids, or donor lymphocyte infusion without conditioning
  • At least 2 weeks since prior local palliative radiotherapy (small port)
  • At least 8 weeks since prior craniospinal radiotherapy or ≥ 50% radiation of pelvis
  • At least 6 weeks since prior other bone marrow radiation
  • At least 1 day since prior green tea containing products, any products containing vitamin C, flavanoids or other antioxidants (e.g., vitamins, herbal supplements), and foods with high vitamin C content
  • No prior radiotherapy to > 25% of lung volume
  • No prior total-body irradiation as part of a hematopoietic stem cell conditioning regimen
  • At least 2 months since prior stem cell transplantation
  • No concurrent graft-vs-host disease prophylactic medication
  • No prior bortezomib or other proteasome inhibitors
  • No other concurrent investigational drugs
  • More than 4 days since prior growth factors that support platelet or white cell number or function
  • No concurrent enzyme-inducing anticonvulsant medications known to be potent inducers of the cytochrome P450 system, including phenytoin, carbamazepine, and phenobarbital

    • Concurrent benzodiazepines and gabapentin allowed
  • No concurrent grapefruit juice with bortezomib
  • No other concurrent cancer chemotherapy or immunomodulating agents
  • No concurrent corticosteroids as anti-emetic therapy

    • Concurrent corticosteroids therapy allowed as treatment or prophylaxis for anaphylactic reactions, symptoms of cytarabine syndrome, and as treatment for presumptive bortezomib-induced pulmonary toxicity.

Sites / Locations

  • University of Alabama at Birmingham
  • Phoenix Childrens Hospital
  • University of Arkansas for Medical Sciences
  • Southern California Permanente Medical Group
  • Miller Children's Hospital
  • Children's Hospital and Research Center at Oakland
  • Childrens Hospital of Orange County
  • Packard Children's Hospital Stanford University
  • University of California San Francisco Medical Center
  • Connecticut Children's Medical Center
  • Alfred I duPont Hospital for Children
  • Children's National Medical Center
  • Broward General Medical Center
  • Lee Memorial Health System
  • Nemours Children's Clinic - Jacksonville
  • University of Miami Miller School of Medicine-Sylvester Cancer Center
  • Nemours Childrens Clinic - Orlando
  • Nemours Children's Clinic - Pensacola
  • All Children's Hospital
  • Saint Joseph Children's Hospital of Tampa
  • Children's Healthcare of Atlanta - Egleston
  • Memorial Health University Medical Center
  • University of Hawaii
  • Childrens Memorial Hospital
  • Southern Illinois University
  • Riley Hospital for Children
  • University of Kentucky
  • Tulane University Health Sciences Center
  • Sinai Hospital of Baltimore
  • Dana-Farber Cancer Institute
  • C S Mott Children's Hospital
  • Michigan State University - Breslin Cancer Center
  • Helen DeVos Children's Hospital at Spectrum Health
  • Children's Hospitals and Clinics of Minnesota - Minneapolis
  • University of Minnesota Medical Center-Fairview
  • Mayo Clinic
  • University of Mississippi Medical Center
  • The Childrens Mercy Hospital
  • Washington University School of Medicine
  • University of Nebraska Medical Center
  • Nevada Cancer Research Foundation CCOP
  • Hackensack University Medical Center
  • UMDNJ - Robert Wood Johnson University Hospital
  • Newark Beth Israel Medical Center
  • Overlook Hospital
  • University of New Mexico
  • Columbia University Medical Center
  • State University of New York Upstate Medical University
  • University of North Carolina
  • Carolinas Medical Center
  • Wake Forest University Health Sciences
  • Children's Hospital Medical Center of Akron
  • Cincinnati Children's Hospital Medical Center
  • Rainbow Babies and Childrens Hospital
  • Cleveland Clinic Foundation
  • Nationwide Children's Hospital
  • The Children's Medical Center of Dayton
  • University of Oklahoma Health Sciences Center
  • Legacy Emanuel Hospital and Health Center
  • Penn State Hershey Children's Hospital
  • Children's Hospital of Philadelphia
  • Childrens Hospital of Pittsburgh
  • Rhode Island Hospital
  • Palmetto Health Richland
  • Sanford University of South Dakota Medical Center
  • East Tennessee Childrens Hospital
  • St. Jude Children's Research Hospital
  • Driscoll Children's Hospital
  • University of Texas Southwestern Medical Center
  • Cook Children's Medical Center
  • Baylor College of Medicine
  • University of Texas Health Science Center
  • Primary Children's Medical Center
  • Seattle Children's Hospital
  • Saint Vincent Hospital
  • Marshfield Clinic
  • Midwest Children's Cancer Center
  • Princess Margaret Hospital for Children
  • CancerCare Manitoba
  • IWK Health Centre
  • Hospital for Sick Children
  • Hospital Sainte-Justine

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Experimental

Experimental

Experimental

Arm Label

Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure

Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp

Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp

Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp

Arm Description

Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.

Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.

Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).

Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity

Outcomes

Primary Outcome Measures

Dose Limiting Toxicity
Number of participants with dose limiting toxicity.
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.

Secondary Outcome Measures

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.
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).
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.
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.

Full Information

First Posted
April 24, 2008
Last Updated
May 21, 2018
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00666588
Brief Title
Bortezomib and Combination Chemotherapy in Treating Younger Patients With Recurrent, Refractory, or Secondary Acute Myeloid Leukemia
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
April 2008 (undefined)
Primary Completion Date
December 2012 (Actual)
Study Completion Date
December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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 Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Acute Monoblastic Leukemia (M5a), Adult Acute Monocytic Leukemia (M5b), Adult Acute Myeloblastic Leukemia With Maturation (M2), Adult Acute Myeloblastic Leukemia Without Maturation (M1), Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myelomonocytic Leukemia (M4), Childhood Acute Basophilic Leukemia, Childhood Acute Eosinophilic Leukemia, Childhood Acute Erythroleukemia (M6), Childhood Acute Megakaryocytic Leukemia (M7), Childhood Acute Minimally Differentiated Myeloid Leukemia (M0), Childhood Acute Monoblastic Leukemia (M5a), Childhood Acute Monocytic Leukemia (M5b), Childhood Acute Myeloblastic Leukemia With Maturation (M2), Childhood Acute Myeloblastic Leukemia Without Maturation (M1), Childhood Acute Myelomonocytic Leukemia (M4), Recurrent Adult Acute Myeloid Leukemia, Recurrent Childhood Acute Myeloid Leukemia, Secondary Acute Myeloid Leukemia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure
Arm Type
Experimental
Arm Description
Bortezomib 1.3mg/m2 to assess efficacy in low prior anthracycline exposure. Patients receive idarubicin IV (12 mg/m2/day) over 15 minutes on days 1-3, low-dose cytarabine IV (100 mg/m2/day) continuously over days 1-7, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (closed as of 08/01/10). Dosage modification based on age < 3 years old.
Arm Title
Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp
Arm Type
Experimental
Arm Description
Bortezomib 1.0 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.0 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity.
Arm Title
Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp
Arm Type
Experimental
Arm Description
Bortezomib 1.3 mg/m2 to assess feasibility in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity (dose-finding phase closed as of 10/10).
Arm Title
Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp
Arm Type
Experimental
Arm Description
Bortezomib 1.3 mg/m2 to assess efficacy in high prior anthracycline exposure. Patients receive etoposide IV (150 mg/m2/dose) over 1 hour on days 1-5, high-dose cytarabine IV (1000 mg/m2/dose) over 1 hour twice daily on days 1-5, and bortezomib IV (1.3 mg/m2) on days 1, 4, and 8. All patients receive intrathecal cytarabine (30 mg - age 1-1.99 years, 50 mg - age 2-2.99 years, 70 mg - age ≥ 3 years) prior to courses 1 and 2. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity
Intervention Type
Drug
Intervention Name(s)
idarubicin
Other Intervention Name(s)
4-demethoxydaunorubicin, 4-DMDR, DMDR, IDA
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
cytarabine
Other Intervention Name(s)
ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside
Intervention Description
Given IV or IT
Intervention Type
Drug
Intervention Name(s)
bortezomib
Other Intervention Name(s)
LDP 341, MLN341, VELCADE
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
etoposide
Other Intervention Name(s)
EPEG, VP-16, VP-16-213
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
laboratory biomarker analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Dose Limiting Toxicity
Description
Number of participants with dose limiting toxicity.
Time Frame
During Course 1
Title
Overall Response (Complete Remission [CR] and CR With Partial Recovery [CRp]) During Course 1
Description
Overall response (complete remission [CR] and CR with partial recovery [CRp]) during course 1.
Time Frame
After course 1
Secondary Outcome Measure Information:
Title
NF-kB Activity by Enzyme-linked Immunosorbent Assay (ELISA)
Description
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
Title
Proteasome Inhibition Activity
Description
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
Title
Protein Expression Assessed by Western Blot
Description
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
Title
Feasibility of Stem Cell Quantitation: Percentage of Leukemia Initiation Cells (LIC) Depletion
Description
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
21 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diagnosis of acute myeloid leukemia (AML) according to WHO classification At least 5% blasts in the bone marrow With or without extramedullary disease To be eligible for the dose-finding phase (closed as of 10/10) : Relapsed patients must meet the following criteria: Must have had a prior diagnosis of AML, but may NOT have inv(16) or t(8;21) cytogenetics May be in first or any subsequent relapse If in first relapse, remission duration must be less than one year Refractory patients must meet the following criteria: Must have had a prior diagnosis of AML May have received one or more attempt at remission induction Patients with treatment-related AML may be previously treated or untreated for secondary AML To be eligible for the efficacy phase: Relapsed patients must meet the following criteria: Must have had a prior diagnosis of AML, with no restriction on prior cytogenetics Must be in first relapse Must not have received prior reinduction therapy Refractory patients must meet the following criteria: Must have had a prior diagnosis of AML Must not have received more than one attempt at remission induction (which may consist of up to two therapy courses) Patients with treatment-related AML must be previously untreated for secondary AML No juvenile myelomonocytic leukemia or acute promyelocytic leukemia (APL; FAB M3) Patients with the following CNS status are eligible only in the absence of neurologic symptoms suggestive of CNS leukemia, such as cranial nerve palsy: CNS 1, defined as absence of blasts in cerebral spinal fluid (CSF) on cytospin preparation, regardless of the number of WBCs CNS 2, defined as presence of < 5/μL WBCs in CSF and cytospin positive for blasts, or > 5/uL WBCs but negative by Steinherz/Bleyer algorithm: CNS 2a: < 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts CNS 2b: ≥ 10/μL RBCs; < 5/μL WBCs and cytospin positive for blasts CNS 2c: ≥ 10/μL RBCs; ≥ 5/μL WBCs and cytospin positive for blasts but negative by Steinherz/Bleyer algorithm Patients with CNS3 disease (presence of ≥ 5/μL WBCs in CSF and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia) are not eligible CNS toxicity ≤ grade 2 Lansky (patients ≤ 16 years of age) or Karnofsky (patients > 16 years of age) performance status (PS) 50-100% ECOG PS 0-2 No Down syndrome No Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome No evidence of active graft-vs-host disease Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR serum creatinine based on age/gender as follows: 0.4 mg/dL for patients 1 month to < 6 months of age 0.5 mg/dL for patients 6 months to < 1 year of age 0.6 mg/dL for patients 1 to < 2 years of age 0.8 mg/dL for patients 2 to < 6 years of age 1 mg/dL for patients 6 to < 10 years of age 1.2 mg/dL for patients 10 to < 13 years of age 1.5 mg/dL (male) or 1.4 mg/dL (female) for patients 13 to < 16 years of age 1.7 mg/dL (male) or 1.4 mg/dL (female) for patients ≥ 16 years of age Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age ALT < 3.0 times ULN for age (unless elevation due to leukemia involvement) Shortening fraction ≥ 27% by ECHO OR LVEF ≥ 50% by gated radionuclide Normal respiratory rate and pulse oximetry > 94% on room air FEV_1 ≥ 80% of predicted FVC and DLCO > 50% (corrected for hemoglobin) Patients who are unable to perform pulmonary function tests (PFTs) (e.g., because of young age) will be excluded provided they have a medical history of significant prior pulmonary events or chronic pulmonary disease (e.g., pneumonia requiring mechanical ventilation support, pulmonary GVHD, pneumonectomy, or pulmonary toxin exposure) Children with histories of resolved bronchiolitis, resolved viral pneumonias and well-controlled asthma are eligible, even if they are unable to perform PFTs Patients with seizure disorder may be enrolled if on a non-enzyme-inducing anticonvulsant and if seizures are well-controlled No uncontrolled infection No known allergy to idarubicin, cytarabine, etoposide, boron, mannitol or bortezomib Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Concurrent radiotherapy allowed for patients who present with a chloroma that is producing or threatens to produce an irreversible neurologic deficit Recovered from all prior chemotherapy, immunotherapy, or radiotherapy More than 2 weeks since prior cytotoxic chemotherapy (4 weeks for nitrosoureas), except for hydroxyurea, which is allowed up to 24 hours prior to first dose of study drug, and intrathecal chemotherapy, which is allowed immediately up to administration of study drug Prior steroid allowed as clinically indicated for patients with asthma Hydrocortisone and methylprednisolone allowed as premedication in patients with a history of severe allergic reactions At least 7 days since prior biologic agents, such as steroids, retinoids, or donor lymphocyte infusion without conditioning At least 2 weeks since prior local palliative radiotherapy (small port) At least 8 weeks since prior craniospinal radiotherapy or ≥ 50% radiation of pelvis At least 6 weeks since prior other bone marrow radiation At least 1 day since prior green tea containing products, any products containing vitamin C, flavanoids or other antioxidants (e.g., vitamins, herbal supplements), and foods with high vitamin C content No prior radiotherapy to > 25% of lung volume No prior total-body irradiation as part of a hematopoietic stem cell conditioning regimen At least 2 months since prior stem cell transplantation No concurrent graft-vs-host disease prophylactic medication No prior bortezomib or other proteasome inhibitors No other concurrent investigational drugs More than 4 days since prior growth factors that support platelet or white cell number or function No concurrent enzyme-inducing anticonvulsant medications known to be potent inducers of the cytochrome P450 system, including phenytoin, carbamazepine, and phenobarbital Concurrent benzodiazepines and gabapentin allowed No concurrent grapefruit juice with bortezomib No other concurrent cancer chemotherapy or immunomodulating agents No concurrent corticosteroids as anti-emetic therapy Concurrent corticosteroids therapy allowed as treatment or prophylaxis for anaphylactic reactions, symptoms of cytarabine syndrome, and as treatment for presumptive bortezomib-induced pulmonary toxicity.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Moscow
Organizational Affiliation
Children's Oncology Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35293
Country
United States
Facility Name
Phoenix Childrens Hospital
City
Phoenix
State/Province
Arizona
ZIP/Postal Code
85016
Country
United States
Facility Name
University of Arkansas for Medical Sciences
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72205
Country
United States
Facility Name
Southern California Permanente Medical Group
City
Downey
State/Province
California
ZIP/Postal Code
90242
Country
United States
Facility Name
Miller Children's Hospital
City
Long Beach
State/Province
California
ZIP/Postal Code
90806
Country
United States
Facility Name
Children's Hospital and Research Center at Oakland
City
Oakland
State/Province
California
ZIP/Postal Code
94609-1809
Country
United States
Facility Name
Childrens Hospital of Orange County
City
Orange
State/Province
California
ZIP/Postal Code
92868-3874
Country
United States
Facility Name
Packard Children's Hospital Stanford University
City
Palo Alto
State/Province
California
ZIP/Postal Code
94304
Country
United States
Facility Name
University of California San Francisco Medical Center
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Connecticut Children's Medical Center
City
Hartford
State/Province
Connecticut
ZIP/Postal Code
06106
Country
United States
Facility Name
Alfred I duPont Hospital for Children
City
Wilmington
State/Province
Delaware
ZIP/Postal Code
19803
Country
United States
Facility Name
Children's National Medical Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20010
Country
United States
Facility Name
Broward General Medical Center
City
Fort Lauderdale
State/Province
Florida
ZIP/Postal Code
33316
Country
United States
Facility Name
Lee Memorial Health System
City
Fort Myers
State/Province
Florida
ZIP/Postal Code
33901
Country
United States
Facility Name
Nemours Children's Clinic - Jacksonville
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32207-8426
Country
United States
Facility Name
University of Miami Miller School of Medicine-Sylvester Cancer Center
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Nemours Childrens Clinic - Orlando
City
Orlando
State/Province
Florida
ZIP/Postal Code
32806
Country
United States
Facility Name
Nemours Children's Clinic - Pensacola
City
Pensacola
State/Province
Florida
ZIP/Postal Code
32504
Country
United States
Facility Name
All Children's Hospital
City
Saint Petersburg
State/Province
Florida
ZIP/Postal Code
33701
Country
United States
Facility Name
Saint Joseph Children's Hospital of Tampa
City
Tampa
State/Province
Florida
ZIP/Postal Code
33607
Country
United States
Facility Name
Children's Healthcare of Atlanta - Egleston
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322
Country
United States
Facility Name
Memorial Health University Medical Center
City
Savannah
State/Province
Georgia
ZIP/Postal Code
31403
Country
United States
Facility Name
University of Hawaii
City
Honolulu
State/Province
Hawaii
ZIP/Postal Code
96813
Country
United States
Facility Name
Childrens Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Southern Illinois University
City
Springfield
State/Province
Illinois
ZIP/Postal Code
62702
Country
United States
Facility Name
Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Kentucky
City
Lexington
State/Province
Kentucky
ZIP/Postal Code
40536
Country
United States
Facility Name
Tulane University Health Sciences Center
City
New Orleans
State/Province
Louisiana
ZIP/Postal Code
70112
Country
United States
Facility Name
Sinai Hospital of Baltimore
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21215
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
C S Mott Children's Hospital
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Michigan State University - Breslin Cancer Center
City
East Lansing
State/Province
Michigan
ZIP/Postal Code
48824-1313
Country
United States
Facility Name
Helen DeVos Children's Hospital at Spectrum Health
City
Grand Rapids
State/Province
Michigan
ZIP/Postal Code
49503
Country
United States
Facility Name
Children's Hospitals and Clinics of Minnesota - Minneapolis
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404
Country
United States
Facility Name
University of Minnesota Medical Center-Fairview
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
University of Mississippi Medical Center
City
Jackson
State/Province
Mississippi
ZIP/Postal Code
39216
Country
United States
Facility Name
The Childrens Mercy Hospital
City
Kansas City
State/Province
Missouri
ZIP/Postal Code
64108
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198-7830
Country
United States
Facility Name
Nevada Cancer Research Foundation CCOP
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89106
Country
United States
Facility Name
Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
UMDNJ - Robert Wood Johnson University Hospital
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08903
Country
United States
Facility Name
Newark Beth Israel Medical Center
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07112
Country
United States
Facility Name
Overlook Hospital
City
Summit
State/Province
New Jersey
ZIP/Postal Code
07902
Country
United States
Facility Name
University of New Mexico
City
Albuquerque
State/Province
New Mexico
ZIP/Postal Code
87106
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
State University of New York Upstate Medical University
City
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
University of North Carolina
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States
Facility Name
Carolinas Medical Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28203
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Children's Hospital Medical Center of Akron
City
Akron
State/Province
Ohio
ZIP/Postal Code
44308
Country
United States
Facility Name
Cincinnati Children's Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Rainbow Babies and Childrens Hospital
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
The Children's Medical Center of Dayton
City
Dayton
State/Province
Ohio
ZIP/Postal Code
45404
Country
United States
Facility Name
University of Oklahoma Health Sciences Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Legacy Emanuel Hospital and Health Center
City
Portland
State/Province
Oregon
ZIP/Postal Code
97227
Country
United States
Facility Name
Penn State Hershey Children's Hospital
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Childrens Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15224
Country
United States
Facility Name
Rhode Island Hospital
City
Providence
State/Province
Rhode Island
ZIP/Postal Code
02903
Country
United States
Facility Name
Palmetto Health Richland
City
Columbia
State/Province
South Carolina
ZIP/Postal Code
29203
Country
United States
Facility Name
Sanford University of South Dakota Medical Center
City
Sioux Falls
State/Province
South Dakota
ZIP/Postal Code
57117-5134
Country
United States
Facility Name
East Tennessee Childrens Hospital
City
Knoxville
State/Province
Tennessee
ZIP/Postal Code
37916
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
Driscoll Children's Hospital
City
Corpus Christi
State/Province
Texas
ZIP/Postal Code
78411
Country
United States
Facility Name
University of Texas Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75390
Country
United States
Facility Name
Cook Children's Medical Center
City
Fort Worth
State/Province
Texas
ZIP/Postal Code
76104
Country
United States
Facility Name
Baylor College of Medicine
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
Facility Name
University of Texas Health Science Center
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229-3900
Country
United States
Facility Name
Primary Children's Medical Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84113
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Saint Vincent Hospital
City
Green Bay
State/Province
Wisconsin
ZIP/Postal Code
54301
Country
United States
Facility Name
Marshfield Clinic
City
Marshfield
State/Province
Wisconsin
ZIP/Postal Code
54449
Country
United States
Facility Name
Midwest Children's Cancer Center
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States
Facility Name
Princess Margaret Hospital for Children
City
Perth
State/Province
Western Australia
ZIP/Postal Code
6008
Country
Australia
Facility Name
CancerCare Manitoba
City
Winnipeg
State/Province
Manitoba
ZIP/Postal Code
R3E 0V9
Country
Canada
Facility Name
IWK Health Centre
City
Halifax
State/Province
Nova Scotia
ZIP/Postal Code
B3J 3G9
Country
Canada
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Hospital Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada

12. IPD Sharing Statement

Learn more about this trial

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

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