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

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St. Jude Children's Research Hospital

Status and phase

Active, not recruiting
Phase 3
Phase 2

Conditions

Acute Lymphoblastic Lymphoma
Acute Lymphoblastic Leukemia

Treatments

Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn
Drug: Thioguanine
Drug: Methotrexate
Drug: Etoposide
Drug: Prednisone
Drug: Dexamethasone
Drug: Dasatinib
Drug: Idarubicin
Drug: Vincristine
Drug: Blinatumomab
Drug: Daunorubicin
Drug: Mercaptopurine
Drug: Cyclophosphamide
Drug: Calaspargase Pegol
Drug: Nelarabine
Drug: Bortezomib
Drug: Erwinase®
Drug: Doxorubicin
Drug: Vorinostat
Drug: Ruxolitinib
Drug: Cytarabine
Drug: Pegaspargase
Drug: Clofarabine

Study type

Interventional

Funder types

Other
Industry

Identifiers

NCT03117751
TOT17
NCI-2017-00582 (Registry Identifier)

Details and patient eligibility

About

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.

Full 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.

Enrollment

790 patients

Sex

All

Ages

1 to 18 years old

Volunteers

No Healthy Volunteers

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.

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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Single Blind

790 participants in 7 patient groups

B-ALL and B-LLy, Low-risk
Experimental group
Description:
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.
Treatment:
Drug: Pegaspargase
Drug: Cytarabine
Drug: Erwinase®
Drug: Calaspargase Pegol
Drug: Mercaptopurine
Drug: Cyclophosphamide
Drug: Daunorubicin
Drug: Blinatumomab
Drug: Vincristine
Drug: Dasatinib
Drug: Dexamethasone
Drug: Prednisone
Drug: Thioguanine
Drug: Methotrexate
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn
B-ALL and B-LLy, Standard-risk
Experimental group
Description:
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
Treatment:
Drug: Pegaspargase
Drug: Cytarabine
Drug: Ruxolitinib
Drug: Doxorubicin
Drug: Erwinase®
Drug: Bortezomib
Drug: Calaspargase Pegol
Drug: Mercaptopurine
Drug: Cyclophosphamide
Drug: Daunorubicin
Drug: Blinatumomab
Drug: Vincristine
Drug: Dasatinib
Drug: Dexamethasone
Drug: Prednisone
Drug: Thioguanine
Drug: Methotrexate
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn
B-ALL and B-LLy, High-risk
Experimental group
Description:
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.
Treatment:
Drug: Clofarabine
Drug: Pegaspargase
Drug: Cytarabine
Drug: Ruxolitinib
Drug: Erwinase®
Drug: Bortezomib
Drug: Calaspargase Pegol
Drug: Mercaptopurine
Drug: Cyclophosphamide
Drug: Daunorubicin
Drug: Blinatumomab
Drug: Vincristine
Drug: Dasatinib
Drug: Dexamethasone
Drug: Prednisone
Drug: Etoposide
Drug: Thioguanine
Drug: Methotrexate
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn
T-ALL and T-LLy, Standard-risk
Experimental group
Description:
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.
Treatment:
Drug: Pegaspargase
Drug: Cytarabine
Drug: Ruxolitinib
Drug: Doxorubicin
Drug: Erwinase®
Drug: Bortezomib
Drug: Nelarabine
Drug: Calaspargase Pegol
Drug: Mercaptopurine
Drug: Cyclophosphamide
Drug: Daunorubicin
Drug: Vincristine
Drug: Dasatinib
Drug: Dexamethasone
Drug: Prednisone
Drug: Thioguanine
Drug: Methotrexate
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn
T-ALL and T-LLy, High-risk
Experimental group
Description:
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..
Treatment:
Drug: Clofarabine
Drug: Pegaspargase
Drug: Cytarabine
Drug: Ruxolitinib
Drug: Vorinostat
Drug: Erwinase®
Drug: Bortezomib
Drug: Nelarabine
Drug: Calaspargase Pegol
Drug: Mercaptopurine
Drug: Cyclophosphamide
Drug: Daunorubicin
Drug: Idarubicin
Drug: Vincristine
Drug: Dasatinib
Drug: Dexamethasone
Drug: Prednisone
Drug: Etoposide
Drug: Thioguanine
Drug: Methotrexate
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn
ALL, CEP72 T/T, Vincristine
Experimental group
Description:
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.
Treatment:
Drug: Vincristine
ALL, CEP72 C/T or C/C, Vincristine
Experimental group
Description:
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:
Drug: Mercaptopurine
Drug: Vincristine
Drug: Dexamethasone
Drug: Methotrexate

Trial contacts and locations

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Data sourced from clinicaltrials.gov

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