Total Therapy Study XVI for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Condition: Acute Lymphoblastic Leukemia
MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
Intervention: Prednisone, Vincristine, Daunorubicin, PEG-L-asparaginase, Erwinia L-asparaginase, Doxorubicin, Cyclophosphamide, Cytarabine, Thioguanine; Clofarabine, Methotrexate, Mercaptopurine, Dexamethasone, Etoposide, Dasatinib
Intervention description: See Detailed Description section for details of treatment interventions.; See Detailed Description section for details of treatment interventions.
Intervention MeSH terms: Cytarabine; Dexamethasone; Dexamethasone acetate; Prednisone; Prednisolone; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Methotrexate; Etoposide; Etoposide phosphate; Vincristine; Daunorubicin; Asparaginase; Dasatinib; Mercaptopurine; Clofarabine; Pegaspargase; Thioguanine; BB 1101
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 600.0
Sex: All
Maximum age: 18 Years
Healthy volunteers: No
Keywords: Leukemia

Summary:

      The primary objective of this study (TOTXVI) is to compare the clinical benefit, the
      pharmacokinetics, and the pharmacodynamics of polyethylene glycol-conjugated (PEG)
      asparaginase given in higher dose (HD PEG) versus those of PEG-asparaginase given in
      conventional dose (CD PEG) during the continuation phase.

      This study has several secondary objectives:

      Therapeutic Objectives:

      To estimate the event-free survival and overall survival of children with ALL who are treated
      with risk-directed therapy.

      To study whether intensifying induction, including fractionated cyclophosphamide and
      thioguanine, in patients with day 15 MRD > 5%, will result in improved leukemia cytoreduction
      in this subgroup compared to TOTXV.

      To assess whether intensification of central nervous system (CNS)-directed intrathecal and
      systemic chemotherapy will improve outcome in patients at high risk of CNS relapse.

      Exploratory Pharmacologic Objectives:

      To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors for
      treatment-related outcomes in the context of the systemic therapy used in the protocol.

      To compare the pharmacokinetics and pharmacodynamics of PEG-asparaginase given in higher dose
      (3,500 or 3,000 units/m2) versus those of PEG-asparaginase given in conventional dose (2,500
      units/m2) in the continuation phase.

      Exploratory Biologic Objectives:

      To determine the prognostic value of levels of minimal residual disease in peripheral blood
      at day 8 of remission induction.

      To validate new markers and methods for MRD detection. To genotype natural killer (NK) cell
      receptors and measure their expressions at diagnosis and before reinduction, and to associate
      these features with treatment outcome.

      To identify new prognostic factors by applying new technologies to study patient material
      (e.g., stored plasma, serum, cerebrospinal fluid, and normal and leukemic cells).

      Exploratory Neuroimaging Objectives:

      To use quantitative MR measures (Diffusion Tensor Imaging and high resolution volumetric
      imaging) to assess differences in myelin and cortical thickness development in patients
      treated for ALL relative to healthy controls matched for age and gender.

      To assess the impact of folate pathway genetic polymorphisms on myelin and cortical thickness
      development and neurocognitive performance.

      To assess the impact of frontal-parietal lobe myelin and cortical thickness development on
      neurocognitive performance in attention, working memory, fluency, visual-spatial reasoning
      and processing speed.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participant has a confirmed diagnosis of precursor B-cell or precursor T-cell acute
             lymphocytic leukemia (ALL) by immunophenotyping

          -  Participant is less than or equal to 18 years of age

          -  Limited prior therapy, including systemic glucocorticoids for one week or less, one
             dose of vincristine, emergency radiation therapy to the mediastinum and one dose of
             intrathecal chemotherapy. Other circumstances must be cleared by principal
             investigator (PI) or co-PI.

          -  Written, informed consent and assent following Institutional Review Board, NCI, FDA,
             and Office for Human Research Protections (OHRP) Guidelines.

        Exclusion Criteria:

          -  Participants with prior therapy, other than that listed above

          -  Pregnant or lactating

          -  Inability or unwillingness of research participant or legal guardian/representative to
             give written informed consent.