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NCT00873093 · CITED IN SOURCE DOCUMENTS

Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

An NCI or FDA source cites this study. A citation does not establish that it applies to an individual diagnosis.

Phase
PHASE2
Status at capture
COMPLETED
Registry last update
2017-01-27

This pilot, phase II trial studies the side effects of giving bortezomib together with combination chemotherapy and to see how well it works in treating young patients with relapsed acute lymphoblastic leukemia or lymphoblastic lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

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baseline

Baseline characteristics

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outcome · POSTED

Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy

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outcome · POSTED

Event Free Survival

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outcome · POSTED

Toxic Death Rate

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outcome · POSTED

Severe Adverse Events (SAE) Rate.

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outcome · POSTED

Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1

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outcome · POSTED

Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2

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outcome · POSTED

Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3

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outcome · POSTED

NF-kB Activity

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outcome · POSTED

Expression of Apoptotic and Cell Cycle Proteins Assessed by Using Gene and Tissue Microarrays and Immunoblots

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outcome · POSTED

Change in Stem Cell Percentage

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outcome · POSTED

Plasma Concentration-time Profiles

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outcome · NOT POSTED

Pharmacokinetics (PK) of Bortezomib in Patients Receiving Multi-agent Combination Therapy.

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adverse events

Adverse events

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more info

Limitations, agreements, and source contact

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Who could take part
eligibility Criteria
Inclusion Criteria: * Diagnosis * Pre-B ALL in first early (\< 36 months from diagnosis) isolated bone marrow (BM) or combined BM/extramedullary relapse; or * T-cell ALL in first isolated BM or combined relapse; or * T-LL in first relapse * Patients with leukemia must have had histologic verification of the malignancy at relapse, including immunophenotyping to confirm diagnosis * Patients with lymphoblastic lymphoma must have measurable disease documented by clinical, radiographic, or histologic criteria; patients must have relapsed or become refractory to conventional therapy * Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2; use Karnofsky for patients \> 16 years of age and Lansky for patients =\< 16 years of age * Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study * Patients who relapse on therapy other than standard ALL maintenance therapy must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study * At least 14 days since the completion of cytotoxic therapy with the exception of hydroxyurea, which is permitted up to 24 hours prior to the start of protocol therapy * At least 7 days since the completion of therapy with a biologic agent or donor lymphocyte infusions (DLI); for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur * No evidence of active graft-vs-host disease (GVHD) and \>= 4 months must have elapsed; must not be receiving GVHD prophylaxis * Creatinine clearance or radioisotope glomerular filtration rate (GFR) \>= 70 mL/min/1.73 m\^2 or a serum creatinine based on age/gender as follows: * 1 month to \< 6 months (0.4 male, 0.4 female) * 6 months to \< 1 year (0.5 male, 0.5 female) * 1 to \< 2 years (0.6 male, 0.6 female) * 2 to \< 6 years (0.8 male, 0.8 female) * 6 to \< 10 years (1 male, 1 female) * 10 to \< 13 years (1.2 male, 1.2 female) * 13 to \< 16 years (1.5 male, 1.4 female) * \>= 16 years (1.7 male, 1.4 female) * Total bilirubin =\< 1.5 x upper limit of normal (ULN) for age * Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase \[ALT\]) \< 3 x ULN for age, unless elevation due to leukemia infiltration * Shortening fraction of \>= 27% by echocardiogram, or * Ejection fraction of \>= 50% by gated radionuclide study * No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry \>= 94% at sea level (\> 90% if at high altitude) * No evidence of acute pulmonary infiltrates on chest radiograph * Patients with seizure disorder may be enrolled if on allowed anticonvulsants and well controlled; benzodiazepines and gabapentin are acceptable * Central nervous system (CNS) toxicity =\< grade 2 * Peripheral nervous system (PNS) toxicity \< grade 3 * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, FDA, and National Cancer Institute (NCI) requirements for human studies must be met Exclusion Criteria: * Patients with Philadelphia chromosome positive ALL are not eligible unless refractory to at least one tyrosine kinase inhibitor (TKI) therapy; patients that are unable to tolerate TKI therapy due to toxicity are eligible * Patients with mature B-cell ALL, ie, leukemia with B-cell (soluble immunoglobulin \[sIg\] positive and kappa or lambda restricted positivity) ALL, with French-American-British (FAB) L3 morphology and/or a myc translocation, are not eligible * Extramedullary disease status: patients with isolated CNS disease or isolated testicular disease are not eligible * Patients with known optic nerve and/or retinal involvement are not eligible; patients presenting with visual disturbances should have an ophthalmological exam and, if indicated, an magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement * Patients with concomitant genetic syndrome: patients with Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome are not eligible * Cumulative prior anthracycline exposure must not exceed 400 mg/m\^2 * Patients taking anticonvulsants known to activate the cytochrome p450 system, in particular anticonvulsants such as phenytoin, carbamazepine, and phenobarbital, are not eligible; benzodiazepines and gabapentin are acceptable * Patients who have previously received bortezomib or other proteasome inhibitors are not eligible * Patients who have a known allergy to doxorubicin, cytarabine, both etoposide and etopophos, boron, mannitol or bortezomib are not eligible * Patients who cannot receive any asparaginase products (E. Coli, PEG-asparaginase, or Erwinia asparaginase) on this study (eg, due to prior severe pancreatitis, stroke or other toxicity) are not eligible; patients who initially receive asparaginase, but must discontinue due to toxicity, remain eligible; patients with clinically significant prior allergies to pegaspargase are eligible if Erwinia L-asparaginase can be substituted * Patients who are pregnant or breast-feeding are not eligible for this study; negative pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use an effective birth control method * Patients must not have received any prior re-induction attempts and must not have received treatment for prior extramedullary relapse; patients with primary induction failure are not eligible
healthy Volunteers
false
maximum Age
31 Years
minimum Age
1 Year
sex
ALL
std Ages
  1. CHILD
  2. ADULT
Treatment arms and interventions
arm Groups
  1. description
    Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.
    intervention Names
    1. Drug: L-asparaginase
    2. Drug: doxorubicin hydrochloride
    3. Drug: therapeutic hydrocortisone
    4. Drug: vincristine sulfate
    5. Drug: cytarabine
    6. Drug: prednisone
    7. Drug: bortezomib
    8. Drug: pegaspargase
    9. Drug: methotrexate
    10. Drug: etoposide phosphate
    11. Drug: cyclophosphamide
    12. Biological: filgrastim
    label
    Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    type
    EXPERIMENTAL
  2. description
    Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.
    intervention Names
    1. Drug: L-asparaginase
    2. Drug: doxorubicin hydrochloride
    3. Drug: therapeutic hydrocortisone
    4. Drug: vincristine sulfate
    5. Drug: cytarabine
    6. Drug: prednisone
    7. Drug: bortezomib
    8. Drug: pegaspargase
    9. Drug: methotrexate
    10. Drug: etoposide phosphate
    11. Drug: cyclophosphamide
    12. Biological: filgrastim
    label
    Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    type
    EXPERIMENTAL
  3. description
    Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.
    intervention Names
    1. Drug: L-asparaginase
    2. Drug: doxorubicin hydrochloride
    3. Drug: therapeutic hydrocortisone
    4. Drug: vincristine sulfate
    5. Drug: cytarabine
    6. Drug: prednisone
    7. Drug: bortezomib
    8. Drug: pegaspargase
    9. Drug: methotrexate
    10. Drug: etoposide phosphate
    11. Drug: cyclophosphamide
    12. Biological: filgrastim
    label
    Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    type
    EXPERIMENTAL
  4. description
    Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.
    intervention Names
    1. Drug: L-asparaginase
    2. Drug: doxorubicin hydrochloride
    3. Drug: therapeutic hydrocortisone
    4. Drug: vincristine sulfate
    5. Drug: cytarabine
    6. Drug: prednisone
    7. Drug: bortezomib
    8. Drug: pegaspargase
    9. Drug: methotrexate
    10. Drug: etoposide phosphate
    11. Drug: cyclophosphamide
    12. Biological: filgrastim
    label
    T-cell ALL (Chemotherapy)
    type
    EXPERIMENTAL
  5. description
    Re-Induction Block 1 patients receive vincristine sulfate, Prednisone, pegaspargase, Doxorubicin hydrochloride. Re-Induction Block 2 patients receive Cyclophosphamide, Etoposide phosphate, and Methotrexate. Re-Induction Block 3 patients receive Cytarabine.
    intervention Names
    1. Drug: L-asparaginase
    2. Drug: doxorubicin hydrochloride
    3. Drug: therapeutic hydrocortisone
    4. Drug: vincristine sulfate
    5. Drug: cytarabine
    6. Drug: prednisone
    7. Drug: bortezomib
    8. Drug: pegaspargase
    9. Drug: methotrexate
    10. Drug: etoposide phosphate
    11. Drug: cyclophosphamide
    12. Biological: filgrastim
    label
    T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    type
    EXPERIMENTAL
interventions
  1. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IM 6000 IU/m2/dose Days 2 and 9
    name
    L-asparaginase
    other Names
    1. ASNase
    2. Colaspase
    3. Crasnitin
    4. Elspar
    5. L-ASP
    type
    DRUG
  2. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IV 60 mg/m2/dose on Day 1
    name
    doxorubicin hydrochloride
    other Names
    1. ADM
    2. ADR
    3. Adria
    type
    DRUG
  3. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IT (8mg - 15mg) Age-based dosing Block 1: Days 8,15, 22 and 29 Block 2: Days 1 and 22
    name
    therapeutic hydrocortisone
    other Names
    1. Aeroseb-HC
    2. Barseb HC
    3. Cetacort
    4. Cort-Dome
    5. Cortef
    type
    DRUG
  4. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IV 1.5 mg/m2 (max 2 mg) on Days 1, 8, 15 and 22
    name
    vincristine sulfate
    other Names
    1. liposomal vincristine
    2. Marqibo
    3. vincristine liposomal
    4. vincristine sulfate liposome injection
    type
    DRUG
  5. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IT or IV 3,000 mg/m2/dose on Days 1, 2, 8 and 9
    name
    cytarabine
    other Names
    1. ARA-C
    2. arabinofuranosylcytosine
    3. arabinosylcytosine
    4. Cytosar-U
    5. cytosine arabinoside
    type
    DRUG
  6. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given PO or IV 40 mg/m2/day on Days 1-28
    name
    prednisone
    other Names
    1. DeCortin
    2. Deltra
    type
    DRUG
  7. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IV 1.3 mg/m2/dose Block 1: Days 1, 4, 8 and 11 Block 2: Days 1, 4 and 8
    name
    bortezomib
    other Names
    1. LDP 341
    2. MLN341
    3. VELCADE
    type
    DRUG
  8. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IM or IV (over 2 hours) 2500 IU/m2/dose on days 2, 8,15 and 22
    name
    pegaspargase
    other Names
    1. L-asparaginase with polyethylene glycol
    2. Oncaspar
    3. PEG-ASP
    4. PEG-L-asparaginase
    type
    DRUG
  9. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IT (8mg - 15mg) Age-based dosing Block 1: Days 15 and 29 Block 2: Days 1 and 22
    name
    methotrexate
    other Names
    1. amethopterin
    2. Folex
    3. methylaminopterin
    4. Mexate
    5. MTX
    type
    DRUG
  10. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IV 100 mg/m2/dose on Days 1-5
    name
    etoposide phosphate
    other Names
    1. ETOP
    2. Etopophos
    type
    DRUG
  11. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IV 440 mg/m2/dose on Days 1-5
    name
    cyclophosphamide
    other Names
    1. CPM
    2. CTX
    3. Cytoxan
    4. Endoxan
    5. Endoxana
    type
    DRUG
  12. arm Group Labels
    1. Pre-B ALL Relapse 18-36 mths from diagnosis (chemo) age<=21 yr
    2. Pre-B ALL Relapse<18 mths from diagnosis (chemo) age<=21 yrs
    3. Pre-B ALL Relapse<36 mths from diagnosis (chemo) age>21 yrs
    4. T-cell ALL (Chemotherapy)
    5. T-cell Lymphoblastic Lymphoma (LL) (Chemotherapy)
    description
    Given IV or SC 5 micrograms/kg/dose Only on Day 6
    name
    filgrastim
    other Names
    1. G-CSF
    2. Neupogen
    type
    BIOLOGICAL
Study design
allocation
NON_RANDOMIZED
intervention Model
SINGLE_GROUP
masking Info
masking
NONE
primary Purpose
TREATMENT
Enrollment
count
148
type
ACTUAL
Registered outcome plans (not posted results)
other Outcomes
  1. description
    NF-kB activity will be measured as a continuous variable (ng NF-kB/ug protein). Differences in NF-kB activity between time points will be assessed using summary statistics such as mean, standard deviation, and range.
    measure
    NF-kB Activity
    time Frame
    Up to 5 years
  2. description
    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. The normality assumption will be assessed on the log-transformed data prior to paired t-test evaluation.
    measure
    Expression of Apoptotic and Cell Cycle Proteins Assessed by Using Gene and Tissue Microarrays and Immunoblots
    time Frame
    Up to 5 years
  3. description
    Will use 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. non-responders, stem cell percentage differences between responders and non-responders will be compared using a paired t-test or equivalent nonparametric test.
    measure
    Change in Stem Cell Percentage
    time Frame
    Baseline to post-treatment with bortezomib
  4. description
    Will be analyzed using descriptive statistics and will be graphically displayed by age group and stratum. PK data will be analyzed using methods such as nonlinear mixed effects modeling to estimate bortezomib clearance and volume of distribution (and the associated 95% confidence intervals) in each age group (2-11 years and 12-16 years of age).
    measure
    Plasma Concentration-time Profiles
    time Frame
    Up to day 8 of block 2
  5. description
    This outcome measure cannot be reported due to the data used for analysis was not collected.
    measure
    Pharmacokinetics (PK) of Bortezomib in Patients Receiving Multi-agent Combination Therapy.
    time Frame
    Day 8 of blocks 1 and 2
primary Outcomes
  1. description
    The percentage of eligible and evaluable patients who have achieved complete response at the end Block 1 of re-induction therapy.
    measure
    Second Complete Remission Rate at the End of Block 1 Reinduction Chemotherapy
    time Frame
    The outcome is measured the end of Block 1 (Day 36 of Block 1) of re-induction therapy.
  2. description
    Percentage of patients who were event free at 4 months
    measure
    Event Free Survival
    time Frame
    4 months after enrollment
  3. description
    The proportion of toxic death rate among all eligible patients.
    measure
    Toxic Death Rate
    time Frame
    4 months
  4. description
    The proportion of SAE rate among all eligible patients
    measure
    Severe Adverse Events (SAE) Rate.
    time Frame
    4 months
secondary Outcomes
  1. description
    Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 1.
    measure
    Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 1
    time Frame
    End of Block 1 (Day 36 of Block 1) of re-induction therapy
  2. description
    Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 2.
    measure
    Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 2
    time Frame
    End of Block 2 (Day 36 of Block 2) of re-induction therapy
  3. description
    Percentage of eligible and evaluable patients with MRD \< 0.01% among those who had successful MRD determination at the end of Block 3.
    measure
    Rate of Minimal Residual Disease (MRD) < 0.01% at End Block 3
    time Frame
    End of Block 3 (Day 36 of Block 3) of re-induction therapy
Full study description
brief Summary
This pilot, phase II trial studies the side effects of giving bortezomib together with combination chemotherapy and to see how well it works in treating young patients with relapsed acute lymphoblastic leukemia or lymphoblastic lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving bortezomib together with combination chemotherapy may kill more cancer cells.
detailed Description
PRIMARY OBJECTIVES: I. To estimate the toxicity, second complete response (CR2) rate at the end of Block 1 therapy, and 4-month event-free survival (EFS) for pediatric and young adult patients with relapsed acute lymphoblastic leukemia (ALL) treated with bortezomib in combination with intensive re-induction chemotherapy. II. To evaluate bortezomib pharmacokinetics (PK) in patients receiving the combination regimen. SECONDARY OBJECTIVES: I. To assess minimal residual disease (MRD) in bone marrow following completion of each therapy block. II. To assess the feasibility of measuring leukemia initiating cells (LIC) in patient samples before and after chemotherapy. III. To discover biologic pathways associated with response and drug resistance using gene and protein expression profiles at baseline and following initial exposure to chemotherapy. IV. To determine if bortezomib inhibits lymphoblast nuclear factor (NF)-kappa (k)-B activity in leukemia patients. OUTLINE: REINDUCTION BLOCK 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV over 1 minute on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15 minutes on day 1; prednisone orally (PO) twice daily (BID) on days 1-28; bortezomib IV over 3-5 seconds on days 1, 4, 8, and 11; and pegaspargase intramuscularly (IM) or IV over 1-2 hours on days 2, 8, 15, and 22. Patients with central nervous system (CNS)-negative disease (CNS1 or CNS2) also receive methotrexate IT on days 15 and 29; patients with CNS-positive disease (CNS3) receive triple intrathecal therapy (TIT) comprising methotrexate, hydrocortisone, and cytarabine IT on days 8, 15, 22, and 29. After completion of reinduction block 1, patients with ALL and M2 or M3 bone marrow proceed directly to reinduction block 2. Patients with ALL and M1 bone marrow or lymphoblastic lymphoma proceed to reinduction block 2 after blood counts recover. Patients with persistent cerebral spinal fluid (CSF) blasts after 6 doses of TIT or patients with progressive lymphoblastic lymphoma are removed from the study. REINDUCTION BLOCK 2: Patients receive etoposide phosphate IV over 1-2 hours on days 1-5; cyclophosphamide IV over 15-30 minutes on days 1-5; bortezomib IV over 3-5 seconds on days 1, 4, and 8; filgrastim (G-CSF) subcutaneously (SC) or IV daily beginning on day 6 and continuing until blood counts recover\*; high-dose methotrexate IV over 24 hours on day 22; and leucovorin calcium PO or IV every 6 hours on days 23 and 24. Patients with CNS-negative disease also receive methotrexate IT on days 1 and 22; patients with CNS-positive disease receive TIT on days 1 and 22. After completion of reinduction block 2, patients proceed to reinduction block 3 immediately or when blood counts recover. Patients with disease progression are removed from the study. NOTE: \*Patients do not receive G-CSF on day 8. REINDUCTION BLOCK 3: Patients receive cytarabine IV over 3 hours BID on days 1, 2, 8, and 9; L-asparaginase IM on days 2 and 9; and G-CSF SC or IV daily beginning on day 10 and continuing until blood counts recover. After completion of study treatment, patients are followed every 6 months for 3 years and then annually for 2 years.
Source references
references
  1. citation
    Horton TM, Whitlock JA, Lu X, O'Brien MM, Borowitz MJ, Devidas M, Raetz EA, Brown PA, Carroll WL, Hunger SP. Bortezomib reinduction chemotherapy in high-risk ALL in first relapse: a report from the Children's Oncology Group. Br J Haematol. 2019 Jul;186(2):274-285. doi: 10.1111/bjh.15919. Epub 2019 Apr 7.
    pmid
    30957229
    type
    DERIVED
  2. citation
    Hanley MJ, Mould DR, Taylor TJ, Gupta N, Suryanarayan K, Neuwirth R, Esseltine DL, Horton TM, Aplenc R, Alonzo TA, Lu X, Milton A, Venkatakrishnan K. Population Pharmacokinetic Analysis of Bortezomib in Pediatric Leukemia Patients: Model-Based Support for Body Surface Area-Based Dosing Over the 2- to 16-Year Age Range. J Clin Pharmacol. 2017 Sep;57(9):1183-1193. doi: 10.1002/jcph.906. Epub 2017 Apr 18.
    pmid
    28419486
    type
    DERIVED
Source notices and limitations
    Discovery and provenance
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      primary nct id
      NCT00873093
      source kind
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        Updated: April 17, 2025
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        April 17, 2025

    Preserved source evidence · Not medical advice