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Standard Chemotherapy With or Without Nelarabine or Rituximab in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia

NCT01085617

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 one drug (combination chemotherapy) may kill more cancer cells. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known which regimen of combination chemotherapy given together with or without monoclonal antibodies is more effective in treating patients with newly diagnosed acute lymphoblastic leukemia. PURPOSE: This randomized phase III trial is studying standard chemotherapy to see how well it works when given together with or without rituximab, and with or without nelarabine in treating patients with newly diagnosed acute lymphoblastic leukemia.

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

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Standard Chemotherapy With or Without Nelarabine or Rituximab in Treating Patients With Newly Diagnosed Acute Lymphoblastic Leukemia
  • Official Title: A Randomized Trial for Adults With Newly Diagnosed Acute Lymphoblastic Leukemia

Clinical Trial IDs

  • ORG STUDY ID: CDR0000667211
  • SECONDARY ID: UCL-08-0167
  • SECONDARY ID: EU-21009
  • SECONDARY ID: 2009-012717-22
  • SECONDARY ID: UCL-UKALL14
  • SECONDARY ID: MREC-09-H0711-90
  • SECONDARY ID: NCRI-UCL-08-0167
  • SECONDARY ID: CRUK-C27995-A9609
  • NCT ID: NCT01085617

Conditions

  • Leukemia
  • Mucositis
  • Oral Complications

Interventions

DrugSynonymsArms
paliferminP1 - standard palifermin
rituximabB2 - Rituximab
cyclophosphamideB1 - Standard therapy
cytarabineB1 - Standard therapy
daunorubicin hydrochlorideB1 - Standard therapy
etoposideB1 - Standard therapy
fludarabine phosphateB1 - Standard therapy
imatinib mesylateB1 - Standard therapy
melphalanB1 - Standard therapy
mercaptopurineB1 - Standard therapy
methotrexateB1 - Standard therapy
nelarabineT2 - Nelarabine
pegaspargaseB1 - Standard therapy
vincristine sulfateB1 - Standard therapy

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 one drug (combination chemotherapy) may kill more cancer cells. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. It is not yet known which regimen of combination chemotherapy given together with or without monoclonal antibodies is more effective in treating patients with newly diagnosed acute lymphoblastic leukemia. PURPOSE: This randomized phase III trial is studying standard chemotherapy to see how well it works when given together with or without rituximab, and with or without nelarabine in treating patients with newly diagnosed acute lymphoblastic leukemia.

Detailed Description

      OBJECTIVES:

      Primary

        -  To determine if the addition of a monoclonal antibody (none vs. rituximab) improves
           event-free survival (EFS) in patients with newly diagnosed precursor B-cell acute
           lymphoblastic leukemia (ALL).

        -  To determine if the addition of nelarabine improves outcome for patients with T-cell
           ALL.

      Secondary

        -  To determine the tolerability of pegaspargase in induction therapy of all patients.

        -  To compare anti-asparaginase antibody levels in patients with B-lineage ALL.

        -  To determine whether risk-adapted introduction of unrelated donor hematopoietic stem
           cell transplantation (HSCT) (myeloablative conditioning in patients ≤ 40 years old and
           non-myeloablative conditioning in patients > 40 years old) results in greater EFS for
           patients at highest risk of relapse.

        -  To compare the efficacy of two schedules (standard vs collapsed) of palifermin in
           preventing severe mucosal toxicity in patients treated with etoposide, total-body
           irradiation, and HSCT-conditioning therapy.

        -  To assess the late effects of this treatment in these patients.

        -  To identify and describe some of the adverse physical and psychosocial consequences of
           this disease and its treatment.

      OUTLINE: This is a multicenter study. There are 3 randomizations at different timepoints in
      the trial, each patient undergoes at least 1 but no more than 2 randomizations.

        -  Part 1 standard induction therapy (all patients*, weeks 1-4): Patients receive
           daunorubicin hydrochloride IV over 20 minutes and vincristine sulfate IV over 5-10
           minutes on days 1, 8, 15, and 22; oral dexamethasone once a day on days 1-5, 8-11, and
           15-18; pegaspargase IV over 1-2 hours on days 4 and 18; and methotrexate intrathecally
           (IT) on day 14.

      NOTE: *Patients with Philadelphia-positive (Ph+) disease should also receive oral imatinib
      mesylate once a day on days 1-28.

        -  Randomized concurrent monoclonal antibody therapy (for patients with precursor B-cell
           acute lymphoblastic leukemia [ALL]): Patients with precursor B-cell ALL are randomized
           to 1 of 4 monoclonal antibody treatment arms (given concurrently with part 1 standard
           induction therapy):

             -  Arm B1: Patients do not receive any monoclonal antibody therapy.

             -  Arm B2 : Patients receive rituximab IV on days 3, 10, 17, and 24.

                  -  Part 2 standard induction therapy (all patients*, weeks 5-8): Patients receive
                     cyclophosphamide IV over 30 minutes on days 1 and 15; cytarabine IV on days
                     2-5, 9-12, 16-19, and 23-26; oral mercaptopurine once a day on days 1-28; and
                     methotrexate IT on days 1, 8, 15, and 22.

      NOTE: *Patients with Ph+ disease should also receive oral imatinib mesylate once a day on
      days 1-30.

        -  Randomized subsequent nelarabine therapy (for Patients with T-cell ALL) Patients with
           T-cell ALL are randomized to 1 of 2 treatment arms, to be administered after completion
           of part 2 standard induction therapy.

             -  Arm T1: Patients do not receive any other therapy during induction.

             -  Arm T2: Patients receive nelarabine IV over 2 hours on days 1, 3, and 5. Patients
                who do not achieve complete remission (CR) after part 2 standard induction therapy
                are taken off study.

                  -  Intensification/central nervous system prophylaxis (patients not eligible for
                     transplant OR patients > 40 years at study entry and eligible for
                     transplant)*: Beginning after recovery from part 2 standard induction therapy,
                     patients receive high-dose methotrexate IV on days 1 and 15 and pegaspargase
                     IV over 1-2 hours on days 2 and 16.

      NOTE: *Patients with Philadelphia-positive (Ph+) disease should also receive oral imatinib
      mesylate once a day on days 1-28.

      Patients eligible for allogeneic hematopoietic stem cell transplantation (HSCT) (i.e., any
      patient with an HLA-compatible sibling donor or high risk patients with a molecularly matched
      donor) undergo transplantation; patients not eligible for HSCT undergo consolidation followed
      by maintenance therapy.

        -  Consolidation therapy* (patients not eligible for transplantation):

             -  Course 1: Beginning after completion of intensification therapy, patients receive
                cytarabine IV and high-dose etoposide IV over 30 minutes on days 1-5, pegaspargase
                IV over 1-2 hours on day 5, and methotrexate IT on day 1. Patients proceed to
                course 2 beginning 3 weeks after the start of course 1 or when neutrophils recover.

             -  Course 2: Patients receive cytarabine IV and high-dose etoposide IV over 30 minutes
                on days 1-5 and methotrexate IT on day 1. Patients proceed to course 3 beginning 3
                weeks after the start of course 2 or when neutrophils recover.

             -  Course 3 (delayed intensification): Patients receive daunorubicin hydrochloride IV
                over 20 minutes and vincristine sulfate IV over 5-10 minutes on days 1, 8, 15, and
                22; pegaspargase IV over 1-2 hours on day 4; oral dexamethasone once a day on days
                1-4, 8-11, 15-18, and 22-25; methotrexate IT on days 2 and 17; cyclophosphamide IV
                on day 29; cytarabine IV on days 30-33 and 37-40; and oral mercaptopurine once a
                day on days 29-42. Patients proceed to course 4 after neutrophils recover.

             -  Course 4: Patients receive cytarabine IV, high-dose etoposide IV, and methotrexate
                IT as in course 2.

      NOTE: *Patients with Ph+ disease should also receive oral imatinib mesylate once a day on
      days 1-7 in courses 1 and 2, on days 2-42 in course 3, and on days 1-8 in course 4.

        -  Maintenance therapy (patients not eligible for transplantation): Patients receive
           vincristine sulfate IV every 3 months, oral prednisolone once a day on days 1-5 every 3
           months, oral mercaptopurine once daily, methotrexate IV or orally once a week, and
           methotrexate IT every 3 months for 2 years.

        -  Transplant conditioning and allogeneic HSCT:

             -  Myeloablative-conditioning and allogeneic HSCT (patients ≤ 40 years old at study
                entry): Patients undergo total-body irradiation on days -7 to -4 and receive
                high-dose etoposide IV over 4 hours on day -3 or high-dose cyclophosphamide IV over
                2 hours on days -3 and -2. Patients then undergo allogeneic HSCT on day 0.

      Patients are stratified according to gender, donor (sibling donor vs. matched unrelated
      donor), and cellular type of ALL (precursor B-lineage vs. T-lineage). Patients are randomized
      to receive 1 of 2 palifermin treatment arms.

        -  Arm P1 (standard dose): Patients receive palifermin IV on days -3 to 2.

        -  Arm P2 (collapsed dose): Patients receive palifermin IV on days -1 to 2.

             -  Non-myeloablative-conditioning and allogeneic HSCT (patients > 40 years old at
                study entry): Patients receive fludarabine phosphate IV over 30-60 minutes on days
                -7 to -3 and melphalan IV over 90 days on day -1. Recipients of unrelated donor
                HSCT also receive alemtuzumab IV over 2 hours on day -2 and -1; recipients of
                sibling HSCT receive alemtuzumab IV over 2 hours on day -1. Patients then undergo
                allogeneic HSCT on day 0. Patients also receive post transplant methotrexate IT
                every 3 months for 2 years.

      Patients undergo blood and bone marrow sample collection periodically for correlative
      studies.

      After completion of study treatment, patients are followed annually.

      Peer Reviewed and Funded or Endorsed by Cancer Research UK
    

Trial Arms

NameTypeDescriptionInterventions
B1 - Standard therapyActive ComparatorStandard chemotherapy for precursor B-cell ALL
  • cyclophosphamide
  • cytarabine
  • daunorubicin hydrochloride
  • etoposide
  • fludarabine phosphate
  • imatinib mesylate
  • melphalan
  • mercaptopurine
  • methotrexate
  • pegaspargase
  • vincristine sulfate
B2 - RituximabExperimentalStandard chemotherapy for precursor B-cell ALL plus weekly rituximab infusions during phase 1 induction
  • rituximab
  • cyclophosphamide
  • cytarabine
  • daunorubicin hydrochloride
  • etoposide
  • fludarabine phosphate
  • imatinib mesylate
  • melphalan
  • mercaptopurine
  • methotrexate
  • pegaspargase
  • vincristine sulfate
T1 - Standard therapyActive ComparatorStandard chemotherapy for T-cell ALL
  • cyclophosphamide
  • cytarabine
  • daunorubicin hydrochloride
  • etoposide
  • fludarabine phosphate
  • melphalan
  • mercaptopurine
  • methotrexate
  • pegaspargase
  • vincristine sulfate
T2 - NelarabineExperimentalStandard chemotherapy for T-cell ALL plus an additional course of treatment with nelarabine following phase 2 induction
  • cyclophosphamide
  • cytarabine
  • daunorubicin hydrochloride
  • etoposide
  • fludarabine phosphate
  • melphalan
  • mercaptopurine
  • methotrexate
  • nelarabine
  • pegaspargase
  • vincristine sulfate
P1 - standard paliferminActive Comparator6 doses of palifermin before/after myeloablative stem cell transplant (randomisation closed due to lack of clinical relevance in 2016)
  • palifermin
P2 - collapsed paliferminExperimental1 x large dose of palifermin before myeloablative stem cell transplant and 3 low doses after transplant (randomisation closed due to lack of clinical relevance in 2016)
  • palifermin

Eligibility Criteria

        DISEASE CHARACTERISTICS:

          -  Newly diagnosed, previously untreated acute lymphoblastic leukemia

               -  A pre-phase steroid treatment of 5-7 days is required and can be started prior to
                  registration

          -  Philadelphia chromosome-negative or -positive patients are eligible

          -  No blast transformation of chronic myeloid leukemia

          -  No mature B-cell leukemia [i.e., Burkitt disease t(8,14)(q24 ;q32)] or variant c-myc
             translocations [e.g., t(2;8)(p12;q24), t(8;22)(q24;q11)]

          -  Patients who undergo study transplantation must have HLA-compatible sibling or
             unrelated donor

               -  8/8 molecular match at -A, -B, -C, and -DR (DQ mismatch is permitted)

          -  Patients meeting ≥ 1 the following criteria are considered high-risk:

               -  Over 40 years old

               -  WBC ≥ 30 x 10^9/L (precursor-B) OR ≥ 100 x 10^9/L (T-lineage)

               -  Any 1 or more of the following cytogenetic abnormalities:

                    -  t(4;11)(q21;q23)/MLL-AF4

                    -  Low hypodiploidy/near triploidy (30-39 chromosomes/60-78 chromosomes)

                    -  Complex karyotype (≥ 5 chromosomal abnormalities)

                    -  Philadelphia chromosome t(9;22) (q34;q11)/BCR-ABL1 (detected by cytogenetic
                       or molecular methods)

               -  High-risk minimal-residual disease after completion of part 2 standard induction
                  therapy

        PATIENT CHARACTERISTICS:

          -  No known HIV infection

          -  Not pregnant or nursing (no nursing during and for 12 months after completion of study
             therapy)

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception during and for up to 12 months after
             completion of study therapy

        PRIOR CONCURRENT THERAPY:

          -  See Disease Characteristics
      
Maximum Eligible Age:65 Years
Minimum Eligible Age:25 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival
Time Frame:3 years
Safety Issue:
Description:Time from randomisation to relapse or death from any cause

Secondary Outcome Measures

Measure:Anti-asparaginase antibodies in patients treated with monoclonal antibody therapy
Time Frame:Throughout treatment
Safety Issue:
Description:Antibody levels in sequential samples during pegylated asparaginase treatment
Measure:Overall survival
Time Frame:3 years
Safety Issue:
Description:Time from randomisation to death from any cause
Measure:Complete remission (CR) rate
Time Frame:Throughout treatment
Safety Issue:
Description:Proportion of patients achieving morphological complete remission
Measure:Minimal-residual disease quantification after first phase of induction and post-transplantation
Time Frame:Throughout treatment
Safety Issue:
Description:Minimal residual disease measured at central laboratory after phase 1 induction and post transplant
Measure:Relapse rate (including bone marrow and CNS relapse)
Time Frame:3 years
Safety Issue:
Description:Proportion of patients experiencing a bone marrow of CNS relapse after entering complete remission
Measure:Death in CR
Time Frame:3 years
Safety Issue:
Description:Proportion of patients dying while their ALL is in complete remission
Measure:Toxicity related to pegaspargase
Time Frame:Throughout treatment
Safety Issue:
Description:Rates of hypersensitivity, changes to Erwinia, or withdrawal of asparaginase treatment
Measure:Mucositis score in patients treated with palifermin
Time Frame:30 days
Safety Issue:
Description:OMQD score, number of doses of methotrexate given, acute GVHD rates

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University College, London

Trial Keywords

  • oral complications
  • mucositis
  • untreated adult acute lymphoblastic leukemia
  • B-cell adult acute lymphoblastic leukemia
  • T-cell adult acute lymphoblastic leukemia
  • Philadelphia chromosome positive adult precursor acute lymphoblastic leukemia

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