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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT03117751
Registration number
NCT03117751
Ethics application status
Date submitted
27/03/2017
Date registered
18/04/2017
Date last updated
5/03/2024
Titles & IDs
Public title
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
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Scientific title
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
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Secondary ID [1]
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NCI-2017-00582
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Secondary ID [2]
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TOT17
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Condition category
Condition code
Cancer
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Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma
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Cancer
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Lymphoma (non Hodgkin's lymphoma) - Low grade lymphoma
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Cancer
0
0
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0
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Leukaemia - Acute leukaemia
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Cancer
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Leukaemia - Chronic leukaemia
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Cancer
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Children's - Leukaemia & Lymphoma
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Prednisone
Treatment: Drugs - Vincristine
Treatment: Drugs - Daunorubicin
Treatment: Drugs - Pegaspargase
Treatment: Drugs - Erwinase®
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Cytarabine
Treatment: Drugs - Mercaptopurine
Treatment: Drugs - Dasatinib
Treatment: Drugs - Methotrexate
Treatment: Drugs - Blinatumomab
Treatment: Drugs - Ruxolitinib
Treatment: Drugs - Bortezomib
Treatment: Drugs - Dexamethasone
Treatment: Drugs - Doxorubicin
Treatment: Drugs - Etoposide
Treatment: Drugs - Clofarabine
Treatment: Drugs - Vorinostat
Treatment: Drugs - Idarubicin
Treatment: Drugs - Nelarabine
Treatment: Drugs - Thioguanine
Treatment: Drugs - Asparaginase Erwinia chrysanthemi (recombinant)-rywn
Treatment: Drugs - Calaspargase Pegol
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 ABL-class fusion. Blinatumomab will be given to patients with certain genetic subtypes and those with Down syndrome.
Interventions: Prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, thioguanine, methotrexate, dexamethasone, blinatumomab.
Experimental: B-ALL and B-LLy, Standard-risk - Induction (6wks), Early Intensification (4wks), Consolidation (8wks) and Continuation (120 wks). Remission Induction: Prednisone dose is 40mg/m^2 and 2 doses daunorubicin are given. Dasatinib: given for patients with Ph+ and those with ABL-class fusion. Ruxolitinib: given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD =5%, LLy patients who don't qualify for complete response at end of Remission Induction and all patients with ETP and T/M MPAL. 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%), certain genetic subtypes and Down syndrome.
Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, thioguanine, methotrexate, dexamethasone, doxorubicin
Experimental: B-ALL and B-LLy, High-risk - Induction (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 and patients with certain genetic subtypes and those with Down syndrome.
Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, etoposide, dexamethasone, clofarabine, thioguanine, methotrexate.
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 ABL-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 T/M MPAL 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®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, dexamethasone, doxorubicin, nelarabine, thioguanine.
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®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, etoposide, dexamethasone, clofarabine, vorinostat, idarubicin, nelarabine, thioguanine..
Experimental: ALL, CEP72 T/T, Vincristine - 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 after Continuation Week 1. Patients in low- risk will complete vincristine in Week 49 and those in standard/high-risk will complete in Week 101.
Intervention: vincristine.
Experimental: ALL, CEP72 C/T or C/C, Vincristine - Patients 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. Patients at low-risk will complete vincristine in Week 49.
Interventions: vincristine, dexamethasone, methotrexate, mercaptopurine.
Treatment: Drugs: Prednisone
Given orally (PO).
Treatment: Drugs: Vincristine
Given intravenously (IV).
Treatment: Drugs: Daunorubicin
Given IV.
Treatment: Drugs: Pegaspargase
Given IV or intramuscularly (IM) .
Treatment: Drugs: Erwinase®
To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM).
Treatment: Drugs: Cyclophosphamide
Given IV.
Treatment: Drugs: Cytarabine
Given IV or by subcutaneous injection (SQ).
Treatment: Drugs: Mercaptopurine
Given PO.
Treatment: Drugs: Dasatinib
Given PO.
Treatment: Drugs: Methotrexate
Given IV.
Treatment: Drugs: Blinatumomab
Given IV.
Treatment: Drugs: Ruxolitinib
Given PO.
Treatment: Drugs: Bortezomib
Given IV or subcutaneously (SQ).
Treatment: Drugs: Dexamethasone
Given PO.
Treatment: Drugs: Doxorubicin
Given IV.
Treatment: Drugs: Etoposide
Given IV.
Treatment: Drugs: Clofarabine
Given IV.
Treatment: Drugs: Vorinostat
Given PO.
Treatment: Drugs: Idarubicin
Given IV.
Treatment: Drugs: Nelarabine
Given IV.
Treatment: Drugs: Thioguanine
Participants with mercaptopurine-related pancreatitis. Given PO.
Treatment: Drugs: Asparaginase Erwinia chrysanthemi (recombinant)-rywn
To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM).
Treatment: Drugs: Calaspargase Pegol
To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Event-free survival of ALL patients (EFS)
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Assessment method [1]
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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.
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Timepoint [1]
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At 3.5 years after enrollment of the last participant
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Primary outcome [2]
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Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation
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Assessment method [2]
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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.
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Timepoint [2]
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At 6 months after the last randomized patient completes Continuation Treatment (Week 120).
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Primary outcome [3]
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Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype
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Assessment method [3]
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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. Standard/high-risk 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.
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Timepoint [3]
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After the last randomized patient is followed for 1 year after Week 101 of Continuation therapy
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Secondary outcome [1]
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5-year overall survival (OS) of ALL patients compared to historical controls
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Assessment method [1]
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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.
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Timepoint [1]
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3.5 years after enrollment of the last patient
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Secondary outcome [2]
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EFS of LLy patients
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Assessment method [2]
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5-year EFS: Kaplan-Meier estimates of EFS curve in patients with LLy will be computed.
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Timepoint [2]
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3.5 years after enrollment of the last patient
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Secondary outcome [3]
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5-year OS of LLy patients
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Assessment method [3]
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Kaplan-Meier estimates of OS curve in patients with LLy will be computed.
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Timepoint [3]
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3.5 years after enrollment of the last patient
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Secondary outcome [4]
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The efficacy of blinatumomab in B-ALL patients
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Assessment method [4]
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Comparison with historical control by log-rank tests will be performed.
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Timepoint [4]
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3.5 years after enrollment of the last patient
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Secondary outcome [5]
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Comparison of MRD measurements between flow cytometry and sequencing
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Assessment method [5]
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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.
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Timepoint [5]
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From Day 8 through Day 42 after remission induction (At 6 months after enrollment of the 40^t^h evaluable patient)
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Secondary outcome [6]
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Log hazard ratio of the association of low level of MRD and treatment outcome
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Assessment method [6]
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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.
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Timepoint [6]
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3.5 years after enrollment of the last patient
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Secondary outcome [7]
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Comparison of bone marrow and peripheral blood MRD
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Assessment method [7]
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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.
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Timepoint [7]
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From Day 15 through Day 42 of remission induction and end of therapy (At 6 months after enrollment of the last evaluable patient)
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Secondary outcome [8]
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Isolated CNS relapse in CNS1b patients
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Assessment method [8]
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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.
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Timepoint [8]
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3.5 years after enrollment of the last patient
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Secondary outcome [9]
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Level of clonal diversity and rise of leukemic clones during treatment
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Assessment method [9]
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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.
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Timepoint [9]
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From Day 1 through week 120 of continuation (at 6 months after the last enrolled patient completes Week 120)
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Secondary outcome [10]
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Number and type of germline or somatic genomic variants associated with drug resistance
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Assessment method [10]
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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.
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Timepoint [10]
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3.5 years after enrollment of the last participant
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Secondary outcome [11]
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Comparison of drug sensitivity of ALL cells between diagnosis and relapse in vitro and in vivo
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Assessment method [11]
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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
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Timepoint [11]
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5 years after enrollment of the last participant
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Secondary outcome [12]
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Change in bone mineral density (BMD) in the tibia
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Assessment method [12]
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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.
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Timepoint [12]
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From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
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Secondary outcome [13]
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Change in markers of bone turnover
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Assessment method [13]
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Linear mixed models or other methods will be used to evaluate this outcome.
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Timepoint [13]
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From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
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Eligibility
Key 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. Patients with MPAL are eligible.
- 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.
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Minimum age
1
Year
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Maximum age
18
Years
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key 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.
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people assessing the outcomes
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 2/Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Active, not recruiting
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
29/03/2017
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
31/03/2028
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Actual
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Sample size
Target
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Accrual to date
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Final
790
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Recruitment in Australia
Recruitment state(s)
VIC
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Recruitment hospital [1]
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The Royal Children's Hospital Melbourne - Parkville
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Recruitment postcode(s) [1]
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3052 - Parkville
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Recruitment outside Australia
Country [1]
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United States of America
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State/province [1]
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California
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Country [2]
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0
United States of America
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State/province [2]
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0
Illinois
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Country [3]
0
0
United States of America
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State/province [3]
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0
Michigan
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Country [4]
0
0
United States of America
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State/province [4]
0
0
North Carolina
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Country [5]
0
0
United States of America
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State/province [5]
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0
Tennessee
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Country [6]
0
0
United States of America
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State/province [6]
0
0
Texas
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Funding & Sponsors
Primary sponsor type
Other
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Name
St. Jude Children's Research Hospital
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
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-acute lymphoblastic leukemia (B-ALL) or B-lymphoblastic lymphoma (B-LLy), and the proteasome inhibitor bortezomib for those lacking targetable lesions. - To improve overall treatment outcome of T acute lymphoblastic leukemia (T-ALL) and T-lymphoblastic lymphoma (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 standard/high-risk 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 to assess the non-inferiority of TOTXVII compared to the historical control given by TOTXVI. - To estimate the event-free survival and overall survival of children with LLy when ALL diagnostic and treatment approaches are used. - To evaluate the efficacy of blinatumomab in B-ALL patients with end of induction MRD =0.01% to <1% and those (regardless of MRD level or TOTXVII risk category) with the genetic subtypes of BCR-ABL1, ABL-class fusion, JAK-STAT activating mutation, hypodiploid, iAMP21, ETV6-RUNX1-like, MEF2D, TCF3-HLF, or BCL2/MYC or with Down syndrome, by comparing event-free survival to historical control from TOTXVI. - 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 deoxyribonucleic acid (DNA) and ribonucleic acid (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 to 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 to investigate the neurocognitive trajectory, mechanisms, and risk factors. - To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover. There are several Exploratory Objectives.
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Trial website
https://clinicaltrials.gov/ct2/show/NCT03117751
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
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Hiroto Inaba, MD, PhD
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Address
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St. Jude Children's Research Hospital
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Phone
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Fax
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Email
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Contact person for public queries
Name
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Address
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Country
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Phone
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Fax
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Email
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Contact person for scientific queries
No information has been provided regarding IPD availability
What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
No documents have been uploaded by study researchers.
Results not provided in
https://clinicaltrials.gov/ct2/show/NCT03117751
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