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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00666588
First received: April 24, 2008
Last updated: May 13, 2014
Last verified: December 2013
  Purpose

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


Condition Intervention Phase
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
Drug: idarubicin
Drug: cytarabine
Drug: bortezomib
Drug: etoposide
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Dose Limiting Toxicity [ Time Frame: During Course 1 ] [ Designated as safety issue: Yes ]
    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 ] [ Designated as safety issue: No ]
    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) [ Time Frame: At baseline, prior to and up to 24 hours after bortezomib treatment ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 52
Study Start Date: April 2008
Study Completion Date: December 2012
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Bortezomib 1.3mg/m2-assess efficacy-low anthracycline exposure
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.
Drug: idarubicin
Given IV
Other Names:
  • 4-demethoxydaunorubicin
  • 4-DMDR
  • DMDR
  • IDA
Drug: cytarabine
Given IV or IT
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Other: laboratory biomarker analysis
Correlative studies
Experimental: Bortezomib 1.0mg/m2-assess feasibility high anthracycline exp
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.
Drug: cytarabine
Given IV or IT
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Other: laboratory biomarker analysis
Correlative studies
Experimental: Bortezomib 1.3 mg/m2-assess feasibility high anthracycline exp
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).
Drug: cytarabine
Given IV or IT
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Other: laboratory biomarker analysis
Correlative studies
Experimental: Bortezomib 1.3 mg/m2-assess efficacy high anthracycline exp
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
Drug: cytarabine
Given IV or IT
Other Names:
  • ARA-C
  • arabinofuranosylcytosine
  • arabinosylcytosine
  • Cytosar-U
  • cytosine arabinoside
Drug: bortezomib
Given IV
Other Names:
  • LDP 341
  • MLN341
  • VELCADE
Drug: etoposide
Given IV
Other Names:
  • EPEG
  • VP-16
  • VP-16-213
Other: laboratory biomarker analysis
Correlative studies

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.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00666588

  Show 82 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Jeffrey Moscow Children's Oncology Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00666588     History of Changes
Other Study ID Numbers: NCI-2009-00323, U10CA098543, CDR0000594224, COG-AAML07P1, NCI-2009-00323
Study First Received: April 24, 2008
Results First Received: December 18, 2013
Last Updated: May 13, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Congenital Abnormalities
Leukemia
Leukemia, Basophilic, Acute
Leukemia, Eosinophilic, Acute
Leukemia, Erythroblastic, Acute
Leukemia, Megakaryoblastic, Acute
Leukemia, Monocytic, Acute
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Leukemia, Myelomonocytic, Acute
Leukemia, Myelomonocytic, Chronic
Hypereosinophilic Syndrome
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Myelodysplastic-Myeloproliferative Diseases
Eosinophilia
Leukocyte Disorders
Cytarabine
Etoposide phosphate
Bortezomib
Etoposide
Idarubicin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents

ClinicalTrials.gov processed this record on July 24, 2014