Trial record 1 of 1 for:    NCT00873093
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Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma

This study has suspended participant recruitment.
(Temporarily Closed to Accrual)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT00873093
First received: March 31, 2009
Last updated: August 12, 2014
Last verified: April 2014

March 31, 2009
August 12, 2014
March 2009
September 2014   (final data collection date for primary outcome measure)
  • Second complete remission rate at the end of block 1 reinduction chemotherapy [ Time Frame: 29 days ] [ Designated as safety issue: No ]
    Descriptive statistics will be used to assess CR2 rates by stratum including calculation of 95% confidence intervals.
  • Bortezomib concentrations in patients receiving multi-agent combination therapy [ Time Frame: Day 8 of blocks 1 and 2 ] [ Designated as safety issue: No ]
  • Toxicity according to NCI CTCAE v4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
  • Second complete remission rate at the end of block 1 reinduction chemotherapy [ Designated as safety issue: No ]
  • Event-free survival at 4 months [ Designated as safety issue: No ]
  • Toxicity as assessed by NCI CTCAE v3.0 [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00873093 on ClinicalTrials.gov Archive Site
Minimal residual disease [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
A one-sample Z-test of proportions (one-sided, alpha= 5%) will be used.
Minimal residual disease [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Bortezomib and Combination Chemotherapy in Treating Young Patients With Relapsed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma
A Phase II Pilot Trial of Bortezomib (PS-341, Velcade®) in Combination With Intensive Re-Induction Therapy for Children With Relapsed Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL)

This phase II trial is studying 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.

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 NF-kappa-B activity in leukemia patients.

OUTLINE:

REINDUCTION BLOCK 1: Patients receive cytarabine intrathecally (IT) on day 1; vincristine sulfate IV on days 1, 8, 15, and 22; doxorubicin hydrochloride IV over 15 minutes on day 1; oral prednisone twice daily on days 1-29; bortezomib IV on days 1, 4, 8, and 11; and pegaspargase intramuscularly (IM) 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 1 hour on days 1-5; bortezomib IV 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 on day 22; and leucovorin calcium orally 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 twice daily 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.

Interventional
Phase 2
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
  • B-cell Adult Acute Lymphoblastic Leukemia
  • B-cell Childhood Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Lymphoblastic Lymphoma
  • Recurrent Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood Lymphoblastic Lymphoma
  • T-cell Adult Acute Lymphoblastic Leukemia
  • T-cell Childhood Acute Lymphoblastic Leukemia
  • Drug: asparaginase
    Given IM
    Other Names:
    • ASNase
    • Colaspase
    • Crasnitin
    • Elspar
    • L-ASP
  • Drug: doxorubicin hydrochloride
    Given IV
    Other Names:
    • ADM
    • ADR
    • Adria
  • Drug: therapeutic hydrocortisone
    Given IT
    Other Names:
    • Aeroseb-HC
    • Barseb HC
    • Cetacort
    • Cort-Dome
    • Cortef
  • Drug: liposomal vincristine sulfate
    Given IV
    Other Names:
    • liposomal vincristine
    • Marqibo
    • vincristine liposomal
    • vincristine sulfate liposome injection
  • Drug: cytarabine
    Given IT or IV
    Other Names:
    • ARA-C
    • arabinofuranosylcytosine
    • arabinosylcytosine
    • Cytosar-U
    • cytosine arabinoside
  • Drug: prednisone
    Given orally
    Other Names:
    • DeCortin
    • Deltra
  • Drug: bortezomib
    Given IV
    Other Names:
    • LDP 341
    • MLN341
    • VELCADE
  • Drug: pegaspargase
    Given IM
    Other Names:
    • L-asparaginase with polyethylene glycol
    • Oncaspar
    • PEG-ASP
    • PEG-L-asparaginase
  • Drug: methotrexate
    Given IT or IV
    Other Names:
    • amethopterin
    • Folex
    • methylaminopterin
    • Mexate
    • MTX
  • Drug: etoposide phosphate
    Given IV
    Other Names:
    • ETOP
    • Etopophos
  • Drug: cyclophosphamide
    Given IV
    Other Names:
    • CPM
    • CTX
    • Cytoxan
    • Endoxan
    • Endoxana
  • Biological: filgrastim
    Given IV or SC
    Other Names:
    • G-CSF
    • Neupogen
  • Drug: leucovorin calcium
    Given IV or orally
    Other Names:
    • CF
    • CFR
    • LV
  • Other: laboratory biomarker analysis
    Correlative studies
Experimental: Treatment (bortezomib and combination chemotherapy)
See Detailed Description
Interventions:
  • Drug: asparaginase
  • Drug: doxorubicin hydrochloride
  • Drug: therapeutic hydrocortisone
  • Drug: liposomal vincristine sulfate
  • Drug: cytarabine
  • Drug: prednisone
  • Drug: bortezomib
  • Drug: pegaspargase
  • Drug: methotrexate
  • Drug: etoposide phosphate
  • Drug: cyclophosphamide
  • Biological: filgrastim
  • Drug: leucovorin calcium
  • Other: laboratory biomarker analysis
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Suspended
60
Not Provided
September 2014   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Diagnosis of 1 of the following:

    • Pre-B acute lymphoblastic leukemia (ALL) in first early (< 36 months from diagnosis) isolated bone marrow or combined bone marrow/extramedullary relapse as documented by histology and immunophenotyping
    • T-cell ALL in first isolated bone marrow or combined relapse as documented by histology and immunophenotyping
    • T-cell lymphoblastic lymphoma in first relapse as documented by histology

      • Measurable disease as documented by clinical, radiographic, or histologic criteria
  • Relapsed or refractory to conventional therapy
  • No Philadelphia chromosome-positive (Ph+) ALL unless refractory to ≥ 1 tyrosine kinase inhibitor therapy

    • Patients who are unable to tolerate tyrosine kinase inhibitor therapy due to toxicity are eligible
  • No mature B-cell ALL (i.e., sIg positive and kappa or lambda restricted positivity) with French-American-British Cooperative Group (FAB) L3 morphology and/or myc translocation
  • No known optic nerve and/or retinal involvement

    • Patients presenting with visual disturbances should have an ophthalmological exam and, if indicated, a magnetic resonance imaging (MRI) to determine optic nerve or retinal involvement
  • No extramedullary disease (i.e., isolated CNS disease or isolated testicular disease)
  • No concurrent genetic syndrome (e.g., Down syndrome, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or any other known bone marrow failure syndrome)
  • 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
  • Creatinine clearance or radioisotope glomerular filtration rate ≥ 70 mL/min OR maximum serum creatinine based on age/gender as follows:

    • 0.4 mg/dL (for patients 1 to 5 months of age)
    • 0.5 mg/dL (for patients 6 to 11 months of age)
    • 0.6 mg/dL (for patients 1 year of age)
    • 0.8 mg/dL (for patients 2 to 5 years of age)
    • 1 mg/dL (for patients 6 to 9 years of age)
    • 1.2 mg/dL (for patients 10 to 12 years of age)
    • 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age)
    • 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients ≥ 16 years of age)
  • Total bilirubin ≤ 1.5 times upper limit of normal (ULN) for age
  • Serum glutamate pyruvate transaminase (SPGT) (alanine aminotransferase [ALT]) < 3 times ULN for age (unless elevation due to leukemia infiltration)
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception
  • Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by gated radionuclide study
  • Pulse oximetry ≥ 94% at sea level (> 90% if at high altitude)
  • No evidence of dyspnea at rest or exercise intolerance
  • No evidence of acute pulmonary infiltrates on chest radiograph
  • No known allergy to doxorubicin, cytarabine, etoposide, etoposide phosphate, boron, mannitol, or bortezomib
  • No CNS toxicity > grade 2
  • Seizure disorder allowed provided patient is on anticonvulsants (e.g., benzodiazepines or gabapentin) and it is well controlled
  • Able to receive asparaginase (i.e., no prior severe pancreatitis, stroke, or other toxicity)

    • Patients who initially receive asparaginase but discontinue drug due to toxicity are eligible
    • Patients with prior allergies to pegaspargase that are clinically significant are eligible provided Erwinia L-asparaginase can be substituted
  • 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
    • Stem cell transplant or rescue: no evidence of active graft-vs-host disease (GVHD) and ≥ 4 months must have elapsed; must not be receiving GVHD prophylaxis
  • No prior cumulative anthracycline exposure > 400 mg/m²
  • No prior bortezomib or other proteasome inhibitors
  • No prior reinduction attempts or treatment for prior extramedullary relapse

    • Patients with primary induction failure are not eligible
  • No concurrent anticonvulsants known to activate the cytochrome p450 system (e.g., phenytoin, carbamazepine, and phenobarbital)

    • Concurrent benzodiazepines or gabapentin allowed
  • No concurrent corticosteroids (including steroids as antiemetics) except as treatment or prophylaxis for anaphylactic reactions OR treatment for pulmonary toxicity
  • No other concurrent anticancer chemotherapy or immunomodulating agents
  • Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study
Both
1 Year to 31 Years
No
Contact information is only displayed when the study is recruiting subjects
United States,   Australia,   Canada,   Puerto Rico
 
NCT00873093
NCI-2011-01908, NCI-2011-01908, CDR0000638413, AALL07P1, AALL07P1, U10CA098543
Not Provided
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Principal Investigator: Terzah Horton Children's Oncology Group
National Cancer Institute (NCI)
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP