Clinical Trials /

Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma

NCT03117751

Description:

The overarching objective of this study is to use novel precision medicine strategies based on inherited and acquired leukemia-specific genomic features and targeted treatment approaches to improve the cure rate and quality of life of children with acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (LLy). Primary Therapeutic Objectives: - To improve the event-free survival of provisional standard- or high-risk patients with genetically or immunologically targetable lesions or minimal residual disease (MRD) ≥ 5% at Day 15 or Day 22 or ≥1% at the end of Remission Induction, by the addition of molecular and immunotherapeutic approaches including tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T cell / blinatumomab for refractory B-AL or B-LLy, and the proteasome inhibitor bortezomib for those lacking targetable lesions. - To improve overall treatment outcome of T-ALL and T-LLy by optimizing pegaspargase and cyclophosphamide treatment and by the addition of new agents in patients with targetable genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the addition of bortezomib for those who have a poor early response to treatment but no targetable lesions, and by administering nelarabine to T-ALL and T-LLy patients with leukemia/lymphoma cells in cerebrospinal fluid at diagnosis or MRD ≥0.01% at the end of induction. - To determine in a randomized study design whether the incidence and/or severity of acute vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of vincristine in patients with the high-risk CEP72 TT genotype or by shortening the duration of vincristine therapy in patients with the CEP72 CC or CT genotype. Secondary Therapeutic Objectives: - To estimate the event-free survival and overall survival of children with ALL and LLy. - To determine the tolerability of combination therapy with ruxolitinib and Early Intensification therapy in patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22 MRD ≥5%, Day 42 MRD ≥1%, or LLy patients without complete response at the End of Induction and all patients with early T cell precursor leukemia. Biological Objectives: - To use data from clinical genomic sequencing of diagnosis, germline/remission and MRD samples to guide therapy, including incorporation of targeted agents and institution of genetic counseling and cancer surveillance. - To evaluate and implement DNA and RNA sequencing-based methods to monitor levels of MRD in bone marrow, blood, and cerebrospinal fluid. - To assess clonal diversity and evolution of pre-leukemic and leukemic populations using DNA variant detection and single-cell genomic analyses in a non-clinical, research setting. - To identify germline or somatic genomic variants associated with drug resistance of ALL cells o conventional and newer targeted anti-leukemic agents in a non- clinical, research setting. - To compare drug sensitivity of ALL cells from diagnosis to relapse in vitro and in vivo and determine if acquired resistance to specific agents is related to specific somatic genome variants that are not detected or found in only a minor clone at initial diagnosis. Supportive Care Objectives - To conduct serial neurocognitive monitoring of patients and to evaluate the benefits of a computer-based cognitive intervention. - To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover. Exploratory Objectives: - To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors of treatment outcome. - To perform a detailed assessment of thiopurine metabolism and 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome. - To establish xenografts of representative subtypes of ALL. - To prospectively determine the risk and epidemiology of breakthrough infection or febrile neutropenia and adverse effects of antibiotics. - To use cell phenotyping and genomic approaches to characterize the non-tumor microenvironment and correlate with responses to conventional and immunotherapeutic approaches.

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

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
  • Official Title: Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: TOT17
  • SECONDARY ID: NCI-2017-00582
  • NCT ID: NCT03117751

Conditions

  • Acute Lymphoblastic Leukemia
  • Acute Lymphoblastic Lymphoma

Interventions

DrugSynonymsArms
PrednisonePrednisolone, Deltasone, Meticorten, Orasone®, Liquid Pred, Pediapred®, Sterapred®B-ALL and B-LLy, High Risk
VincristineVincristine sulfate, Oncovin®, VCR, LCRALL, CEP72 C/T or C/C, Vincristine
DaunorubicinDaunomycin, rubidomycin, Cerubidine®B-ALL and B-LLy, High Risk
PegaspargasePEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-asparaginase, Oncaspar®B-ALL and B-LLy, High Risk
Erwinase®Erwinia chrysanthemi, Asparaginase Erwinia chrysanthemi, Erwinaze^TM, CrisantaspaseB-ALL and B-LLy, High Risk
CyclophosphamideCytoxan®B-ALL and B-LLy, High Risk
CytarabineCytosine arabinoside, Ara-C, Cytosar®B-ALL and B-LLy, High Risk
Mercaptopurine6-MP, Purinethol®, Purixan^TM, 6-mercaptopurineALL, CEP72 C/T or C/C, Vincristine
DasatinibSprycel®B-ALL and B-LLy, High Risk
MethotrexateMTX, amethopterin, Trexall®ALL, CEP72 C/T or C/C, Vincristine
BlinatumomabBlincyto®B-ALL and B-LLy, High Risk
RuxolitinibJakafi®B-ALL and B-LLy, High Risk
BortezomibVelcade®B-ALL and B-LLy, High Risk
DexamethasoneDecadron®, Hexadrol®, Dexone®, Dexameth®ALL, CEP72 C/T or C/C, Vincristine
DoxorubicinAdriamycin®B-ALL and B-LLy, Standard Risk
EtoposideEtoposide Phosphate, VePesid®, Etopophos®, VP-16B-ALL and B-LLy, High Risk
ClofarabineClolar®B-ALL and B-LLy, High Risk
VorinostatZolinza®, Suberoylanilide Hydroxamic Acid, SAHAT-ALL and T-LLy, High Risk
IdarubicinIdarubicin HCl, 4-Demethoxydaunorubicin, 4-DMD, DMDR, Idamycin PFS®T-ALL and T-LLy, High Risk
NelarabineArranon®, Atriance®, Compound 506U78T-ALL and T-LLy, High Risk
Thioguanine6-thioguanine, Tioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, WR-1141, Tabloid®, Lanvis®B-ALL and B-LLy, High Risk

Purpose

The overarching objective of this study is to use novel precision medicine strategies based on inherited and acquired leukemia-specific genomic features and targeted treatment approaches to improve the cure rate and quality of life of children with acute lymphoblastic leukemia (ALL) and acute lymphoblastic lymphoma (LLy). Primary Therapeutic Objectives: - To improve the event-free survival of provisional standard- or high-risk patients with genetically or immunologically targetable lesions or minimal residual disease (MRD) ≥ 5% at Day 15 or Day 22 or ≥1% at the end of Remission Induction, by the addition of molecular and immunotherapeutic approaches including tyrosine kinase inhibitors or chimeric antigen receptor (CAR) T cell / blinatumomab for refractory B-AL or B-LLy, and the proteasome inhibitor bortezomib for those lacking targetable lesions. - To improve overall treatment outcome of T-ALL and T-LLy by optimizing pegaspargase and cyclophosphamide treatment and by the addition of new agents in patients with targetable genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the addition of bortezomib for those who have a poor early response to treatment but no targetable lesions, and by administering nelarabine to T-ALL and T-LLy patients with leukemia/lymphoma cells in cerebrospinal fluid at diagnosis or MRD ≥0.01% at the end of induction. - To determine in a randomized study design whether the incidence and/or severity of acute vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of vincristine in patients with the high-risk CEP72 TT genotype or by shortening the duration of vincristine therapy in patients with the CEP72 CC or CT genotype. Secondary Therapeutic Objectives: - To estimate the event-free survival and overall survival of children with ALL and LLy. - To determine the tolerability of combination therapy with ruxolitinib and Early Intensification therapy in patients with activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22 MRD ≥5%, Day 42 MRD ≥1%, or LLy patients without complete response at the End of Induction and all patients with early T cell precursor leukemia. Biological Objectives: - To use data from clinical genomic sequencing of diagnosis, germline/remission and MRD samples to guide therapy, including incorporation of targeted agents and institution of genetic counseling and cancer surveillance. - To evaluate and implement DNA and RNA sequencing-based methods to monitor levels of MRD in bone marrow, blood, and cerebrospinal fluid. - To assess clonal diversity and evolution of pre-leukemic and leukemic populations using DNA variant detection and single-cell genomic analyses in a non-clinical, research setting. - To identify germline or somatic genomic variants associated with drug resistance of ALL cells o conventional and newer targeted anti-leukemic agents in a non- clinical, research setting. - To compare drug sensitivity of ALL cells from diagnosis to relapse in vitro and in vivo and determine if acquired resistance to specific agents is related to specific somatic genome variants that are not detected or found in only a minor clone at initial diagnosis. Supportive Care Objectives - To conduct serial neurocognitive monitoring of patients and to evaluate the benefits of a computer-based cognitive intervention. - To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover. Exploratory Objectives: - To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors of treatment outcome. - To perform a detailed assessment of thiopurine metabolism and 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome. - To establish xenografts of representative subtypes of ALL. - To prospectively determine the risk and epidemiology of breakthrough infection or febrile neutropenia and adverse effects of antibiotics. - To use cell phenotyping and genomic approaches to characterize the non-tumor microenvironment and correlate with responses to conventional and immunotherapeutic approaches.

Detailed Description

      Participants will be classified into one of three categories (low-, standard-, or high-risk)
      based on the presenting age, leukocyte count/lymphoma staging, presence or absence of CNS-3
      status or testicular disease, immunophenotype, molecular genetics, DNA index, and early
      response to therapy.

      Treatment will consist of three main phases: Remission Induction, Consolidation, and
      Continuation. Early Intensification therapy will be given prior to Consolidation to patients
      with provisional standard-risk or high-risk ALL/LLy or any provisional low-risk patients with
      Day 15 MRD ≥1% as well as provisional low-risk LLy patients who do not obtain complete
      response at the end of Induction.

      Brief outline of treatment plan:

      Patients will be assigned to treatment based on risk group: Low-Risk, Standard-Risk and
      High-Risk and cell type (T or B cell).

      Remission Induction initially consists of prednisone (28 days), vincristine (4 weekly doses),
      daunorubicin (1 to 3 weekly doses), and pegaspargase (2 doses). The second part (given over 2
      weeks and overlapping with the last week of the first part of induction) consists of
      cyclophosphamide, cytarabine, and mercaptopurine combinations. Dasatinib will be added for
      patients with Ph+ and Ph-like ABL1-class fusions and bortezomib will be given to patients
      with no targetable lesions and Day 15 or Day 22 minimal residual disease (MRD) ≥ 5% on Days
      29 and 32.

      Early Intensification will be given prior to Consolidation to patients with provisional
      standard-risk or high-risk ALL/LLy or any provisional low-risk patients with Day 15 MRD ≥1%
      as well as provisional low-risk LLy patients who do not obtain complete response at the end
      of Induction. For patients with Ph-like ALL that is targetable with JAK inhibitor and Day 15
      or Day 22 MRD level ≥5% or end of Remission Induction ≥1% as well as all patients with early
      T cell precursor (ETP) ALL, ruxolitinib will be used. This includes, but is not limited to
      CRLF2, JAK2, and EPOR rearrangements and sequence/structural changes in JAK1/2, TYK2, IL7R,
      and SH2B3. Ruxolitinib will be added in LLy patients with activation of JAK-STAT signaling
      that can be inhibited by ruxolitinib whose responses do not qualify complete response at the
      end of Remission Induction. Dasatinib will continue for patients with ABL-class fusions.
      Bortezomib will be added for patients with no targetable lesions and Day 15 or Day 22 MRD ≥
      5% or LLy patients without complete response at the End of Induction.

      Consolidation Therapy will consist of high dose methotrexate (HDMTX) (every other week for 4
      doses); daily mercaptopurine and IT chemotherapy on the same dates of HDMTX. Dasatinib will
      continue for patients with ABL-class fusions. Ruxolitinib will continue for patients with
      activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22
      MRD ≥5% or Day 42 MRD ≥1% (or for LLy patients who do not qualify complete response at the
      end of Remission Induction) and all cases with ETP ALL.

      Immunotherapy: CAR T-cell therapy will be considered for High-risk B-ALL and B-LLy patients.
      Blinatumomab will be given to patients with Standard risk B-ALL and B-LLy with residual
      disease at the end of induction and High Risk B-ALL and B-LLy patients who are not able to
      receive CAR T-cell therapy.

      Reintensification therapy will be offered to certain High Risk patients with persistent MRD
      after Immunotherapy (B-ALL and B-LLy) or Early Intensification (T-ALL and T-LLy), or those
      who cannot receive Immunotherapy.

      Continuation Treatment will consist of 120 weeks of risk-directed therapy. Dasatinib will
      continue in patients with ABL1-class fusion. Ruxolitinib will continue in patients with
      activation of JAK-STAT signaling that can be inhibited by ruxolitinib and Day 15 or Day 22
      MRD ≥5% or Day 42 MRD ≥1% (or for LLy patients who do not qualify complete response at the
      end of Remission Induction) and all cases with ETP ALL. T-ALL and T-LLy patients with
      leukemia/lymphoma cells in cerebrospinal fluid at diagnosis or MRD ≥0.01% at the end of
      Induction will receive nelarabine. ALL/LLy Patients with the CEP72 rs904627T/T genotype (16%
      of patients) will be randomized (unblinded design except those who evaluate neuropathies) to
      receive either 1.5 mg/m2 or 1 mg/m2 of vincristine after Continuation Week 1. Patients with
      either a CEP72 rs904627 C/T or C/C genotype (84% of patients) will be randomized to receive
      vincristine and dexamethasone pulses through Week 49 of Continuation Treatment or through
      Week 101 of Continuation Treatment.
    

Trial Arms

NameTypeDescriptionInterventions
B-ALL and B-LLy, Low RiskExperimentalPatients with low-risk B ALL and LLy will have Induction (6 weeks), Consolidation (8 weeks), and Continuation (120 weeks). During Remission Induction therapy, prednisone dose is 40mg/m^2 and 1-2 doses of daunorubicin (based on day 8 peripheral blood MRD in patients with ETV6-RUNX1 or hyperdiploid) are given. Dasatinib is given for patients with ABL1-class fusion. Interventions: Prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, thioguanine, methotrexate, dexamethasone.
  • Prednisone
  • Vincristine
  • Daunorubicin
  • Pegaspargase
  • Erwinase®
  • Cyclophosphamide
  • Cytarabine
  • Mercaptopurine
  • Dasatinib
  • Methotrexate
  • Dexamethasone
  • Thioguanine
B-ALL and B-LLy, Standard RiskExperimentalInduction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Continuation (120 wks). During Remission Induction therapy, prednisone dose is 40mg/m^2 and 2 doses daunorubicin are given. Dasatinib is given for patients with Ph+ and those with ABL1-class fusion. Ruxolitinib is given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD ≥5% and LLy patients who don't qualify for complete response at end of Remission Induction. Bortezomib is given to patients without targetable lesions and Day 15 or Day 22 MRD >5%. Blinatumomab will be given to patients with residual disease at the end of induction (≥0.01% and <1%). Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, thioguanine, methotrexate, dexamethasone, doxorubicin.
  • Prednisone
  • Vincristine
  • Daunorubicin
  • Pegaspargase
  • Erwinase®
  • Cyclophosphamide
  • Cytarabine
  • Mercaptopurine
  • Dasatinib
  • Methotrexate
  • Blinatumomab
  • Ruxolitinib
  • Bortezomib
  • Dexamethasone
  • Doxorubicin
  • Thioguanine
B-ALL and B-LLy, High RiskExperimentalInduction (6 weeks), Early Intensification (4 weeks), Consolidation (8 weeks), and Immunotherapy (chimeric antigen receptor [CAR] T cells). Patients who do not respond to Immunotherapy will receive Reintensification therapy. During Remission Induction therapy, prednisone dose is 40mg/m^2 and 2 doses of daunorubicin are given. Dasatinib, ruxolitinib, and bortezomib are given as done for patients with standard risk B-ALL but are discontinued in Immunotherapy and Reintensification therapy. Blinatumomab will be given to patients who are not able to receive CAR T cell therapy. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, etoposide, dexamethasone, clofarabine, thioguanine, methotrexate.
  • Prednisone
  • Vincristine
  • Daunorubicin
  • Pegaspargase
  • Erwinase®
  • Cyclophosphamide
  • Cytarabine
  • Mercaptopurine
  • Dasatinib
  • Methotrexate
  • Blinatumomab
  • Ruxolitinib
  • Bortezomib
  • Dexamethasone
  • Etoposide
  • Clofarabine
  • Thioguanine
T-ALL and T-LLy, Standard RiskExperimentalInduction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Continuation (120 wks). During Remission Induction therapy, prednisone dose is 60mg/m^2 and 3 doses daunorubicin are given. Dasatinib is given for patients with Ph+ and those with ABL1-class fusion. Ruxolitinib is given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD ≥5% and all patients with ETP and LLy patients who don't qualify for complete response at end of Remission Induction. Bortezomib is given to patients without targetable lesions and Day 15 or Day 22 MRD ≥ 5%. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, dexamethasone, doxorubicin, nelarabine, thioguanine.
  • Prednisone
  • Vincristine
  • Daunorubicin
  • Pegaspargase
  • Erwinase®
  • Cyclophosphamide
  • Cytarabine
  • Mercaptopurine
  • Dasatinib
  • Methotrexate
  • Ruxolitinib
  • Bortezomib
  • Dexamethasone
  • Doxorubicin
  • Nelarabine
  • Thioguanine
T-ALL and T-LLy, High RiskExperimentalInduction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Reintensification. During Remission Induction therapy, prednisone dose is 60mg/m^2 and 3 doses daunorubicin are given. Dasatinib, ruxolitinib, and bortezomib given as done for patients with standard risk T-ALL but are discontinued in Reintensification therapy. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, etoposide, dexamethasone, clofarabine, vorinostat, idarubicin, nelarabine, thioguanine..
  • Prednisone
  • Vincristine
  • Daunorubicin
  • Pegaspargase
  • Erwinase®
  • Cyclophosphamide
  • Cytarabine
  • Mercaptopurine
  • Dasatinib
  • Methotrexate
  • Ruxolitinib
  • Bortezomib
  • Dexamethasone
  • Etoposide
  • Clofarabine
  • Vorinostat
  • Idarubicin
  • Nelarabine
  • Thioguanine
ALL, CEP72 T/T, VincristineExperimentalPatients with the CEP72 rs904627T/T genotype (~16% of patients) will be randomized (unblinded design, only those who evaluate neuropathy are blinded) to receive either 1.5 mg/m^2 or 1 mg/m^2 of vincristine beginning with Continuation Week 1. Intervention: vincristine.
  • Vincristine
ALL, CEP72 C/T or C/C, VincristineExperimentalPatients with either a CEP72 rs904627 C/T or C/C genotype (~84% of patients) will be randomized (unblinded design, only those who evaluate neuropathy are blinded) to receive vincristine (2 mg/m^2 per dose except during Reinduction I and Reinduction II when 3 weekly doses of 1.5 mg/m^2 will be given) and dexamethasone pulses through Week 49 of Continuation Treatment or through Week 101 of Continuation Treatment. Interventions: vincristine, dexamethasone, methotrexate, mercaptopurine.
  • Vincristine
  • Mercaptopurine
  • Methotrexate
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          -  Diagnosis of B- or T-ALL or LLy by immunophenotyping:

          -  LLy participants must have < 25% tumor cells in bone marrow and peripheral blood by
             morphology and flow cytometry. If any of these show >25% blasts, patient will be
             considered to have leukemia.

          -  Age 1-18 years (inclusive).

          -  No prior therapy, or limited prior therapy, including systemic glucocorticoids for one
             week or less, one dose of vincristine, emergency radiation therapy (e.g., to the
             mediastinum, head and neck, orbit, etc.) and one dose of intrathecal chemotherapy.

          -  Written, informed consent and assent following Institutional Review Board (IRB),
             National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office of
             Human Research Protections (OHRP) Guidelines.

        Exclusion Criteria:

          -  Participants who are pregnant or lactating. Males or females of reproductive potential
             must agree to use effective contraception for the duration of study participation.

          -  Inability or unwillingness of research participant or legal guardian/representative to
             give written informed consent.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Event-free survival of ALL patients (EFS)
Time Frame:At 3.5 years after enrollment of the last participant
Safety Issue:
Description:5-year EFS: Kaplan-Meier estimates of EFS curve of ALL patients will be computed and compared historically with those of the St. Jude Children's Research Hospital's (SJCRH) TOTXVI study (NCT00549848). All eligible patients entered on the current TOT17 study will be included in these comparisons. Comparisons by log-rank tests will be made both un-stratified and stratified by risk groups.

Secondary Outcome Measures

Measure:5-year overall survival (OS) of ALL patients compared to historical controls
Time Frame:3.5 years after enrollment of the last patient
Safety Issue:
Description:Kaplan-Meier estimates of OS curve of ALL patients will be computed and compared historically with those of the St. Jude Children's Research Hospital's (SJCRH) TOTXVI study (NCT00549848). All eligible patients entered on the current TOT17 study will be included in these comparisons. Comparisons by log-rank tests will be made both un-stratified and stratified by risk groups.
Measure:EFS of LLy patients
Time Frame:3.5 years after enrollment of the last patient
Safety Issue:
Description:5-year EFS: Kaplan-Meier estimates of EFS curve in patients with LLy will be computed.
Measure:5-year OS of LLy patients
Time Frame:3.5 years after enrollment of the last patient
Safety Issue:
Description:Kaplan-Meier estimates of OS curve in patients with LLy will be computed.
Measure:Comparison of MRD measurements between flow cytometry and sequencing
Time Frame:From Day 8 through Day 42 after remission induction (At 6 months after enrollment of the 40^t^h evaluable patient)
Safety Issue:
Description:For this comparison, 40 patients will be accrued for Day 8, Day 15 and Day 42 MRD, and primarily assess the correlation and concordance between the two methods at these time points if sufficient cells are available, and secondarily analyze for Day 22 and MRD levels obtained after remission induction.
Measure:Log hazard ratio of the association of low level of MRD and treatment outcome
Time Frame:3.5 years after enrollment of the last patient
Safety Issue:
Description:The investigators will analyze the association of next-generation sequencing-determined MRD level (as a continuous variable) with the risk of relapses in bone marrow and possibly other sites (bone marrow or combined relapses). Fine-Gray regression model will be applied to estimate the hazard ratio of relapse as a function of the increase in MRD level.
Measure:Comparison of bone marrow and peripheral blood MRD
Time Frame:From Day 15 through Day 42 of remission induction and end of therapy (At 6 months after enrollment of the last evaluable patient)
Safety Issue:
Description:Parametric (linear) or non-parametric (if necessary) regression models will be fitted to analyze the relationship between the MRD levels in peripheral blood by sequencing methods and MRD levels in bone marrow (by sequencing or flow cytometry). The peripheral blood MRD level corresponding to 0.01% in bone marrow is then obtained by solving the (regression) equation for the peripheral blood MRD level.
Measure:Isolated CNS relapse in CNS1b patients
Time Frame:3.5 years after enrollment of the last patient
Safety Issue:
Description:Traditional CNS2 patients with negative TdT and negative next-generation sequencing results will receive CNS1 therapy on TOT17. Risk of isolated CNS relapse in this subset of patients will be compared to that in the CNS2 patients treated on TOTXV and TOTXVI, using stratified (by protocol) Gray's test.
Measure:Level of clonal diversity and rise of leukemic clones during treatment
Time Frame:From Day 1 through week 120 of continuation (at 6 months after the last enrolled patient completes Week 120)
Safety Issue:
Description:In this study the investigators will use single-cell, cell-free, and bulk population sequencing to monitor somatic mutations in peripheral blood as patients undergo treatment, which will be correlated with clonal diversity at diagnosis, in vitro chemotherapy resistance, MRD, and patient outcome.
Measure:Number and type of germline or somatic genomic variants associated with drug resistance
Time Frame:3.5 years after enrollment of the last participant
Safety Issue:
Description:The number and type of germline or somatic genomic variants associated with drug resistance of ALL cells to conventional and newer targeted anti-leukemic agents in a non-clinical, research setting will be given.
Measure:Comparison of drug sensitivity of ALL cells between diagnosis and relapse in vitro and in vivo
Time Frame:5 years after enrollment of the last participant
Safety Issue:
Description:To compare drug sensitivity of ALL cells from diagnosis to relapse in vitro and in vivo and determine if acquired resistance to specific agents is related to specific somatic genome variants that are not detected or found in only a minor clone at initial diagnosis
Measure:Magnitude change in spatial span backward standard score (SSB)
Time Frame:From continuation week 73 to 3-4 months after end of therapy (continuation week 120)
Safety Issue:
Description:A single-blind (psychological examiner), randomized, controlled, group sequential design will be used to evaluate the impact of computer-based cognitive intervention (Cogmed) administered during therapy, relative to the end of therapy, on neurocognitive outcomes. Patients will be randomized according to the procedure outlined in the protocol. Randomization will be stratified based on age (4-8; >9 years old) and treatment risk arm (low; standard/high) in order to roughly balance the groups on these factors. Patients will be randomized according to a 2:2:1 allocation (2 - On Therapy, 2 - End of Therapy, 1 - Control). The investigators will use a block-randomization scheme proposed by Zelen with a block size of 4. The change from pre to post intervention will be given.
Measure:Change in bone mineral density (BMD) in the tibia
Time Frame:From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
Safety Issue:
Description:The primary outcome is BMD in the tibia, measured at baseline and the end of intervention. The changes from baseline to the end of the intervention between the treatment and control groups will be compared using a two-sample t-test, or Wilcoxon rank sum test if normality does not hold. Furthermore, the linear mixed model will be used to analyze the time effect, group effect and their interaction, adjusting for the factors used for stratification (gender, pubertal status, and risk group) and possible confounders (i.e., hormonal function and vitamin D metabolism, physical activity, etc.).
Measure:Change in markers of bone turnover
Time Frame:From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
Safety Issue:
Description:Linear mixed models will be used to evaluate this outcome. If normality does not hold, the investigators will consider transforming the outcome measures for analysis. A linear mixed effects approach will also be used to allow for potential random missingness to make use of all available data in analysis

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:St. Jude Children's Research Hospital

Trial Keywords

  • Leukemia
  • Lymphoma
  • Pediatric
  • B-Cell
  • T-Cell

Last Updated

February 10, 2020