Clinical Trials /

Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia in Children and Adolescents

NCT03020030

Description:

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The cancer comes from a cell in the blood called a lymphocyte. Normal lymphocytes are produced in the bone marrow (along with other blood cells) and help fight infections. In ALL, the cancerous lymphocytes are called lymphoblasts. They do not help fight infection and crowd out the normal blood cells in the bone marrow so that the body cannot make enough normal blood cells. ALL is always fatal if it is not treated. With current treatments, most children and adolescents with this disease will be cured. The standard treatment for ALL involves about 2 years of chemotherapy. The drugs that are used, and the doses of the drugs, are similar but not identical for all children and adolescents with ALL. Some children and adolescents receive stronger treatment, especially during the first several months. A number of factors are used to decide how strong the treatment should be to give the best chance for cure. These factors are called "risk factors". This trial is studying the use of a new, updated set of risk factors to decide how strong the treatment will be. The study also will test a new way of dosing a chemotherapy drug called pegaspargase (which is part of the standard treatment for ALL) based on checking levels of the drug in the blood and adjusting the dose based on the levels.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia in Children and Adolescents
  • Official Title: Treatment of Newly Diagnosed Acute Lymphoblastic Leukemia in Children and Adolescents

Clinical Trial IDs

  • ORG STUDY ID: 16-001
  • NCT ID: NCT03020030

Conditions

  • Acute Lymphoblastic Leukemia, Pediatric

Interventions

DrugSynonymsArms
PegaspargaseInitial Low Risk (Initial LR)
Erwinia asparaginaseERWINAZE®, ERWINIA CHRYSANTHEMI, ERWINASE®Initial Low Risk (Initial LR)
CyclophosphamideCYTOXANInitial Low Risk (Initial LR)
CYTARABINECYTOSINE ARABINOSIDE, ARA-C, CYTOSAR®Initial Low Risk (Initial LR)
DASATINIBInitial Very High Risk (Initial VHR)
DEXAMETHASONEDECADRON®, HEXADROL®,, DEXONE®,, DEXAMETH®Initial Low Risk (Initial LR)
DexrazoxaneZinecardInitial High Risk (Initial HR)
DoxorubicinADRIAMYCIN®Initial High Risk (Initial HR)
ETOPOSIDEVePesidInitial Very High Risk (Initial VHR)
HYDROCORTISONEInitial Low Risk (Initial LR)
LEUCOVORIN CALCIUMInitial Low Risk (Initial LR)
MERCAPTOPURINE6-MPInitial Low Risk (Initial LR)
METHOTREXATEInitial Low Risk (Initial LR)
NELARABINEInitial Very High Risk (Initial VHR)
VincristineOncovinInitial Low Risk (Initial LR)

Purpose

Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in children. The cancer comes from a cell in the blood called a lymphocyte. Normal lymphocytes are produced in the bone marrow (along with other blood cells) and help fight infections. In ALL, the cancerous lymphocytes are called lymphoblasts. They do not help fight infection and crowd out the normal blood cells in the bone marrow so that the body cannot make enough normal blood cells. ALL is always fatal if it is not treated. With current treatments, most children and adolescents with this disease will be cured. The standard treatment for ALL involves about 2 years of chemotherapy. The drugs that are used, and the doses of the drugs, are similar but not identical for all children and adolescents with ALL. Some children and adolescents receive stronger treatment, especially during the first several months. A number of factors are used to decide how strong the treatment should be to give the best chance for cure. These factors are called "risk factors". This trial is studying the use of a new, updated set of risk factors to decide how strong the treatment will be. The study also will test a new way of dosing a chemotherapy drug called pegaspargase (which is part of the standard treatment for ALL) based on checking levels of the drug in the blood and adjusting the dose based on the levels.

Detailed Description

      There are a standard set of risk factors which are used to decide how strong treatment should
      be for a child with ALL. These risk factors include the child's age when the leukemia is
      diagnosed, how high the white blood cell count (WBC) is in the blood, whether or not leukemia
      cells are seen in the spinal fluid (referred to as Central Nervous System or CNS status), and
      whether or not the leukemia has certain abnormalities in their chromosomes (genetic material
      in the cell). Another risk factor is the amount of leukemia in the marrow that can be
      measured by a special laboratory test called "MRD" (Minimal Residual Disease) after the first
      month of treatment.

      Over the last several years, new factors have been identified which help predict how well a
      child's leukemia may respond to treatment. These new risk factors include additional
      abnormalities in the genes of the leukemia cell, as well the amount of leukemia (MRD level)
      at second time point (about 2-3 months after starting treatment).

      In this trial, the investigators will use the new risk factors along with old risk factors to
      decide how strong the treatment will be. The goal is to better identify those participants
      who might benefit from stronger treatment in order to improve their chance for cure. The
      investigators also hope to better identify participants who have a high chance of being cured
      with standard treatment in order to reduce their chance of side effects while maintaining the
      chance of cure.

      This trial also aims to study the dosing of a drug called pegaspargase. Pegaspargase is a
      chemotherapy drug that is an important part of ALL treatment but it is also can cause many
      side effects. With the standard dose of pegaspargase, levels of the drug in the blood are
      higher than may be necessary to effectively treat leukemia.

      On this research study, the investigators will be comparing the standard dose of pegaspargase
      with a new way of dosing the drug based on levels of the drug that we can measure in the
      blood. With the new way of doing, treatment will begin with a lower dose. If the levels are
      high, the dose will be decreased one more time; however, if at any time the levels are too
      low, dosing will be switched back up to the standard dose. The goal of this research study is
      to learn whether this new way of dosing (starting at a lower dose and changing the dose based
      on drug levels in the blood) will decrease side effects but still be as effective as the
      standard dosing of the drug.
    

Trial Arms

NameTypeDescriptionInterventions
Initial Low Risk (Initial LR)OtherMeets all the following criteria: B-ALL, Age 1-<15 years, WBC < 50,000/microliter, CNS-1 or CNS-2, no BCR-ABL1, no iAMP21, and no VHR characteristics. Treated with Induction IA (vincristine, dexamethasone, pegaspargase), Induction IB (cyclophosphamide, cytarabine, mercaptopurine), Consolidation IA (vincristine, high-dose methotrexate + leucovorin, mercaptopurine). IT chemotherapy in all phases. Final risk group assigned by end of Consolidation IA.
  • Pegaspargase
  • Erwinia asparaginase
  • Cyclophosphamide
  • CYTARABINE
  • DEXAMETHASONE
  • HYDROCORTISONE
  • LEUCOVORIN CALCIUM
  • MERCAPTOPURINE
  • METHOTREXATE
  • Vincristine
Initial High Risk (Initial HR)OtherMeets at least one of the following criteria: Age >=15 years, WBC >=50,000/microliter, CNS-3, T-ALL, iAMP21, BCR-ABL1 And: No VHR characteristics Treated with Induction IA (vincristine, dexamethasone, pegaspargase, doxorubicin + dexrazoxane), Induction IB (cyclophosphamide, cytarabine, mercaptopurine), Consolidation IA (vincristine, high-dose methotrexate + leucovorin, mercaptopurine). IT chemotherapy in all phases. Final risk group assigned by end of Consolidation IA.
  • Pegaspargase
  • Erwinia asparaginase
  • Cyclophosphamide
  • CYTARABINE
  • DEXAMETHASONE
  • Dexrazoxane
  • Doxorubicin
  • HYDROCORTISONE
  • LEUCOVORIN CALCIUM
  • MERCAPTOPURINE
  • METHOTREXATE
  • Vincristine
Initial Very High Risk (Initial VHR)OtherAny of the following are present: IKZF1 deletion, MLL (KMT2A) rearrangement, low hypodiploidy, t(17;19) Treated with Induction IA (vincristine, dexamethasone, pegaspargase, doxorubicin + dexrazoxane), Induction IB (cyclophosphamide, cytarabine, mercaptopurine), Consolidation IA (vincristine, high-dose methotrexate + leucovorin, mercaptopurine). IT chemotherapy in all phases. Final risk group assigned by end of Consolidation IA.
  • Pegaspargase
  • Erwinia asparaginase
  • Cyclophosphamide
  • CYTARABINE
  • DASATINIB
  • DEXAMETHASONE
  • Dexrazoxane
  • Doxorubicin
  • ETOPOSIDE
  • HYDROCORTISONE
  • LEUCOVORIN CALCIUM
  • MERCAPTOPURINE
  • METHOTREXATE
  • NELARABINE
  • Vincristine
Final Low Risk (Final LR)OtherInitial Low Risk and Low MRD (<0.0001) at first time point (Day 32) Final Risk Group assigned at end of Consolidation IA. Subsequent therapy as follows: CNS phase (vincristine, dexamethasone, mercaptopurine, pegaspargase [by randomization or direct assignment], IT chemotherapy); Consolidation II (vincristine, dexamethasone, mercaptopurine, methotrexate, pegaspargase [by randomization or direct assignment], IT chemotherapy); Continuation (vincristine, dexamethasone, mercaptopurine, methotrexate, IT chemotherapy). All treatment completed 24 months from date of complete remission.
  • Pegaspargase
  • Erwinia asparaginase
  • CYTARABINE
  • DEXAMETHASONE
  • HYDROCORTISONE
  • MERCAPTOPURINE
  • METHOTREXATE
  • Vincristine
Final Intermediate Risk (Final IR)OtherInitial High Risk and Low MRD (<0.0001) at first time point (Day 32) Final Risk Group assigned at end of Consolidation IA. Subsequent therapy as follows: CNS phase (vincristine, dexamethasone, mercaptopurine, pegaspargase [by randomization or direct assignment], IT chemotherapy); Consolidation II (vincristine, dexamethasone, mercaptopurine, doxorubicin + dexrazoxane, pegaspargase [by randomization or direct assignment], IT chemotherapy); Continuation (vincristine, dexamethasone, mercaptopurine, methotrexate, IT chemotherapy). All treatment completed 24 months from date of complete remission.
  • Pegaspargase
  • Erwinia asparaginase
  • CYTARABINE
  • DEXAMETHASONE
  • Dexrazoxane
  • Doxorubicin
  • HYDROCORTISONE
  • MERCAPTOPURINE
  • METHOTREXATE
  • Vincristine
Final High Risk (Final HR)OtherInitial Low Risk or Initial High Risk with High MRD (>=0.0001) at first time point (Day 32) but low MRD (<0.001) at second time point (week 10-12) Final Risk Group assigned at end of Consolidation IA. Subsequent therapy as follows: CNS phase (vincristine, dexamethasone, mercaptopurine, pegaspargase [by randomization or direct assignment], IT chemotherapy); Consolidation II (vincristine, dexamethasone, mercaptopurine, doxorubicin + dexrazoxane, pegaspargase [by randomization or direct assignment], IT chemotherapy); Continuation (vincristine, dexamethasone, mercaptopurine, methotrexate, IT chemotherapy). All treatment completed 24 months from date of complete remission.
  • Pegaspargase
  • Erwinia asparaginase
  • CYTARABINE
  • DEXAMETHASONE
  • Dexrazoxane
  • Doxorubicin
  • HYDROCORTISONE
  • MERCAPTOPURINE
  • METHOTREXATE
  • Vincristine
Final Very High Risk (Final VHR)OtherInitial VHR or any patient with high MRD (>=0.001) at second time point (week 10-12) Final Risk Group assigned at end of Consolidation IA. Subsequent therapy as follows: Consolidation IB/B-ALL (High-dose methotrexate + leucovorin, cyclophosphamide, etoposide, IT chemotherapy); Consolidation IB/T-ALL (nelararbine, cyclophosphamide, etoposide); Consolidation IC (High-dose cytarabine, etoposide, dexamethasone, pegaspargase [by direct assignment], IT chemotherapy); CNS phase (vincristine, dexamethasone, mercaptopurine, pegaspargase [by direct assignment], IT chemotherapy); Consolidation II (vincristine, dexamethasone, mercaptopurine, doxorubicin + dexrazoxane, pegaspargase [by direct assignment], IT chemotherapy); Continuation (vincristine, dexamethasone, mercaptopurine, methotrexate, IT chemotherapy). Dasatinib administered daily during all phases to pts with ABL1-class fusions. All treatment completed 24 months from date of complete remission.
  • Pegaspargase
  • Erwinia asparaginase
  • Cyclophosphamide
  • CYTARABINE
  • DASATINIB
  • DEXAMETHASONE
  • Dexrazoxane
  • Doxorubicin
  • ETOPOSIDE
  • HYDROCORTISONE
  • LEUCOVORIN CALCIUM
  • MERCAPTOPURINE
  • METHOTREXATE
  • NELARABINE
  • Vincristine
Fixed Dose PegaspargaseActive ComparatorFinal LR, IR, HR patients who consent to randomization and are assigned to receive 15 doses of pegaspargase every 2-weeks at standard fixed-dose (2500 IU/m2/dose).
  • Pegaspargase
  • Erwinia asparaginase
Reduced Dose (PK-Adjusted) PegaspargaseExperimentalFinal LR, IR, HR patients who consent to randomization and are assigned to receive 15 doses of pegaspargase every 2-weeks beginning at a reduced dose (2000 IU/m2/dose); subsequent doses adjusted based on nadir serum asparaginase activity (NSAA) levels, with goal of maintaining NSAA between 0.4 and 1.0 IU/mL
  • Pegaspargase
  • Erwinia asparaginase
Direct AssignmentOtherAll VHR patients, and any Final LR, IR, HR patients who decline randomization: Assigned to receive standard dosing of pegaspargase (15 doses of pegaspargase every 2-weeks at standard fixed-dose; 2500 IU/m2/dose).
  • Pegaspargase
  • Erwinia asparaginase

Eligibility Criteria

        Inclusion Criteria:

          1. Confirmed diagnosis of acute lymphoblastic leukemia. Diagnosis should be made by bone
             marrow aspirate or biopsy demonstrating ≥ 25% involvement by lymphoblasts, with flow
             cytometry or immunohistochemistry confirming B-precursor or T-ALL phenotype.

             -- For patients with circulating blasts in the peripheral blood, flow cytometry
             confirmation of B-ALL or T-ALL phenotype is sufficient for registration onto the
             study. Bone marrow aspirate and/or biopsy should be performed as soon as feasible,
             preferably prior to the initiation of any therapy.

          2. Prior Therapy: No prior therapy is allowed except for the following:

               -  Corticosteroids: Short courses of corticosteroid (defined as ≤ 7 days of
                  corticosteroids within the 4-weeks preceding registration) are allowed prior to
                  registration.

                  --- Participants who have been on corticosteroids chronically (defined as more
                  than 7 days of corticosteroids within the 4-weeks preceding registration or more
                  than 28 days of corticosteroids over the preceding 6 months) are not eligible.

               -  IT cytarabine: A single dose of intrathecal cytarabine (at the time of the
                  diagnostic lumbar puncture) is allowed prior to registration. If patient has
                  received IT cytarabine prior to registration, Day 1 IT cytarabine should not be
                  administered.

               -  Emergent Radiation Therapy: Emergent radiation to the mediastinum or other
                  life-threatening masses is allowed prior to registration.

          3. Age: 365 days to < 22 years

          4. Direct bilirubin < 1.4 mg/dL (23.9 micromoles/L).

          5. Ability of parent or guardian to understand and the willingness to sign a written
             informed consent document.

        Exclusion Criteria:

          1. Mature B-cell (Burkitt's) ALL (defined by the presence of surface immunoglobulin
             and/or the t(8;14)(q24;q32), t(8;22), or t(2;8) translocation and/or c-myc-gene
             rearrangement).

          2. World Health Organization diagnostic criteria of mixed phenotype acute leukemia (MPAL)
             or leukemia of ambiguous lineage

          3. Any chemotherapy or radiotherapy for previous malignancy are not eligible.

          4. Treatment in past with any anti-neoplastic agent, including methotrexate,
             6-mercaptopurine, 6-thioguanine, vincristine cyclophosphamide, cytarabine (except for
             IT cytarabine), or any anthracycline, for any reason (eg, rheumatologic or autoimmune
             condition).

          5. Currently receiving any investigational agents.

          6. Known HIV-positivity

          7. Uncontrolled intercurrent illness including, but not limited to ongoing infection with
             vital sign instability (hypotension, respiratory insufficiency), life-threatening
             acute tumor lysis syndrome (eg, with renal failure), symptomatic congestive heart
             failure, cardiac arrhythmia, intracranial or other uncontrolled bleeding, or
             psychiatric illness/social situations that would limit compliance with study
             requirements.

          8. Pregnant women are excluded from this study because many of the agents used on this
             protocol have potential for teratogenic and/or abortifacient effects. Because there is
             an unknown but potential risk of adverse events in nursing infants secondary to
             treatment of the mother with these chemotherapy agents, breastfeeding should be
             discontinued if the mother is enrolled.

          9. History of a previous malignancy. Exception: Individuals with a previous malignancy
             treated with surgery only (no chemotherapy or radiotherapy) more than 5 years prior to
             registration may be enrolled.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete Remission Rate
Time Frame:After 1 month of treatment (Induction IA) for all participants, assessed at the end of first month of treatment in all participants through study completion (expected to take 4-5 years to accrue)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:From registration to the time of death from any cause, assessed up to 60 months.
Safety Issue:
Description:
Measure:Disease Free Survival
Time Frame:From randomization or direct assignment (for participants who achieved a complete remission and were assigned a final risk group) to the time of relapse, death, or second malignancy, whichever came first, assessed up to 60 months.
Safety Issue:
Description:
Measure:Nadir Serum Asparaginase Activity (NSAA)
Time Frame:During post-induction therapy with 30-weeks of pegaspargase (15 doses), collected during the first 6 months of therapy for all participants through study completion (expected to take 4-5 years to accrue)
Safety Issue:
Description:Proportion of patients receiving pegaspargase with NSAA >= 1.0 IU/mL
Measure:Non-allergic Asparaginase Toxicity
Time Frame:During post-induction therapy with 30-weeks of pegaspargase (15 doses). collected during the first 6 months of therapy for all participants through study completion (expected to take 4-5 years to accrue)
Safety Issue:
Description:Frequency of non-allergic asparaginase-related toxicities, an average of 5 years.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Dana-Farber Cancer Institute

Trial Keywords

  • acute lymphoblastic leukemia

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