Acute Lymphoblastic LeukemiaPhase 2/3NCT03117751
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
A Phase 2/3 study testing Prednisone, Vincristine and Daunorubicin in people with Acute Lymphoblastic Leukemia and Acute Lymphoblastic Lymphoma, run by St. Jude Children's Research Hospital at 8 sites in 2 countries.
Trial 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… Read more about this study
- Who is it for?
- Ages 1 year to 18 years
- Conditions the study is for
- Acute Lymphoblastic Leukemia, Acute Lymphoblastic Lymphoma
- What is being tested?
- Prednisone, Vincristine and Daunorubicin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 790 participants
- Where
- 8 sitesin 2 countries
- Study dates
- 29 Mar 2017to 30 Sep 2028
- Phase
- Phase 2/3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year to 18 years
- All sexes
- No healthy volunteers
- Child, Adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
8 sites in 2 countries.
8 sites in 2 countries
United States7 sites
St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital
Charlotte, North Carolina, 28204
Children's Hospital of Michigan
Detroit, Michigan, 48201
Cook Children's Medical Center
Fort Worth, Texas, 76104
St. Jude Children's Research Hospital
Memphis, Tennessee, 38105
Lucile Packard Children's Hospital Stanford University
Palo Alto, California, 94305
Children's Hospital of Illinois at OSF-Saint Francis Medical Center (St. Jude Midwest Affiliate - Peoria)
Peoria, Illinois, 61637
Rady Children's Hospital San Diego
San Diego, California, 92123
Australia1 site
The Royal Children's Hospital Melbourne
Parkville, Victoria, 3052
About this study
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:
Read more
- 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.
Read the 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. Patients with mixed phenotype acute leukemia (MPAL) are treated by using the same treatment stratification used in ALL although analysis is performed separately from ALL or LLy cohorts.
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 1 dose for all patients and 2 doses for those with Day 15 MRD 1% or higher. 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 ABL-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 and T/M MPAL, 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 Treatment 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 and T/M MPAL.
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. Blinatumomab is also given to patients with the following genetic subtypes (BCR-ABL1, ABL-class fusion, JAK-STAT activating mutation, hypodiploid, iAMP21, ETV6-RUNX1-like, MEF2D, TCF3/HLF, or BCL2/MYC) or with Down syndrome, regardless of MRD level and/or Total 17 risk category.
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 ABL-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 in low- risk will complete vincristine in Week 49 and those in standard/high-risk will complete in Week 101. Standard/high-risk 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. Low-risk patients will complete vincristine in Week 49.
Intrathecal therapy is given throughout the treatment. The number of intrathecal therapy is based on the risk factors of central nervous system relapse.
- Being tested
- Prednisone, Vincristine, Daunorubicin, Pegaspargase, Erwinase®
- Keywords
- Leukemia, Lymphoma, Pediatric, B-Cell, T-Cell
- Medical subject headings
- Precursor Cell Lymphoblastic Leukemia-Lymphoma, Leukemia, Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PrednisoneDrug
Also called Prednisolone, Deltasone, Meticorten, Orasone®
Given orally (PO).
VincristineDrug
Also called Vincristine sulfate, Oncovin®, VCR, LCR
Given intravenously (IV).
DaunorubicinDrug
Also called Daunomycin, rubidomycin, Cerubidine®
Given IV.
PegaspargaseDrug
Also called PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-asparaginase
Given IV or intramuscularly (IM) .
Erwinase®Drug
Also called Erwinia chrysanthemi, Asparaginase Erwinia chrysanthemi, Erwinaze^TM, Crisantaspase
To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM).
CyclophosphamideDrug
Also called Cytoxan®
Given IV.
CytarabineDrug
Also called Cytosine arabinoside, Ara-C, Cytosar®
Given IV or by subcutaneous injection (SQ).
MercaptopurineDrug
Also called 6-MP, Purinethol®, Purixan^TM, 6-mercaptopurine
Given PO.
DasatinibDrug
Also called Sprycel®
Given PO.
MethotrexateDrug
Also called MTX, amethopterin, Trexall®
Given IV.
BlinatumomabDrug
Also called Blincyto®
Given IV.
RuxolitinibDrug
Also called Jakafi®
Given PO.
BortezomibDrug
Also called Velcade®
Given IV or subcutaneously (SQ).
DexamethasoneDrug
Also called Decadron®, Hexadrol®, Dexone®, Dexameth®
Given PO.
DoxorubicinDrug
Also called Adriamycin®
Given IV.
EtoposideDrug
Also called Etoposide Phosphate, VePesid®, Etopophos®, VP-16
Given IV.
ClofarabineDrug
Also called Clolar®
Given IV.
VorinostatDrug
Also called Zolinza®, Suberoylanilide Hydroxamic Acid, SAHA
Given PO.
IdarubicinDrug
Also called Idarubicin HCl, 4-Demethoxydaunorubicin, 4-DMD, DMDR
Given IV.
NelarabineDrug
Also called Arranon®, Atriance®, Compound 506U78
Given IV.
ThioguanineDrug
Also called 6-thioguanine, Tioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, WR-1141
Participants with mercaptopurine-related pancreatitis. Given PO.
Asparaginase Erwinia chrysanthemi (recombinant)-rywnDrug
Also called Rylaze™, Recombinant Erwinia
To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM).
Calaspargase PegolDrug
Also called ASPARLAS
To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.
| Study group | Role | What they receive |
|---|---|---|
| B-ALL and B-LLy, Low-risk | Experimental | 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. Receives: Drug: Prednisone; Drug: Vincristine; Drug: Daunorubicin; Drug: Pegaspargase; Drug: Erwinase®; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Dasatinib; Drug: Methotrexate; Drug: Blinatumomab; Drug: Dexamethasone; Drug: Thioguanine; Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn; Drug: Calaspargase Pegol |
| B-ALL and B-LLy, Standard-risk | Experimental | 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 Receives: Drug: Prednisone; Drug: Vincristine; Drug: Daunorubicin; Drug: Pegaspargase; Drug: Erwinase®; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Dasatinib; Drug: Methotrexate; Drug: Blinatumomab; Drug: Ruxolitinib; Drug: Bortezomib; Drug: Dexamethasone; Drug: Doxorubicin; Drug: Thioguanine; Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn; Drug: Calaspargase Pegol |
| B-ALL and B-LLy, High-risk | Experimental | 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. Receives: Drug: Prednisone; Drug: Vincristine; Drug: Daunorubicin; Drug: Pegaspargase; Drug: Erwinase®; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Dasatinib; Drug: Methotrexate; Drug: Blinatumomab; Drug: Ruxolitinib; Drug: Bortezomib; Drug: Dexamethasone; Drug: Etoposide; Drug: Clofarabine; Drug: Thioguanine; Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn; Drug: Calaspargase Pegol |
| T-ALL and T-LLy, Standard-risk | Experimental | 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. Receives: Drug: Prednisone; Drug: Vincristine; Drug: Daunorubicin; Drug: Pegaspargase; Drug: Erwinase®; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Dasatinib; Drug: Methotrexate; Drug: Ruxolitinib; Drug: Bortezomib; Drug: Dexamethasone; Drug: Doxorubicin; Drug: Nelarabine; Drug: Thioguanine; Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn; Drug: Calaspargase Pegol |
| T-ALL and T-LLy, High-risk | Experimental | 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.. Receives: Drug: Prednisone; Drug: Vincristine; Drug: Daunorubicin; Drug: Pegaspargase; Drug: Erwinase®; Drug: Cyclophosphamide; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Dasatinib; Drug: Methotrexate; Drug: Ruxolitinib; Drug: Bortezomib; Drug: Dexamethasone; Drug: Etoposide; Drug: Clofarabine; Drug: Vorinostat; Drug: Idarubicin; Drug: Nelarabine; Drug: Thioguanine; Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn; Drug: Calaspargase Pegol |
| ALL, CEP72 T/T, Vincristine | Experimental | 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. Receives: Drug: Vincristine |
| ALL, CEP72 C/T or C/C, Vincristine | Experimental | 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. Receives: Drug: Vincristine; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Dexamethasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Event-free survival of ALL patients (EFS)
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.
Measured: At 3.5 years after enrollment of the last participant
Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation
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.
Measured: At 6 months after the last randomized patient completes Continuation Treatment (Week 120).
Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype
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.
Measured: After the last randomized patient is followed for 1 year after Week 101 of Continuation therapy
Secondary outcomes (13)
5-year overall survival (OS) of ALL patients compared to historical controls
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.
Measured: 3.5 years after enrollment of the last patient
EFS of LLy patients
5-year EFS: Kaplan-Meier estimates of EFS curve in patients with LLy will be computed.
Measured: 3.5 years after enrollment of the last patient
5-year OS of LLy patients
Kaplan-Meier estimates of OS curve in patients with LLy will be computed.
Measured: 3.5 years after enrollment of the last patient
The efficacy of blinatumomab in B-ALL patients
Comparison with historical control by log-rank tests will be performed.
Measured: 3.5 years after enrollment of the last patient
Comparison of MRD measurements between flow cytometry and sequencing
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.
Measured: From Day 8 through Day 42 after remission induction (At 6 months after enrollment of the 40^t^h evaluable patient)
Log hazard ratio of the association of low level of MRD and treatment outcome
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.
Measured: 3.5 years after enrollment of the last patient
Comparison of bone marrow and peripheral blood MRD
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.
Measured: From Day 15 through Day 42 of remission induction and end of therapy (At 6 months after enrollment of the last evaluable patient)
Isolated CNS relapse in CNS1b patients
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.
Measured: 3.5 years after enrollment of the last patient
Level of clonal diversity and rise of leukemic clones during treatment
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.
Measured: From Day 1 through week 120 of continuation (at 6 months after the last enrolled patient completes Week 120)
Number and type of germline or somatic genomic variants associated with drug resistance
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.
Measured: 3.5 years after enrollment of the last participant
Comparison of drug sensitivity of ALL cells between diagnosis and relapse in vitro and in vivo
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
Measured: 5 years after enrollment of the last participant
Change in bone mineral density (BMD) in the tibia
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.
Measured: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
Change in markers of bone turnover
Linear mixed models or other methods will be used to evaluate this outcome.
Measured: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2017
- Study start29 Mar 2017
- Primary completion30 Sep 2026 (estimated)
- Study completion30 Sep 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Acute Lymphoblastic LeukemiaStudies of the same condition, open and under way.
- More trials run by St. Jude Children's Research HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 790 participants (actual)
Sponsor and investigators
- Lead sponsor
- St. Jude Children's Research Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Incyte Corporation, Amgen, Servier
- Responsible party
- Sponsor
- Investigators
- Hiroto Inaba, MD, PhD, Principal investigator, St. Jude Children's Research Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03117751
- Sponsor's protocol ID
- TOT17
- Other IDs
- NCI-2017-00582
- Status last verified
- Jun 2026
- First submitted
- 27 Mar 2017
- Last updated
- 17 Jun 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Montanaro A, Monica G, Zamponi R, D'Antuono A, Andreani A, Andrei P, Su AH, Ciringione A, Sammarelli G, Todaro G, Rosati R, La Starza R, Mecucci C, Elia L, Gherli A, Vento F, Simoncini E, Lorusso B, Lagrasta CAM, Giaimo M, Pagliaro L, Marchesini M, Jimenez CR, Quaini F, Stegmaier K, Roti G. Inhibition of the atypical kinase WNK1 as a therapeutic strategy in TAL-related T-cell acute lymphoblastic leukemia. Blood. 2026 Sep 10;148(11):1423-1439. doi: 10.1182/blood.2025029901.
PubMed 42154791
Study at a glance
From the registry record, last updated by the sponsor on 17 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
- ClinicalTrials.gov ID
- NCT03117751
- Acronym / sponsor ID
- TOT17
- Keywords
- Leukemia, Lymphoma, Pediatric, B-Cell, T-Cell
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Active, not recruiting
- Enrolment
- 790 participants (actual)
- Lead sponsor
- St. Jude Children's Research HospitalUniversity, hospital or other
- Collaborators
- Incyte Corporation, Amgen, Servier
- Study start
- 29 Mar 2017 (actual)
- Primary completion
- 30 Sep 2026 (estimated)
- Study completion
- 30 Sep 2028 (estimated)
- First posted
- 18 Apr 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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. Patients with mixed phenotype acute leukemia (MPAL) are treated by using the same treatment stratification used in ALL although analysis is performed separately from ALL or LLy cohorts.
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 1 dose for all patients and 2 doses for those with Day 15 MRD 1% or higher. 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 ABL-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 and T/M MPAL, 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 Treatment 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 and T/M MPAL.
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. Blinatumomab is also given to patients with the following genetic subtypes (BCR-ABL1, ABL-class fusion, JAK-STAT activating mutation, hypodiploid, iAMP21, ETV6-RUNX1-like, MEF2D, TCF3/HLF, or BCL2/MYC) or with Down syndrome, regardless of MRD level and/or Total 17 risk category.
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 ABL-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 in low- risk will complete vincristine in Week 49 and those in standard/high-risk will complete in Week 101. Standard/high-risk 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. Low-risk patients will complete vincristine in Week 49.
Intrathecal therapy is given throughout the treatment. The number of intrathecal therapy is based on the risk factors of central nervous system relapse.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 7
| Arm | Type | Receives |
|---|---|---|
| B-ALL and B-LLy, Low-risk | Experimental | Drug: Prednisone, Drug: Vincristine, Drug: Daunorubicin, Drug: Pegaspargase, Drug: Erwinase®, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Mercaptopurine, Drug: Dasatinib, Drug: Methotrexate, Drug: Blinatumomab, Drug: Dexamethasone, Drug: Thioguanine, Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn, Drug: Calaspargase PegolPatients 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. |
| B-ALL and B-LLy, Standard-risk | Experimental | Drug: Prednisone, Drug: Vincristine, Drug: Daunorubicin, Drug: Pegaspargase, Drug: Erwinase®, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Mercaptopurine, Drug: Dasatinib, Drug: Methotrexate, Drug: Blinatumomab, Drug: Ruxolitinib, Drug: Bortezomib, Drug: Dexamethasone, Drug: Doxorubicin, Drug: Thioguanine, Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn, Drug: Calaspargase PegolInduction (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 |
| B-ALL and B-LLy, High-risk | Experimental | Drug: Prednisone, Drug: Vincristine, Drug: Daunorubicin, Drug: Pegaspargase, Drug: Erwinase®, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Mercaptopurine, Drug: Dasatinib, Drug: Methotrexate, Drug: Blinatumomab, Drug: Ruxolitinib, Drug: Bortezomib, Drug: Dexamethasone, Drug: Etoposide, Drug: Clofarabine, Drug: Thioguanine, Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn, Drug: Calaspargase PegolInduction (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. |
| T-ALL and T-LLy, Standard-risk | Experimental | Drug: Prednisone, Drug: Vincristine, Drug: Daunorubicin, Drug: Pegaspargase, Drug: Erwinase®, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Mercaptopurine, Drug: Dasatinib, Drug: Methotrexate, Drug: Ruxolitinib, Drug: Bortezomib, Drug: Dexamethasone, Drug: Doxorubicin, Drug: Nelarabine, Drug: Thioguanine, Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn, Drug: Calaspargase PegolInduction (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. |
| T-ALL and T-LLy, High-risk | Experimental | Drug: Prednisone, Drug: Vincristine, Drug: Daunorubicin, Drug: Pegaspargase, Drug: Erwinase®, Drug: Cyclophosphamide, Drug: Cytarabine, Drug: Mercaptopurine, Drug: Dasatinib, Drug: Methotrexate, Drug: Ruxolitinib, Drug: Bortezomib, Drug: Dexamethasone, Drug: Etoposide, Drug: Clofarabine, Drug: Vorinostat, Drug: Idarubicin, Drug: Nelarabine, Drug: Thioguanine, Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn, Drug: Calaspargase PegolInduction (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.. |
| ALL, CEP72 T/T, Vincristine | Experimental | Drug: VincristinePatients 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. |
| ALL, CEP72 C/T or C/C, Vincristine | Experimental | Drug: Vincristine, Drug: Mercaptopurine, Drug: Methotrexate, Drug: DexamethasonePatients 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. |
Who may qualify
- Ages
- 1 year to 18 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PrednisoneAlso: Prednisolone, Deltasone, Meticorten, Orasone®Given orally (PO). | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| VincristineAlso: Vincristine sulfate, Oncovin®, VCR, LCRGiven intravenously (IV). | Drug | ALL, CEP72 C/T or C/C, Vincristine, ALL, CEP72 T/T, Vincristine, B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| DaunorubicinAlso: Daunomycin, rubidomycin, Cerubidine®Given IV. | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| PegaspargaseAlso: PEG-asparaginase, PEGLA, PEG-L-asparaginase, polyethylene glycol-L-asparaginaseGiven IV or intramuscularly (IM) . | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| Erwinase®Also: Erwinia chrysanthemi, Asparaginase Erwinia chrysanthemi, Erwinaze^TM, CrisantaspaseTo be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM). | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| CyclophosphamideAlso: Cytoxan®Given IV. | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| CytarabineAlso: Cytosine arabinoside, Ara-C, Cytosar®Given IV or by subcutaneous injection (SQ). | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| MercaptopurineAlso: 6-MP, Purinethol®, Purixan^TM, 6-mercaptopurineGiven PO. | Drug | ALL, CEP72 C/T or C/C, Vincristine, B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| DasatinibAlso: Sprycel®Given PO. | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| MethotrexateAlso: MTX, amethopterin, Trexall®Given IV. | Drug | ALL, CEP72 C/T or C/C, Vincristine, B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| BlinatumomabAlso: Blincyto®Given IV. | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk |
| RuxolitinibAlso: Jakafi®Given PO. | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| BortezomibAlso: Velcade®Given IV or subcutaneously (SQ). | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| DexamethasoneAlso: Decadron®, Hexadrol®, Dexone®, Dexameth®Given PO. | Drug | ALL, CEP72 C/T or C/C, Vincristine, B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| DoxorubicinAlso: Adriamycin®Given IV. | Drug | B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, Standard-risk |
| EtoposideAlso: Etoposide Phosphate, VePesid®, Etopophos®, VP-16Given IV. | Drug | B-ALL and B-LLy, High-risk, T-ALL and T-LLy, High-risk |
| ClofarabineAlso: Clolar®Given IV. | Drug | B-ALL and B-LLy, High-risk, T-ALL and T-LLy, High-risk |
| VorinostatAlso: Zolinza®, Suberoylanilide Hydroxamic Acid, SAHAGiven PO. | Drug | T-ALL and T-LLy, High-risk |
| IdarubicinAlso: Idarubicin HCl, 4-Demethoxydaunorubicin, 4-DMD, DMDRGiven IV. | Drug | T-ALL and T-LLy, High-risk |
| NelarabineAlso: Arranon®, Atriance®, Compound 506U78Given IV. | Drug | T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| ThioguanineAlso: 6-thioguanine, Tioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, WR-1141Participants with mercaptopurine-related pancreatitis. Given PO. | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| Asparaginase Erwinia chrysanthemi (recombinant)-rywnAlso: Rylaze™, Recombinant ErwiniaTo be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM). | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
| Calaspargase PegolAlso: ASPARLASTo be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV. | Drug | B-ALL and B-LLy, High-risk, B-ALL and B-LLy, Low-risk, B-ALL and B-LLy, Standard-risk, T-ALL and T-LLy, High-risk, T-ALL and T-LLy, Standard-risk |
Primary outcome
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.
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.
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. 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.
13 secondary outcomes
5-year overall survival (OS) of ALL patients compared to historical controls
Time frame: 3.5 years after enrollment of the last patient
EFS of LLy patients
Time frame: 3.5 years after enrollment of the last patient
5-year OS of LLy patients
Time frame: 3.5 years after enrollment of the last patient
The efficacy of blinatumomab in B-ALL patients
Time frame: 3.5 years after enrollment of the last patient
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)
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
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)
Isolated CNS relapse in CNS1b patients
Time frame: 3.5 years after enrollment of the last patient
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)
Number and type of germline or somatic genomic variants associated with drug resistance
Time frame: 3.5 years after enrollment of the last participant
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
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)
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)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2026.
- Derived from this study: PubMed 42154791Montanaro A, Monica G, Zamponi R, D'Antuono A, Andreani A, Andrei P, Su AH, Ciringione A, Sammarelli G, Todaro G, Rosati R, La Starza R, Mecucci C, Elia L, Gherli A, Vento F, Simoncini E, Lorusso B, Lagrasta CAM, Giaimo M, Pagliaro L, Marchesini M, Jimenez CR, Quaini F, Stegmaier K, Roti G. Inhibition of the atypical kinase WNK1 as a therapeutic strategy in TAL-related T-cell acute lymphoblastic leukemia. Blood. 2026 Sep 10;148(11):1423-1439. doi: 10.1182/blood.2025029901.
- St. Jude Children's Research HospitalLink provided by the sponsor.
- ClinicalTrials Open at St. JudeLink provided by the sponsor.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hiroto Inaba, MD, PhD principal investigator
St. Jude Children's Research Hospital
8 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Prednisone, Vincristine and Daunorubicin in people with Acute Lymphoblastic Leukemia and Acute Lymphoblastic Lymphoma, run by St. Jude Children's Research Hospital at 8 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: under way, not looking for participants, as of the sponsor's last update on 17 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in United States, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Event-free survival of ALL patients (EFS) (time frame: At 3.5 years after enrollment of the last participant). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03117751, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jun 2026.