Clinical Trials /

Clofarabine or High-Dose Cytarabine and Pegaspargase in Children With ALL

NCT01228331

Description:

RATIONALE: 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 more than once drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses high-energy x-rays to kill cancer cells. It is not yet known whether giving clofarabine or high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride is more effective in treating young patients with acute lymphoblastic leukemia. PURPOSE: This randomized phase II/III trial is studying the side effects of giving clofarabine compared with giving high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride and to see how well it works in treating young patients with T-cell acute lymphoblastic leukemia or precursor B-cell acute lymphoblastic leukemia.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • T-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Clofarabine or High-Dose Cytarabine and Pegaspargase in Children With ALL
  • Official Title: A Randomized Multi-Center Treatment Study (COALL 08-09) to Improve the Survival of Children With Acute Lymphoblastic Leukemia on Behalf of the German Society of Pediatric Hematology and Oncology

Clinical Trial IDs

  • ORG STUDY ID: CDR0000686545
  • SECONDARY ID: 2009-012758-18
  • NCT ID: NCT01228331

Conditions

  • Leukemia

Interventions

DrugSynonymsArms
AmsacrineArm I intensification (cytarabine)
ClofarabineArm II intensification (clofarabine)
CyclophosphamideArm I intensification (cytarabine)
CytarabineArm I intensification (cytarabine)
Daunorubicin hydrochlorideArm II intensification (clofarabine)
DexamethasoneArm I intensification (cytarabine)
Doxorubicin hydrochlorideArm III reinduct.(doxorubicin hydrochl.)
Etoposide phosphateArm I intensification (cytarabine)
MercaptopurineArm III reinduct.(doxorubicin hydrochl.)
MethotrexateArm I intensification (cytarabine)
MethylprednisoloneArm I intensification (cytarabine)
PegaspargaseArm I intensification (cytarabine)
ThioguanineArm I intensification (cytarabine)
Vincristine sulfateArm I intensification (cytarabine)

Purpose

RATIONALE: 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 more than once drug (combination chemotherapy) may kill more cancer cells. Radiation therapy uses high-energy x-rays to kill cancer cells. It is not yet known whether giving clofarabine or high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride is more effective in treating young patients with acute lymphoblastic leukemia. PURPOSE: This randomized phase II/III trial is studying the side effects of giving clofarabine compared with giving high-dose cytarabine, pegaspargase, and combination chemotherapy followed by daunorubicin hydrochloride or doxorubicin hydrochloride and to see how well it works in treating young patients with T-cell acute lymphoblastic leukemia or precursor B-cell acute lymphoblastic leukemia.

Detailed Description

      OBJECTIVES:

      Primary

        -  To investigate the safety and efficacy of clofarabine combined with pegaspargase in
           patients with high-risk acute lymphoblastic leukemia during the first phase of the
           study. (Phase II)

        -  To investigate, in terms of minimal-residual disease (MRD), the cytotoxic efficacy of
           clofarabine compared with high-dose cytarabine in combination with pegaspargase in these
           patients. (Phase III)

        -  To compare the incidence of infectious complications after the administration of
           daunorubicin hydrochloride versus doxorubicin hydrochloride during reinduction.

      Secondary

        -  To compare the safety profiles of clofarabine and pegaspargase versus high-dose
           cytarabine and pegaspargase in these patients.

        -  To compare, in terms of MRD, the efficacy of clofarabine and pegaspargase and high-dose
           cytarabine and pegaspargase, respectively, versus methotrexate, cyclophosphamide, and
           asparaginase in study GER-COALL-07-03, the historical control group (retrospective
           comparison).

        -  To determine the influence of MRD-based stratification in COALL-09 on overall survival
           and event-free survival in a historical comparison of previous COALL studies.

      OUTLINE: This is a multicenter, sequential phase II/III study. Patients are stratified to low
      risk (LR) or high risk (HR) depending on peripheral white blood cell count on diagnosis, age
      on diagnosis, and immunological subtype. Patients undergo 2 randomizations (1 during
      intensification and 1 during reinduction) in the study.

        -  Preliminary treatment: All patients receive daunorubicin hydrochloride IV over 24 hours
           on day -7 and methotrexate intrathecally (IT) once on day -9, -8, or -7.

        -  Induction: All patients receive vincristine IV on days 1, 8, 15, and 22; daunorubicin
           hydrochloride IV over 24 hours on days 1, 8, and 15; and oral prednisone 3-4 times daily
           on days 1-28.

      Patients are assessed for minimal-residual disease (MRD) status after induction phase.
      Patients not in remission on day 29 are treated off study. Patients with LR disease are
      further stratified to LR-reduced (LR-R), LR-standard (LR-S), and LR-intensified (LR-I)
      groups; patients with HR disease are further stratified to HR-reduced (HR-R), HR-standard
      (HR-S), and HR-intensified (HR-I) groups. Patients in the LR-R and HR-R groups do not undergo
      randomization during study.

        -  Intensification (randomization 1): Patients receive therapy according to risk and
           disease subtypes. Some patients in different risk group are randomized* to receive
           high-dose (HD) cytarabine and pegaspargase or clofarabine and pegaspargase.

             -  LR-R and LR-S: Patients receive medium-high-dose (mHD) methotrexate IV over 24
                hours on days 50, 64, and 78; etoposide phosphate IV over 1-2 hours and cytarabine
                IV over 1 hour on day 66; oral mercaptopurine on days 50-56 and 78-120; oral
                thioguanine on days 64-70; and methotrexate IT on days 29, 50, 64, and 78. Patients
                in LR-S group who still have a detectable MRD load on day 29 are randomized
                (randomization 1) to 1 of 2 arms to receive cytarabine and pegaspargase vs.
                clofarabine and pegaspargase.

                  -  Arm I (cytarabine and pegaspargase) Patients receive HD cytarabine IV over 3
                     hours twice daily on days 29-31 and pegaspargase IV over 2 hours on days 31,
                     52, and 80.

                  -  Arm II (clofarabine and pegaspargase) Patients receive clofarabine IV over 2
                     hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 52, and 80.

             -  LR-I and precursor B-cell acute lymphoblastic leukemia (ALL) HR-S and HR-I:
                Patients receive cyclophosphamide IV over 30 minutes on days 50 and 64; mHD IV over
                24 hours on days 51, 65, 78, and 92; etoposide phosphate IV over 1-2 hours and
                cytarabine IV over 1 hour on days 80 and 94; oral mercaptopurine on days 64-70 and
                92-98; oral thioguanine on days 78-84; and methotrexate IT on days 29, 51, 65, 78,
                and 92. All precursor B-cell ALL patients with a detectable MRD load on day 29 and
                T-cell ALL patients with an MRD load ≥ 10³ on day 29 are randomized* (randomization
                1) to 1 of 2 arms to receive cytarabine and pegaspargase vs. clofarabine and
                pegaspargase.

                  -  Arm I (cytarabine and pegaspargase) Patients receive HD cytarabine IV over 3
                     hours twice daily on days 29-31 and 106-108 and pegaspargase IV over 2 hours
                     on days 31, 53, 67, and 108.

                  -  Arm II (clofarabine and pegaspargase) Patients receive clofarabine* IV over 2
                     hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 53, 67, and
                     108.

             -  NOTE: *In phase II, all patients with an MRD load of ≥ 104 (on day 29) receive
                clofarabine and pegaspargase without randomization.

             -  T-cell ALL HR (HR-R, HR-S, and HR-I): Patients receive cyclophosphamide IV over 30
                minutes on days 29 and 64; mHD methotrexate IV over 24 hours on days 30, 65, 78,
                and 92; etoposide phosphate IV over 1-2 hours and cytarabine IV over 1 hour on days
                80 and 94; oral mercaptopurine on days 64-70 and 92-98; oral thioguanine on days
                78-84; and methotrexate IT on days 30, 43, 65, 78, and 92. Patients in HR-S and
                HR-I group are randomized* (randomization 1) to 1 of 2 arms to receive cytarabine
                and pegaspargase vs. clofarabine and pegaspargase.

                  -  Arm I (cytarabine and pegaspargase): Patients receive HD cytarabine IV over 3
                     hours twice daily on days 43-45 and 106-108 and pegaspargase IV over 2 hours
                     on days 32, 45, 67, and 108.

                  -  Arm II (clofarabine and pegaspargase): Patients receive clofarabine IV over 2
                     hours on days 43-47 and pegaspargase IV over 2 hours on days 32, 47, 67, and
                     108.

      Patients in HR-I group also receive amsacrine IV over 4 hours and etoposide phosphate IV over
      2 hours on days 127 and 128, methylprednisolone IV over 30 minutes on days 127-130, and
      methotrexate IT on day 127, at the end of intensification.

      NOTE: *In phase II, all patients with an MRD load of ≥ 103 (on day 43) receive clofarabine
      and pegaspargase without randomization.

        -  CNS therapy: All patients with initial CNS involvement undergo cranial radiotherapy for
           a total of 12 or 18 Gy. HR patients (precursor B-cell ALL with initial WBC count ≥
           200/nL and T-cell ALL with initial WBC count ≥ 100/nL) with no initial CNS involvement
           also undergo cranial radiotherapy for a total of 12 Gy, beginning 2-3 weeks after the
           last dose of HD cytarabine or clofarabine. LR patients and HR patients (precursor B-cell
           ALL with initial WBC count < 200/nL and T-cell ALL with initial WBC count < 100/nL) with
           no initial CNS involvement do not receive initial cranial radiotherapy. At the beginning
           of CNS therapy, before cranial radiotherapy, HR-I patients receive vincristine IV on day
           1; doxorubicin hydrochloride IV over 24 hours on day 1; oral dexamethasone 3 times daily
           on days 1-7; and pegaspargase IV over 2 hours on day 7.

      All patients receive interim therapy comprising 3 doses (2 in week 1 and 1 in week 3) of
      methotrexate IT and oral mercaptopurine daily during the 4 weeks between intensification and
      reinduction.

        -  Reinduction (randomization 2): Patients undergo reinduction immediately after completion
           of interim therapy. Patients in LR-S, LR-I, HR-S, and HR-I groups are randomized to 1 of
           2 arms (doxorubicin hydrochloride vs. daunorubicin hydrochloride)

             -  LR-S: Patients receive vincristine IV on days 1 and 8, oral dexamethasone on days
                1-14, pegaspargase IV over 2 hours on day 9, cyclophosphamide IV over 30 minutes on
                day 22, cytarabine IV or intramuscularly (IM) on days 23-26, oral thioguanine on
                days 22-28, and methotrexate IT on days 1, 22, and 36.

                  -  Arm III (doxorubicin hydrochloride) Patients receive doxorubicin hydrochloride
                     IV over 24 hours on days 1 and 8.

                  -  Arm IV (daunorubicin hydrochloride): Patients receive daunorubicin
                     hydrochloride IV over 24 hours on days 1 and 8.

             -  LR-R and HR-R: Patients are not randomized. They receive vincristine IV on days 1
                and 8, oral dexamethasone on days 1-14, pegaspargase IV over 2 hours on day 8, and
                methotrexate IT on days 1 and 15.

             -  LR-I, HR-S, and HR-I: Patients receive vincristine IV on days 1, 8, 22, and 29;
                oral dexamethasone twice daily on days 1-14 and 22-35; cyclophosphamide IV over 30
                minutes on days 43 and 57; cytarabine IV or IM on days 43-46 and 57-60; oral
                thioguanine on days 43-49 and 57-63; and methotrexate IT* on days 1, 22, and 43.

                  -  Arm III (doxorubicin hydrochloride) Patients receive doxorubicin hydrochloride
                     IV over 24 hours on days 1, 8, 22, and 29.

                  -  Arm IV (daunorubicin hydrochloride) Patients receive daunorubicin
                     hydrochloride IV over 24 hours on days 1, 8, 22, and 29.

      NOTE: *Patients who underwent cranial radiotherapy do not receive methotrexate IT.

        -  Maintenance: Beginning 2-3 weeks after reinduction, all patients receive oral
           mercaptopurine daily and oral methotrexate weekly for 2 years. Except for LR-R and HR-R,
           patients also receive pegaspargase IV over 2 hours every 3 weeks for 3 doses. Patients
           who have not undergone CNS radiotherapy receive methotrexate IT at 3, 6, and 9 months.

      Blood and bone marrow samples may be collected periodically for research studies.

      After completion of study treatment, patients are followed monthly for 1 year, every 3 months
      for 2 years, every 6 months for 2 years, and then annually for 5 years.

      PROJECTED ACCRUAL: A total of 41 high-risk patients will be accrued for phase II, 296
      patients for the first randomization (phase III), and 396 patients for the second
      randomization will be accrued for this study.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I intensification (cytarabine)Active ComparatorLR-S patients receive HD cytarabine IV 4 x 3 g over 12 hours daily on days 29-31 and pegaspargase IV over 2 hours on days 31, 52, and 80. LR-I and precursor B-cell ALL HR-S and HR-I patients receive HD cytarabine IV 2.500 over 3 hours twice daily on days 29-31 and 106-108 and pegaspargase IV over 2 hours on days 31, 53, 67, and 108. Followed by standard consolidation therapy regarding to stratification containing: methotrexate, cyclophosphamide, thioguanin, mercaptopurine, etoposide phosphate, amsacrine, cytarabine, methylprednisolone, dexamethasone, vincristine sulfate; whole-brain radiation therapy only if indicated in patients with cns involvement or T-cell ALL
  • Amsacrine
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Etoposide phosphate
  • Methotrexate
  • Methylprednisolone
  • Pegaspargase
  • Thioguanine
  • Vincristine sulfate
Arm II intensification (clofarabine)Active ComparatorLR-S patients receive clofarabine* IV 5 x 40 mg over 2 hours every day on days 29-33 and pegaspargase IV over 2 hours on days 33, 52, and 80. LR-I and precursor B-cell ALL HR-S and HR-I patients receive clofarabine* IV over 2 hours on days 29-33 and pegaspargase IV over 2 hours on days 33, 53, 67, and 108. Followed by standard consolidation therapy regarding to stratification containing: methotrexate, cyclophosphamide, thioguanin, mercaptopurine, etoposide phosphate, amsacrine, cytarabine, methylprednisolone, dexamethasone, vincristine sulfate; whole-brain radiation therapy only if indicated in patients with cns involvement or T-cell ALL
  • Amsacrine
  • Clofarabine
  • Cyclophosphamide
  • Daunorubicin hydrochloride
  • Dexamethasone
  • Etoposide phosphate
  • Methotrexate
  • Methylprednisolone
  • Pegaspargase
  • Thioguanine
  • Vincristine sulfate
Arm III reinduct.(doxorubicin hydrochl.)Active ComparatorLR-S patients receive doxorubicin hydrochloride IV 30 mg/m2 over 24 hours on days 1 and 8. LR-I, HR-S and HR-I Patients receive doxorubicin hydrochloride IV 30 mg/m2 over 24 hours on days 1, 8, 22, and 29. Followed by standard reinduction and maintenance therapy containing: cyclophophamide, cytarabine, thioguanine, mercaptopurine, methotrexate and pegaspargase, dexamethasone, vincristine sulfate
  • Cyclophosphamide
  • Cytarabine
  • Dexamethasone
  • Doxorubicin hydrochloride
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Vincristine sulfate
Arm IV reinduct.(daunorubicin hydrochl.)Active ComparatorLR-S patients receive daunorubicin hydrochloride IV 36 mg/m2 over 24 hours on days 1 and 8. LR-I, HR-S and HR-I Patients receive daunorubicin hydrochloride IV 36 mg/m2 over 24 hours on days 1, 8, 22, and 29. Followed by standard reinduction and maintenance therapy containing: cyclophophamide, cytarabine, thioguanine, mercaptopurine, methotrexate and pegaspargase, dexamethasone, vincristine sulfate
  • Cyclophosphamide
  • Cytarabine
  • Daunorubicin hydrochloride
  • Dexamethasone
  • Mercaptopurine
  • Methotrexate
  • Pegaspargase
  • Vincristine sulfate

Eligibility Criteria

        Inclusion criteria:

        diagnosis after the first and before the 18th birthday AND confirmed diagnosis of acute
        B-precursor or or T-cell leukemia AND parents or guardians/patients give consent for
        inclusion in the study and transmission of data AND if none of exclusion criteria is
        accomplished

        Exclusion criteria:

        BCR/ABL rearrangement positive OR prior cytostatic treatment lasting > 7 days or prior
        treatment with cytostatic drugs other than vincristine, daunorubicin and prednisone OR
        prior severe illnesses which make treatment per the protocol impossible from the outset
        (BUT trisomy 21 is not an exclusion criterion) OR absence of the baseline data required for
        assignment to a risk group in accordance with the protocol (BUT patients for whom the MRD
        value could not be determined for technical reasons will be treated as protocol patients)
        OR the disease is a secondary malignancy or relapse OR death before the start of treatment
      
Maximum Eligible Age:17 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and efficacy of clofarabine combined with pegaspargase (phase II)
Time Frame:at day 21 after chemotherapy
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of infectious complications after administration of daunorubicin hydrochloride vs doxorubicin hydrochloride
Time Frame:at the end of reinduction therapy
Safety Issue:
Description:

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Universitätsklinikum Hamburg-Eppendorf

Trial Keywords

  • childhood acute lymphoblastic leukemia
  • untreated childhood acute lymphoblastic leukemia

Last Updated

May 26, 2017