Clinical Trials /

Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

NCT01700946

Description:

The overall objective of this protocol is to improve the cure rate of relapsed precursor B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. This phase II trial is studying risk-directed therapy for B-lymphoblastic leukemia or lymphoma in first relapse. Standard risk (SR) and high risk (HR) participants will receive different therapy. Treatment will consist of chemotherapy for SR participants, and chemotherapy followed by hematopoietic stem cell transplant (HSCT) for HR in first relapse. Induction therapy consists of three blocks of chemotherapy. The first block is a novel immunotherapy regimen that includes chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. SR participants will continue to receive chemotherapy for a total duration of approximately 2 years. HR participants will be candidates for HSCT and will proceed to transplant once a suitable donor is found and their minimal residual disease (MRD) is negative.

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Lymphoblastic Lymphoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma
  • Official Title: A Phase II Study of Therapy for Pediatric Relapsed or Refractory Precursor B-Cell Acute Lymphoblastic Leukemia and Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: ALLR18
  • SECONDARY ID: NCI-2012-00587
  • NCT ID: NCT01700946

Conditions

  • Recurrent B-Cell Childhood Acute Lymphoblastic Leukemia
  • Recurrent Childhood B-Lymphoblastic Lymphoma

Interventions

DrugSynonymsArms
dexamethasoneDecadron(R)High Risk
vincristine sulfateOncovin(R)High Risk
rituximabRituxan(R)High Risk
clofarabineClolar(TM), clofarexHigh Risk
cyclophosphamideCytoxan(R)High Risk
etoposideVP-16, Vepesid(R)High Risk
aldesleukinIL-2, interleukin-2, Proleukin (R)High Risk
pegaspargasePEG-ASP, Peg-L-asparaginase, PEG-asparaginase, Oncaspar(R)High Risk
methotrexateMTX, HDMTXHigh Risk
mercaptopurine6-MP, Purinethol(R)High Risk
cytarabineAra-C, Cytosar-U(R)High Risk
mitoxantroneNovantrone(R)High Risk
teniposideVM-26, Vumon(R)Standard Risk
vinblastineVelban(R)Standard Risk
natural killer cell infusionNK cell infusionHigh Risk
therapeutic hydrocortisoneCortefHigh Risk

Purpose

The overall objective of this protocol is to improve the cure rate of relapsed precursor B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma. This phase II trial is studying risk-directed therapy for B-lymphoblastic leukemia or lymphoma in first relapse. Standard risk (SR) and high risk (HR) participants will receive different therapy. Treatment will consist of chemotherapy for SR participants, and chemotherapy followed by hematopoietic stem cell transplant (HSCT) for HR in first relapse. Induction therapy consists of three blocks of chemotherapy. The first block is a novel immunotherapy regimen that includes chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells. SR participants will continue to receive chemotherapy for a total duration of approximately 2 years. HR participants will be candidates for HSCT and will proceed to transplant once a suitable donor is found and their minimal residual disease (MRD) is negative.

Detailed Description

      Primary objective

        -  To estimate the 3-year survival rate of participants with first relapse or primary
           refractory precursor B-cell ALL and lymphoblastic lymphoma treated with risk-directed
           therapy.

      Secondary objectives

        -  To determine minimal residual disease (MRD) levels at the end of remission induction
           therapy for participants with relapsed precursor B-cell ALL and compare the results with
           those in protocol ALLR17

        -  To estimate levels of CD20 expression at baseline, during treatment with
           dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of
           remission induction therapy for relapsed precursor B-cell ALL.

      STUDY DESCRIPTION:

      The general treatment plan will consist of chemotherapy for standard-risk participants and
      chemotherapy followed by HSCT for high risk participants in first relapse of B-precursor ALL
      or lymphoblastic lymphoma. Remission induction for all participants consists of three blocks
      of therapy, wherein the first block is a novel immunotherapy regimen that includes cytotoxic
      chemotherapy, rituximab and infusion of haploidentical natural killer (NK) cells.
      Standard-risk patients will continue to receive chemotherapy for a total duration of
      approximately 2 years. High-risk patients will be candidates for HSCT and will proceed to
      transplant once a suitable donor is found and the patient achieves negative MRD.

      Participants will be assigned to the standard arm if they experience late relapse (> or = 6
      months after completion of frontline therapy) AND maximum residual disease (MRD) is <0.01% at
      the end of Block II of remission induction therapy. Provisional standard risk participants
      (i.e., late relapse) will be re-assigned to high risk if MRD is > or = 0.01% at the end of
      Block II. Participants with lymphoma must be in complete remission at the end of Block III.

      High risk participants will meet one of the following criteria:

        -  Early relapse (on therapy or <6 months after completion of frontline therapy), OR

        -  Any relapse after hematopoietic stem cell transplant, OR

        -  MRD > or = 0.01% at the end of Block II of remission induction therapy, OR

        -  Re-emergence of MRD at any time after attaining negative MRD on this clinical trial.

      Natural killer (NK) cell collection: Donors who meet eligibility criteria will undergo
      apheresis once. The cells obtained will be purified for CD56+ cells utilizing the CliniMACS
      selection system. The NK cell product will undergo quality control testing following standard
      operating procedures of the St. Jude Human Applications Laboratory.

      OUTLINE (STANDARD RISK):

      REMISSION INDUCTION:

      BLOCK I: Patients receive dexamethasone orally (PO) or intravenously (IV) thrice daily (TID)
      on days 1-8 and 21-28; vincristine sulfate IV on days 1, 21, 28, and 35; rituximab IV on days
      4, 13, 20, and 27; clofarabine, cyclophosphamide, and etoposide IV on days 6-10; aldesleukin
      subcutaneously (SC) once every other day (QOD) on days 11-19; and pegaspargase IV on days 21
      and 35. Patients also undergo natural killer (NK) cell infusion on day 12. Patients may
      receive triple intrathecal therapy comprising methotrexate, therapeutic hydrocortisone, and
      cytarabine on days 1, 5, 8, 11, 21, and 28. Patients continue on to Block II after count
      recovery.

      BLOCK II: Patients receive methotrexate IV over 24 hours on days 1 and 8 and mercaptopurine
      PO on days 1-21. Patients also receive triple intrathecal therapy on day 1. High-risk
      patients with negative MRD continue on to transplantation. All patients with positive MRD
      continue on to Block III after count recovery.

      BLOCK III: Patients receive cytarabine IV over 2 hours twice daily (BID) on days 1-4 and
      mitoxantrone hydrochloride IV over 1 hour on days 3-5. Patients also receive triple
      intrathecal therapy on day 7.

      INTERIM CONTINUATION (for patients unable to tolerate dose intensive chemotherapy): Patients
      receive etoposide and cyclophosphamide IV on day 1, methotrexate IV on day 8, mercaptopurine
      PO on days 8-14, teniposide and cytarabine IV on day 15, dexamethasone PO TID on days 22-26,
      and vinblastine IV on day 22.

      RE-INDUCTION THERAPY: Patients receive clofarabine, cyclophosphamide, and etoposide IV on
      days 1-5; dexamethasone PO on days 1-6; and pegaspargase on days 6 and 20 and vincristine
      sulfate IV on days 6, 13, and 20. Patients may also receive triple intrathecal therapy on
      days 1 and 15. Patients continue on to continuation treatment after count recovery.

      CONTINUATION TREATMENT: Patients receive methotrexate IV over 2 hours on day 1 and
      mercaptopurine PO on days 1-7 of weeks 1, 2, 5, and 6; teniposide and cytarabine IV on day 1
      of weeks 3 and 7; vincristine sulfate IV on day 1 of week 4; dexamethasone PO TID on days 1-5
      of weeks 4 and 8; and vinblastine IV on day 1 of week 8. Treatment repeats every 8 weeks for
      up to 10 courses in the absence of disease progression or unacceptable toxicity. Patients may
      also receive triple intrathecal therapy on day 1 of week 1 of all courses and day 1 of week
      5, courses 1-5.

      Due to the unavailability of the drug Teniposide (VM-26), etoposide (VP-16) will be
      substituted for the remaining doses for patients currently on this study. The protocol
      Section 5.1.3 allows this substitution.

      OUTLINE: GROUP 2 (high risk defined as participants not meeting the standard risk criteria
      noted above):

      Patients receive Remission Induction (Blocks I, II, and III) treatment as described above for
      Group 1. Patients then undergo allogeneic hematopoietic stem cell transplantation (HSCT) as
      soon as they have negative MRD. Patients with negative MRD may continue chemotherapy until a
      suitable donor is found.

      After completion of study treatment, patients are followed up every 4 months for 1 year,
      every 6 months for 1 year, and then yearly for up to 10 years.
    

Trial Arms

NameTypeDescriptionInterventions
Standard RiskActive ComparatorInterventions: dexamethasone, vincristine sulfate, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, teniposide, vinblastine, natural killer cell infusion, laboratory biomarker analysis, therapeutic hydrocortisone Cells for infusion are prepared using the CliniMACS System.
  • dexamethasone
  • vincristine sulfate
  • rituximab
  • clofarabine
  • cyclophosphamide
  • etoposide
  • aldesleukin
  • pegaspargase
  • methotrexate
  • mercaptopurine
  • cytarabine
  • mitoxantrone
  • teniposide
  • vinblastine
  • natural killer cell infusion
  • therapeutic hydrocortisone
High RiskActive ComparatorInterventions: dexamethasone, vincristine, rituximab, clofarabine, cyclophosphamide, etoposide, aldesleukin, pegaspargase, methotrexate, mercaptopurine, cytarabine, mitoxantrone, natural killer cell infusion, allogeneic hematopoietic stem cell transplantation, laboratory biomarker analysis, therapeutic hydrocortisone Cells for infusion are prepared using the CliniMACS System.
  • dexamethasone
  • vincristine sulfate
  • rituximab
  • clofarabine
  • cyclophosphamide
  • etoposide
  • aldesleukin
  • pegaspargase
  • methotrexate
  • mercaptopurine
  • cytarabine
  • mitoxantrone
  • natural killer cell infusion
  • therapeutic hydrocortisone

Eligibility Criteria

        INCLUSION CRITERIA:

          -  Must have relapsed or refractory precursor B-cell acute lymphoblastic leukemia or
             acute lymphoblastic lymphoma.

          -  Participants with leukemia must meet one of the following:

               1. In first hematologic relapse, defined as the reappearance (in a patient who has
                  previously achieved remission) of leukemia blasts in the bone marrow or
                  peripheral blood, OR

               2. Refractory to one or two courses of frontline induction therapy (≥ 5% blasts in
                  the bone marrow or peripheral blood confirmed by flow cytometric analysis).

          -  Participant with lymphoma must meet one of the following:

               1. In first relapse, OR

               2. Refractory to one or two courses of frontline induction therapy with measurable
                  disease

                    -  Should flow cytometric analyses suggest relapse (by the reappearance of a
                       similar immunophenotype to the original leukemia) in the presence of <5%
                       blasts morphologically, a repeat bone marrow test is recommended to confirm
                       relapse.

                    -  Molecular or genetic relapse is characterized by the reappearance of a
                       cytogenetic or molecular abnormality.

                    -  Early relapse is defined as relapse on therapy or < 6 months after
                       completion of frontline therapy. Late relapse is defined as relapse
                       occurring ≥ 6 months after completion of frontline therapy.

          -  Participant's age is < 22 years at time of enrollment (e.g. participant is eligible
             until 22nd birthday).

          -  Prior therapy:

               1. There is no waiting period for participants who relapse while receiving frontline
                  therapy and are free from side effects attributable to such therapy.

               2. Emergent radiation therapy, one dose of intrathecal chemotherapy, and up to 7
                  days of steroids for treatment of relapse are permitted before start of treatment
                  in participants who relapse after completion of frontline therapy.

               3. At least 90 days have elapsed since bone marrow transplant and participant is off
                  immune suppression for a minimum of 2 weeks, if applicable. Participants with ALL
                  or NHL who were transplanted in first remission are eligible for this study.

        Organ function requirements

          -  Hepatic: Total bilirubin ≤ upper limit of normal (ULN) for age, or if total bilirubin
             is > ULN, direct bilirubin ≤ 1.4 mg/dl

          -  Cardiac: Shortening fraction ≥ 28%

          -  Renal: Glomerular filtration rate >50cc/min/1.73 m^2, OR maximum serum creatinine (SC)
             based on age as follows:

               -  If age is 1 to 2 years, then maximum SC is 0.6 mg/dL

               -  If age is 2 to 6 years, then maximum SC is 0.8 mg/dL

               -  If age is 6 to 10 years, then maximum SC is 1 mg/dL

               -  If age is 10 to <13 years, then maximum SC is 1.2 mg/dL

               -  If age is 13 to 16 years, then maximum SC is 1.5 mg/dL for males and 1.4 mg/dL
                  for females

               -  If age is >16 years, then maximum SC is 1.7 mg/dL for males and 1.4 mg/dL for
                  females

        EXCLUSION CRITERIA:

          -  Leukemia participants ages 1 to 5 years with induction failure AND favorable
             cytogenetics (i.e., hyperdiploidy defined as DNA index ≥1.16 or modal chromosome
             number ≥51, or ETV6-RUNXI).

          -  Hepatitis B or HIV infection.

          -  Pregnant or breast-feeding

          -  Inability or unwillingness or research participant or legal guardian/representative to
             give written informed consent.

        INCLUSION CRITERIA FOR NK CELL DONORS:

          -  Donor is at least 18 years of age.

          -  Donor is a family member.
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:3-year overall survival rate of patients with relapsed ALL
Time Frame:At 3 years of follow-up since the on-study date of the last enrolled patient
Safety Issue:
Description:Estimate the 3-year survival rate of participants with first relapse or primary refractory precursor B-cell ALL treated with risk-directed therapy.

Secondary Outcome Measures

Measure:Proportion of participants with positive minimal residual disease
Time Frame:At 3 months after the on-study date of the last enrolled patient
Safety Issue:
Description:To determine minimal residual disease (MRD) levels at the end of remission induction therapy for participants with relapsed precursor B-cell ALL and compare the results with those in protocol ALLR17.
Measure:Mean of CD20 expression levels
Time Frame:approximately 5 weeks after the on-study date of the last enrolled patient
Safety Issue:
Description:To estimate mean levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of remission induction therapy for relapsed precursor B-cell ALL.
Measure:Median CD20 expression levels
Time Frame:approximately 5 weeks after the on-study date of the last enrolled patient
Safety Issue:
Description:To estimate median levels of CD20 expression at baseline, during treatment with dexamethasone-containing chemotherapy and following rituximab treatment in Block 1 of remission induction therapy for relapsed precursor B-cell ALL.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Completed
Lead Sponsor:St. Jude Children's Research Hospital

Trial Keywords

  • leukemia
  • lymphoma
  • Non-Hodgkins

Last Updated

August 24, 2021