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

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ClinicalTrials.gov Identifier: NCT03117751
Recruitment Status : Recruiting
First Posted : April 18, 2017
Last Update Posted : July 11, 2018
Sponsor:
Collaborators:
Bristol-Myers Squibb
Incyte Corporation
Shire
Information provided by (Responsible Party):
St. Jude Children's Research Hospital

Brief Summary:

The overarching objective of this study is to use novel precision medicine strategies based on inherited and 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 ≥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-ALL, and the proteasome inhibitor bortezomib for those lacking targetable lesions.
  • To improve overall treatment outcome of T-ALL 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 patients with leukemia cells in cerebrospinal fluid at diagnosis or MRD ≥0.01% at the end of induction.
  • To examine in a randomized study design whether the administration of two doses of rituximab to children with B-ALL during early Remission Induction therapy decreases allergic reactions to pegaspargase.
  • 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 examine whether the administration of two doses of rituximab can lower the minimal residual disease (MRD) levels.
  • To determine the tolerability of combination therapy with ruxolitinib.

Biological Objectives:

  • To use data from clinical genomic sequencing and sequencing-based MRD in bone marrow, blood and cerebrospinal fluid.
  • To assess clonal diversity and evolution of pre-leukemic and leukemic populations.
  • To identify germline or somatic genomic variants associated with drug resistance of ALL cells.
  • To compare drug sensitivity of ALL cells from diagnosis to relapse.

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.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Acute Lymphoblastic Lymphoma Drug: Prednisone Drug: Vincristine Drug: Daunorubicin Drug: Pegaspargase Drug: Erwinase® Drug: Rituximab Drug: Cyclophosphamide Drug: Cytarabine Drug: Mercaptopurine Drug: Dasatinib Drug: Methotrexate Drug: Blinatumomab Drug: Ruxolitinib Drug: Bortezomib Drug: Dexamethasone Drug: Doxorubicin Drug: Etoposide Drug: Clofarabine Drug: Vorinostat Drug: Idarubicin Drug: Nelarabine Phase 2 Phase 3

  Show Detailed Description

Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Masking Description: Only certain outcome measures as indicated will be blinded to the outcomes assessor.
Primary Purpose: Treatment
Official Title: Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Actual Study Start Date : March 29, 2017
Estimated Primary Completion Date : September 30, 2026
Estimated Study Completion Date : March 31, 2028


Arm Intervention/treatment
Experimental: B-ALL and B-LLy, Low Risk

Patients 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, rituximab, dasatinib, methotrexate, dexamethasone.

Drug: Prednisone
Given orally (PO).
Other Names:
  • Prednisolone
  • Deltasone
  • Meticorten
  • Orasone®
  • Liquid Pred
  • Pediapred®
  • Sterapred®

Drug: Vincristine
Given intravenously (IV).
Other Names:
  • Vincristine sulfate
  • Oncovin®
  • VCR
  • LCR

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • rubidomycin
  • Cerubidine®

Drug: Pegaspargase
Given IV or intramuscularly (IM) .
Other Names:
  • PEG-asparaginase
  • PEGLA
  • PEG-L-asparaginase
  • polyethylene glycol-L-asparaginase
  • Oncaspar®

Drug: Erwinase®
To be used in case of hypersensitivity or intolerance to Pegaspargase. Given IV or intramuscularly (IM).
Other Names:
  • Erwinia chrysanthemi
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze^TM
  • Crisantaspase

Drug: Rituximab
Given IV.
Other Names:
  • Rituxan®
  • Biogen-IDEC-C2B8

Drug: Cyclophosphamide
Given IV.
Other Name: Cytoxan®

Drug: Cytarabine
Given IV.
Other Names:
  • Cytosine arabinoside
  • Ara-C
  • Cytosar®

Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
  • Purinethol®
  • Purixan^TM
  • 6-mercaptopurine

Drug: Dasatinib
Given PO.
Other Name: Sprycel®

Drug: Methotrexate
Given IV.
Other Names:
  • MTX
  • amethopterin
  • Trexall®

Drug: Dexamethasone
Given PO.
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®

Experimental: B-ALL and B-LLy, Standard Risk

Induction (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 MRD ≥5% or Day 42 MRD ≥1% and LLy patients who don't qualify for complete response at end of Remission Induction. Bortezomib is given to patients without targetable lesions; ALL patients with Day 15 MRD ≥5% and/or end of Remission Induction MRD ≥1% and LLy patients who don't qualify for complete response at end of Remission Induction.

Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®), cyclophosphamide, cytarabine, mercaptopurine, rituximab, dasatinib, bortezomib, ruxolitinib, methotrexate, dexamethasone, doxorubicin.

Drug: Prednisone
Given orally (PO).
Other Names:
  • Prednisolone
  • Deltasone
  • Meticorten
  • Orasone®
  • Liquid Pred
  • Pediapred®
  • Sterapred®

Drug: Vincristine
Given intravenously (IV).
Other Names:
  • Vincristine sulfate
  • Oncovin®
  • VCR
  • LCR

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • rubidomycin
  • Cerubidine®

Drug: Pegaspargase
Given IV or intramuscularly (IM) .
Other Names:
  • PEG-asparaginase
  • PEGLA
  • PEG-L-asparaginase
  • polyethylene glycol-L-asparaginase
  • Oncaspar®

Drug: Erwinase®
To be used in case of hypersensitivity or intolerance to Pegaspargase. Given IV or intramuscularly (IM).
Other Names:
  • Erwinia chrysanthemi
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze^TM
  • Crisantaspase

Drug: Rituximab
Given IV.
Other Names:
  • Rituxan®
  • Biogen-IDEC-C2B8

Drug: Cyclophosphamide
Given IV.
Other Name: Cytoxan®

Drug: Cytarabine
Given IV.
Other Names:
  • Cytosine arabinoside
  • Ara-C
  • Cytosar®

Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
  • Purinethol®
  • Purixan^TM
  • 6-mercaptopurine

Drug: Dasatinib
Given PO.
Other Name: Sprycel®

Drug: Methotrexate
Given IV.
Other Names:
  • MTX
  • amethopterin
  • Trexall®

Drug: Ruxolitinib
Given PO.
Other Name: Jakafi®

Drug: Bortezomib
Given IV or subcutaneously (SQ).
Other Name: Velcade®

Drug: Dexamethasone
Given PO.
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®

Drug: Doxorubicin
Given IV.
Other Name: Adriamycin®

Experimental: B-ALL and B-LLy, High Risk

Induction (6 weeks), Early Intensification (4 weeks), Consolidation (8 weeks), and Immunotherapy. 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.

Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®), cyclophosphamide, cytarabine, mercaptopurine, rituximab, dasatinib, bortezomib, ruxolitinib, blinatumomab, etoposide, cytarabine, dexamethasone, clofarabine.

Drug: Prednisone
Given orally (PO).
Other Names:
  • Prednisolone
  • Deltasone
  • Meticorten
  • Orasone®
  • Liquid Pred
  • Pediapred®
  • Sterapred®

Drug: Vincristine
Given intravenously (IV).
Other Names:
  • Vincristine sulfate
  • Oncovin®
  • VCR
  • LCR

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • rubidomycin
  • Cerubidine®

Drug: Pegaspargase
Given IV or intramuscularly (IM) .
Other Names:
  • PEG-asparaginase
  • PEGLA
  • PEG-L-asparaginase
  • polyethylene glycol-L-asparaginase
  • Oncaspar®

Drug: Erwinase®
To be used in case of hypersensitivity or intolerance to Pegaspargase. Given IV or intramuscularly (IM).
Other Names:
  • Erwinia chrysanthemi
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze^TM
  • Crisantaspase

Drug: Rituximab
Given IV.
Other Names:
  • Rituxan®
  • Biogen-IDEC-C2B8

Drug: Cyclophosphamide
Given IV.
Other Name: Cytoxan®

Drug: Cytarabine
Given IV.
Other Names:
  • Cytosine arabinoside
  • Ara-C
  • Cytosar®

Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
  • Purinethol®
  • Purixan^TM
  • 6-mercaptopurine

Drug: Dasatinib
Given PO.
Other Name: Sprycel®

Drug: Methotrexate
Given IV.
Other Names:
  • MTX
  • amethopterin
  • Trexall®

Drug: Blinatumomab
Given IV.
Other Name: Blincyto®

Drug: Ruxolitinib
Given PO.
Other Name: Jakafi®

Drug: Bortezomib
Given IV or subcutaneously (SQ).
Other Name: Velcade®

Drug: Dexamethasone
Given PO.
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®

Drug: Etoposide
Given IV.
Other Names:
  • Etoposide Phosphate
  • VePesid®
  • Etopophos®
  • VP-16

Drug: Clofarabine
Given IV.
Other Name: Clolar®

Experimental: T-ALL and T-LLy, Standard Risk

Induction (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 MRD ≥5% or Day 42 MRD ≥1% 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; ALL patients with Day 15 MRD ≥5% and/or end of Remission Induction MRD ≥1% and LLy patients who don't qualify for complete response at end of Remission Induction.

Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, dexamethasone, doxorubicin, nelarabine.

Drug: Prednisone
Given orally (PO).
Other Names:
  • Prednisolone
  • Deltasone
  • Meticorten
  • Orasone®
  • Liquid Pred
  • Pediapred®
  • Sterapred®

Drug: Vincristine
Given intravenously (IV).
Other Names:
  • Vincristine sulfate
  • Oncovin®
  • VCR
  • LCR

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • rubidomycin
  • Cerubidine®

Drug: Pegaspargase
Given IV or intramuscularly (IM) .
Other Names:
  • PEG-asparaginase
  • PEGLA
  • PEG-L-asparaginase
  • polyethylene glycol-L-asparaginase
  • Oncaspar®

Drug: Erwinase®
To be used in case of hypersensitivity or intolerance to Pegaspargase. Given IV or intramuscularly (IM).
Other Names:
  • Erwinia chrysanthemi
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze^TM
  • Crisantaspase

Drug: Cyclophosphamide
Given IV.
Other Name: Cytoxan®

Drug: Cytarabine
Given IV.
Other Names:
  • Cytosine arabinoside
  • Ara-C
  • Cytosar®

Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
  • Purinethol®
  • Purixan^TM
  • 6-mercaptopurine

Drug: Dasatinib
Given PO.
Other Name: Sprycel®

Drug: Methotrexate
Given IV.
Other Names:
  • MTX
  • amethopterin
  • Trexall®

Drug: Ruxolitinib
Given PO.
Other Name: Jakafi®

Drug: Bortezomib
Given IV or subcutaneously (SQ).
Other Name: Velcade®

Drug: Dexamethasone
Given PO.
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®

Drug: Doxorubicin
Given IV.
Other Name: Adriamycin®

Drug: Nelarabine
Given IV.
Other Names:
  • Arranon®
  • Atriance®
  • Compound 506U78

Experimental: T-ALL and T-LLy, High Risk

Induction (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.

Drug: Prednisone
Given orally (PO).
Other Names:
  • Prednisolone
  • Deltasone
  • Meticorten
  • Orasone®
  • Liquid Pred
  • Pediapred®
  • Sterapred®

Drug: Vincristine
Given intravenously (IV).
Other Names:
  • Vincristine sulfate
  • Oncovin®
  • VCR
  • LCR

Drug: Daunorubicin
Given IV.
Other Names:
  • Daunomycin
  • rubidomycin
  • Cerubidine®

Drug: Pegaspargase
Given IV or intramuscularly (IM) .
Other Names:
  • PEG-asparaginase
  • PEGLA
  • PEG-L-asparaginase
  • polyethylene glycol-L-asparaginase
  • Oncaspar®

Drug: Erwinase®
To be used in case of hypersensitivity or intolerance to Pegaspargase. Given IV or intramuscularly (IM).
Other Names:
  • Erwinia chrysanthemi
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze^TM
  • Crisantaspase

Drug: Cyclophosphamide
Given IV.
Other Name: Cytoxan®

Drug: Cytarabine
Given IV.
Other Names:
  • Cytosine arabinoside
  • Ara-C
  • Cytosar®

Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
  • Purinethol®
  • Purixan^TM
  • 6-mercaptopurine

Drug: Dasatinib
Given PO.
Other Name: Sprycel®

Drug: Methotrexate
Given IV.
Other Names:
  • MTX
  • amethopterin
  • Trexall®

Drug: Ruxolitinib
Given PO.
Other Name: Jakafi®

Drug: Bortezomib
Given IV or subcutaneously (SQ).
Other Name: Velcade®

Drug: Dexamethasone
Given PO.
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®

Drug: Etoposide
Given IV.
Other Names:
  • Etoposide Phosphate
  • VePesid®
  • Etopophos®
  • VP-16

Drug: Clofarabine
Given IV.
Other Name: Clolar®

Drug: Vorinostat
Given PO.
Other Names:
  • Zolinza®
  • Suberoylanilide Hydroxamic Acid
  • SAHA

Drug: Idarubicin
Given IV.
Other Names:
  • Idarubicin HCl
  • 4-Demethoxydaunorubicin
  • 4-DMD
  • DMDR
  • Idamycin PFS®

Drug: Nelarabine
Given IV.
Other Names:
  • Arranon®
  • Atriance®
  • Compound 506U78

Experimental: B-ALL, Rituximab

Patients with B-ALL will be randomized (unblinded) for administration of a dose of rituximab on Day 3 prior to the first dose of pegaspargase to prevent sensitization to asparaginase and subsequent asparaginase reaction and to improve anti-leukemia outcome.

Interventions: rituximab, pegaspargase (or Erwinase®).

Drug: Pegaspargase
Given IV or intramuscularly (IM) .
Other Names:
  • PEG-asparaginase
  • PEGLA
  • PEG-L-asparaginase
  • polyethylene glycol-L-asparaginase
  • Oncaspar®

Drug: Erwinase®
To be used in case of hypersensitivity or intolerance to Pegaspargase. Given IV or intramuscularly (IM).
Other Names:
  • Erwinia chrysanthemi
  • Asparaginase Erwinia chrysanthemi
  • Erwinaze^TM
  • Crisantaspase

Drug: Rituximab
Given IV.
Other Names:
  • Rituxan®
  • Biogen-IDEC-C2B8

Experimental: ALL, CEP72 T/T, Vincristine

ALL (both B and T) patients 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.

Drug: Vincristine
Given intravenously (IV).
Other Names:
  • Vincristine sulfate
  • Oncovin®
  • VCR
  • LCR

Experimental: ALL, CEP72 C/T or C/C, Vincristine

ALL patients (both B and T) 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 (1.5 mg/m^2 per dose) and dexamethasone pulses through Week 49 of Continuation Treatment or through Week 101 of Continuation Treatment.

Interventions: vincristine, dexamethasone, methotrexate, mercaptopurine.

Drug: Vincristine
Given intravenously (IV).
Other Names:
  • Vincristine sulfate
  • Oncovin®
  • VCR
  • LCR

Drug: Mercaptopurine
Given PO.
Other Names:
  • 6-MP
  • Purinethol®
  • Purixan^TM
  • 6-mercaptopurine

Drug: Methotrexate
Given IV.
Other Names:
  • MTX
  • amethopterin
  • Trexall®

Drug: Dexamethasone
Given PO.
Other Names:
  • Decadron®
  • Hexadrol®
  • Dexone®
  • Dexameth®




Primary Outcome Measures :
  1. Event-free survival of ALL patients (EFS) [ Time Frame: At 3.5 years after enrollment of the last participant ]
    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.

  2. Rate of allergic reactions to pegaspargase in B-ALL patients [ Time Frame: At 6 months after the last randomized patient completes Reinduction II ]
    This study will use un-blinded stratified randomization, and analysis be reported by group. All B-ALL patients will be randomized before Day 3 of Remission Induction, at a 1:1 ratio into two groups, in one of which rituximab will be administered, and no rituximab in the other. The randomization will be stratified by diagnostic WBC levels (<50 x 10^9/L vs. ≥50 x 10^9/L) and CD20 expression (positive vs. negative) because these are factors known to affect rituximab effect. In the final analysis the investigators will also compare the allergic reaction rate between the two groups by logistic regression, accounting for potential confounding factors, such as Day 15 MRD status (>5% vs. not), risk and subtypes that affect treatment intensity

  3. Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation [ Time Frame: At 6 months after the last randomized patient completes Continuation Treatment (Week 120). ]
    This will be a single-blind, stratified block randomized experiment. Although the investigators who evaluate neuropathy and neuropathic pain and the patients are blinded for treatment assignment, treating clinicians and pharmacy staff are not. Patients will be randomized at a 1:1 ratio into two treatment groups: 1.5 mg/m^2 vs. 1 mg/m^2 vincristine (VCR) dose. Randomization will be stratified by two factors known to significantly affect neuropathy during the Continuation phase, namely, Grade 2 or higher neuropathy prior to Continuation (none, 1 episode, 2 or more episodes) and race (black, others). The proportion of patients who develop two or more episodes of Grade 2 or higher neuropathy during Continuation Treatment will be compared between the two VCR dose groups, using a Z-test for two sample proportions.

  4. Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype [ Time Frame: After the last randomized patient is followed for 1 year after Week 101 of Continuation therapy ]
    This will be a single blind stratified block randomized experiment. The investigators who evaluate neuropathy and neuropathic pain and the patients are blinded for treatment assignment. Treating clinicians and pharmacy staff will not be blinded. Patients will be randomized at a 1:1 ratio into two treatment groups at Week 49 of Continuation therapy: to vincristine + dexamethasone (VCR+DEX) pulses or to 6-mercaptopurine + methotrexate (6MP+MTX). The primary analysis will compare the cumulative incidence of the first episode of Grade 2 or higher neuropathy or neuropathic pain (the end point) by stratified Gray's test. Adverse events other than the endpoint rendering a patient drop out after Continuation Week 49 are regarded as competing events.


Secondary Outcome Measures :
  1. 5-year overall survival (OS) of ALL patients compared to historical controls [ Time Frame: 3.5 years after enrollment of the last patient ]
    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.

  2. EFS of LLy patients [ Time Frame: 3.5 years after enrollment of the last patient ]
    5-year EFS: Although the lymphoblastic lymphoma (LLy) patients will receive essentially the same treatment as the ALL patients, these two cohorts of patients will be analyzed and reported separately. Kaplan-Meier estimates of EFS curve in patients with LLy will be computed.

  3. 5-year OS of LLy patients [ Time Frame: 3.5 years after enrollment of the last patient ]
    Kaplan-Meier estimates of OS curve in patients with LLy will be computed.

  4. Comparison of minimum residual disease (MRD) in B-ALL patients [ Time Frame: Day 15 through Day 42 during Remission induction therapy (At 6 months after enrollment of the last patient) ]
    The 85th percentile of the MRD distribution in the rituximab group vs. that in the control group will be compared by the percentile ratio method.

  5. Number of patients with dose-limiting toxicities (DLT) of ruxolitinib in patients with early T cell precursor leukemia [ Time Frame: Through up to 49 days after start of Early Intensification therapy of last evaluable patient ]
    Any participant who experiences a DLT at any time during Early Intensification therapy is considered evaluable for toxicity. For dose escalation phase, Early Intensification therapy is 28 days (49 days for evaluation of hematologic toxicity).

  6. Maximum tolerated dose (MTD) of ruxolitinib [ Time Frame: Through up to 49 days after start of Early Intensification therapy of last evaluable patient ]
    The MTD is empirically defined as the highest dose level at which six participants have been treated with at most one participant experiencing a DLT. The rolling-6 design will be used to determine dose escalation and reduction within each stratum separately.

  7. 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) ]
    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.

  8. 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 ]
    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.

  9. 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) ]
    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.

  10. Isolated CNS relapse in CNS1b patients [ Time Frame: 3.5 years after enrollment of the last patient ]
    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.

  11. 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) ]
    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.

  12. Number and type of germline or somatic genomic variants associated with drug resistance [ Time Frame: 3.5 years after enrollment of the last participant ]
    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.

  13. 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 ]
    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

  14. 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) ]
    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.

  15. 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) ]
    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.).

  16. 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) ]
    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


Other Outcome Measures:
  1. Log odds ratio of pharmacogenetic predictors of treatment outcome (host toxicity or in vivo efficacy) [ Time Frame: 5 years after enrollment of the last participant ]
    The log odds ratio of pharmacogenetics predictors of treatment outcome will be given.

  2. Log odds ratio of pharmacokinetic predictors of treatment outcome (host toxicity or in vivo efficacy) [ Time Frame: 5 years after enrollment of the last participant ]
    The log odds ratio of pharmacokinetic predictors of treatment outcome will be given.

  3. Log odds ratio of pharmacodynamic predictors of treatment outcome (host toxicity or in vivo efficacy) [ Time Frame: 5 years after enrollment of the last participant ]
    The log odds ratio of pharmacodynamic predictors of treatment outcome will be given.

  4. Thiopurine metabolism [ Time Frame: 3.5 years after enrollment of the last participant ]
    A detailed assessment of thiopurine metabolism will be done and correlated with 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome.

  5. Number of participants experiencing specific therapy-related infection events [ Time Frame: 1 year after completion of therapy for last enrolled patient (up to 3.5 years after enrollment) ]
    All enrolled participants will be eligible for this component. Descriptive statistics, such as frequency and proportion, will be summarized for breakthrough infections, antibiotic-resistant infections, febrile neutropenia episodes and adverse events. Cumulative incidence of breakthrough infection, febrile neutropenia and adverse events will also be explored, with competing risks and/or recurrent event appropriately adjusted.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03117751


Contacts
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Contact: Hiroto Inaba, MD, PhD 866-278-5833 referralinfo@stjude.org

Locations
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United States, Tennessee
St. Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38105
Contact: Hiroto Inaba, MD, PhD    866-278-5833    referralinfo@stjude.org   
Principal Investigator: Hiroto Inaba, MD, PhD         
Sponsors and Collaborators
St. Jude Children's Research Hospital
Bristol-Myers Squibb
Incyte Corporation
Shire
Investigators
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Principal Investigator: Hiroto Inaba, MD, PhD St. Jude Children's Research Hospital

Additional Information:
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Responsible Party: St. Jude Children's Research Hospital
ClinicalTrials.gov Identifier: NCT03117751     History of Changes
Other Study ID Numbers: TOT17
NCI-2017-00582 ( Registry Identifier: NCI Clinical Trial Registration Program )
First Posted: April 18, 2017    Key Record Dates
Last Update Posted: July 11, 2018
Last Verified: July 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by St. Jude Children's Research Hospital:
Leukemia
Lymphoma
Pediatric
B-Cell
T-Cell

Additional relevant MeSH terms:
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Lymphoma
Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Dexamethasone
Dexamethasone acetate
Prednisone
Cyclophosphamide
Rituximab
Doxorubicin
Liposomal doxorubicin
Methotrexate
Bortezomib
Etoposide
Etoposide phosphate
Cytarabine
Vincristine
Dasatinib
Vorinostat
Daunorubicin
Clofarabine
Idarubicin
Asparaginase
Mercaptopurine