Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
| Status: | Recruiting |
|---|---|
| Conditions: | Blood Cancer, Lymphoma |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 1 - 18 |
| Updated: | 7/13/2018 |
| Start Date: | March 29, 2017 |
| End Date: | March 31, 2028 |
| Contact: | Hiroto Inaba, MD, PhD |
| Email: | referralinfo@stjude.org |
| Phone: | 866-278-5833 |
The overarching objective of this study is to use novel precision medicine strategies based
on inherited and leukemia-specific genomic features and targeted treatment approaches to
improve the cure rate and quality of life of children with acute lymphoblastic leukemia (ALL)
and acute lymphoblastic lymphoma (LLy).
Primary Therapeutic Objectives:
- To improve the event-free survival of provisional standard- or high-risk patients with
genetically or immunologically targetable lesions or minimal residual disease (MRD) ≥ 5%
at Day 15 or ≥1% at the end of Remission Induction, by the addition of molecular and
immunotherapeutic approaches including tyrosine kinase inhibitors or chimeric antigen
receptor (CAR) T cell / blinatumomab for refractory B-ALL, and the proteasome inhibitor
bortezomib for those lacking targetable lesions.
- To improve overall treatment outcome of T-ALL by optimizing pegaspargase and
cyclophosphamide treatment and by the addition of new agents in patients with targetable
genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the
addition of bortezomib for those who have a poor early response to treatment but no
targetable lesions, and by administering nelarabine to T-ALL patients with leukemia
cells in cerebrospinal fluid at diagnosis or MRD ≥0.01% at the end of induction.
- To examine in a randomized study design whether the administration of two doses of
rituximab to children with B-ALL during early Remission Induction therapy decreases
allergic reactions to pegaspargase.
- To determine in a randomized study design whether the incidence and/or severity of acute
vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of
vincristine in patients with the high-risk CEP72 TT genotype or by shortening the
duration of vincristine therapy in patients with the CEP72 CC or CT genotype.
Secondary Therapeutic Objectives:
- To estimate the event-free survival and overall survival of children with ALL and LLy.
- To examine whether the administration of two doses of rituximab can lower the minimal
residual disease (MRD) levels.
- To determine the tolerability of combination therapy with ruxolitinib.
Biological Objectives:
- To use data from clinical genomic sequencing and sequencing-based MRD in bone marrow,
blood and cerebrospinal fluid.
- To assess clonal diversity and evolution of pre-leukemic and leukemic populations.
- To identify germline or somatic genomic variants associated with drug resistance of ALL
cells.
- To compare drug sensitivity of ALL cells from diagnosis to relapse.
Supportive Care Objectives
- To conduct serial neurocognitive monitoring of patients and to evaluate the benefits of
a computer-based cognitive intervention.
- To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone
mineral density and markers of bone turnover.
Exploratory Objectives:
- To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors of treatment
outcome.
- To perform a detailed assessment of thiopurine metabolism and 6-mercaptopurine (6MP)
tolerance, toxicity, and treatment outcome.
- To establish xenografts of representative subtypes of ALL.
- To prospectively determine the risk and epidemiology of breakthrough infection or
febrile neutropenia and adverse effects of antibiotics.
on inherited and leukemia-specific genomic features and targeted treatment approaches to
improve the cure rate and quality of life of children with acute lymphoblastic leukemia (ALL)
and acute lymphoblastic lymphoma (LLy).
Primary Therapeutic Objectives:
- To improve the event-free survival of provisional standard- or high-risk patients with
genetically or immunologically targetable lesions or minimal residual disease (MRD) ≥ 5%
at Day 15 or ≥1% at the end of Remission Induction, by the addition of molecular and
immunotherapeutic approaches including tyrosine kinase inhibitors or chimeric antigen
receptor (CAR) T cell / blinatumomab for refractory B-ALL, and the proteasome inhibitor
bortezomib for those lacking targetable lesions.
- To improve overall treatment outcome of T-ALL by optimizing pegaspargase and
cyclophosphamide treatment and by the addition of new agents in patients with targetable
genomic abnormalities (e.g., activated tyrosine kinases or JAK/STAT mutations) or by the
addition of bortezomib for those who have a poor early response to treatment but no
targetable lesions, and by administering nelarabine to T-ALL patients with leukemia
cells in cerebrospinal fluid at diagnosis or MRD ≥0.01% at the end of induction.
- To examine in a randomized study design whether the administration of two doses of
rituximab to children with B-ALL during early Remission Induction therapy decreases
allergic reactions to pegaspargase.
- To determine in a randomized study design whether the incidence and/or severity of acute
vincristine-induced peripheral neuropathy can be reduced by decreasing the dosage of
vincristine in patients with the high-risk CEP72 TT genotype or by shortening the
duration of vincristine therapy in patients with the CEP72 CC or CT genotype.
Secondary Therapeutic Objectives:
- To estimate the event-free survival and overall survival of children with ALL and LLy.
- To examine whether the administration of two doses of rituximab can lower the minimal
residual disease (MRD) levels.
- To determine the tolerability of combination therapy with ruxolitinib.
Biological Objectives:
- To use data from clinical genomic sequencing and sequencing-based MRD in bone marrow,
blood and cerebrospinal fluid.
- To assess clonal diversity and evolution of pre-leukemic and leukemic populations.
- To identify germline or somatic genomic variants associated with drug resistance of ALL
cells.
- To compare drug sensitivity of ALL cells from diagnosis to relapse.
Supportive Care Objectives
- To conduct serial neurocognitive monitoring of patients and to evaluate the benefits of
a computer-based cognitive intervention.
- To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone
mineral density and markers of bone turnover.
Exploratory Objectives:
- To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors of treatment
outcome.
- To perform a detailed assessment of thiopurine metabolism and 6-mercaptopurine (6MP)
tolerance, toxicity, and treatment outcome.
- To establish xenografts of representative subtypes of ALL.
- To prospectively determine the risk and epidemiology of breakthrough infection or
febrile neutropenia and adverse effects of antibiotics.
Participants will be classified into one of three categories (low-, standard-, or high-risk)
based on the presenting age, leukocyte count/lymphoma staging, presence or absence of CNS-3
status or testicular disease, immunophenotype, molecular genetics, DNA index, and early
response to therapy.
Treatment will consist of three main phases: Remission Induction, Consolidation, and
Continuation. Early Intensification therapy will be given prior to Consolidation to patients
with provisional standard-risk or high-risk ALL/LLy or any provisional low-risk patients with
Day 15 MRD ≥1% as well as provisional low-risk LLy patients who do not obtain complete
response at the end of Induction.
Brief outline of treatment plan:
Patients will be assigned to treatment based on risk group: Low-Risk, Standard-Risk and
High-Risk and cell type (T or B cell).
Remission Induction initially consists of prednisone (28 days), vincristine (4 weekly doses),
daunorubicin (1 to 3 weekly doses), and pegaspargase (2 doses). The second part (given over 2
weeks and overlapping with the last week of the first part of induction) consists of
cyclophosphamide, cytarabine, and mercaptopurine combinations. Patients with B-ALL will be
randomized for administration of 2 doses of rituximab on Days 6 and 24 prior to the first and
second doses of pegaspargase to prevent sensitization to asparaginase and subsequent
asparaginase reaction and to improve anti-leukemia outcome. Dasatinib will be added for
patients with Ph+ and Ph-like ABL1-class fusions and bortezomib will be given to patients
with no targetable lesions and Day 15 minimal residual disease (MRD) >5%.
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
MRD level ≥5% or end of Remission Induction ≥1% as well as all patients with early T cell
precursor (ETP) ALL, ruxolitinib will be used. This includes, but is not limited to CRLF2,
JAK2, and EPOR rearrangements and sequence/structural changes in JAK1/2/3, TYK2, IL7R, and
SH2B3. Ruxolitinib will be added in LLy patients with activation of JAK-STAT signaling whose
responses do not qualify complete response at the end of Remission Induction. Activation of
JAK-STAT signaling is defined in ALL/LLy that contains genetic alterations associated with
JAK-STAT pathway. Dasatinib will continue for patients with ABL1-class fusions. Bortezomib
will be added for patients with no targetable lesions and Day 15 MRD >5% or Day 42 MRD >1%
and LLy patients without targetable lesions whose responses do not qualify complete response
at the end of Remission Induction.
Consolidation Therapy will consist of high dose methotrexate (HDMTX) (every other week for 4
doses); daily mercaptopurine and IT chemotherapy on the same dates of HDMTX. Standard and
high-risk patients will also receive pegaspargase. Dasatinib will continue for patients with
ABL1-class fusions. Ruxolitinib will continue for patients with activation of JAK-STAT
signaling and Day 15 MRD ≥5% or Day 42 MRD ≥1% (or for LLy patients who do not qualify
complete response at the end of Remission Induction) and all cases with ETP ALL.
Immunotherapy: CAR T-cell therapy will be considered for High-risk B-ALL and B-LLy patients.
Blinatumomab will be given to patients with Standard risk B-ALL and B-LLy with residual
disease at the end of induction and High Risk B-ALL and B-LLy patients who are not able to
receive CAR T-cell therapy.
Reintensification therapy will be offered to certain High Risk patients with persistent MRD
after Immunotherapy (B-ALL and B-LLy) or Early Intensification (T-ALL and T-LLy), or those
who cannot receive Immunotherapy.
Continuation Treatment will consist of 120 weeks of risk-directed therapy. Dasatinib will
continue in patients with ABL1-class fusion. Ruxolitinib will continue in patients with
activation of JAK-STAT signaling and Day 15 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 patients with leukemia cells in cerebrospinal fluid at diagnosis or MRD ≥0.01%
at the end of Induction will receive nelarabine (LLy patients will not receive nelarabine).
ALL 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/m^2 or 1
mg/m^2 of vincristine after Continuation Week 1. Patients with either a CEP72 rs904627 C/T or
C/C genotype (84% of patients) will be randomized to receive vincristine and dexamethasone
pulses through Week 49 of Continuation Treatment or through Week 101 of Continuation
Treatment.
based on the presenting age, leukocyte count/lymphoma staging, presence or absence of CNS-3
status or testicular disease, immunophenotype, molecular genetics, DNA index, and early
response to therapy.
Treatment will consist of three main phases: Remission Induction, Consolidation, and
Continuation. Early Intensification therapy will be given prior to Consolidation to patients
with provisional standard-risk or high-risk ALL/LLy or any provisional low-risk patients with
Day 15 MRD ≥1% as well as provisional low-risk LLy patients who do not obtain complete
response at the end of Induction.
Brief outline of treatment plan:
Patients will be assigned to treatment based on risk group: Low-Risk, Standard-Risk and
High-Risk and cell type (T or B cell).
Remission Induction initially consists of prednisone (28 days), vincristine (4 weekly doses),
daunorubicin (1 to 3 weekly doses), and pegaspargase (2 doses). The second part (given over 2
weeks and overlapping with the last week of the first part of induction) consists of
cyclophosphamide, cytarabine, and mercaptopurine combinations. Patients with B-ALL will be
randomized for administration of 2 doses of rituximab on Days 6 and 24 prior to the first and
second doses of pegaspargase to prevent sensitization to asparaginase and subsequent
asparaginase reaction and to improve anti-leukemia outcome. Dasatinib will be added for
patients with Ph+ and Ph-like ABL1-class fusions and bortezomib will be given to patients
with no targetable lesions and Day 15 minimal residual disease (MRD) >5%.
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
MRD level ≥5% or end of Remission Induction ≥1% as well as all patients with early T cell
precursor (ETP) ALL, ruxolitinib will be used. This includes, but is not limited to CRLF2,
JAK2, and EPOR rearrangements and sequence/structural changes in JAK1/2/3, TYK2, IL7R, and
SH2B3. Ruxolitinib will be added in LLy patients with activation of JAK-STAT signaling whose
responses do not qualify complete response at the end of Remission Induction. Activation of
JAK-STAT signaling is defined in ALL/LLy that contains genetic alterations associated with
JAK-STAT pathway. Dasatinib will continue for patients with ABL1-class fusions. Bortezomib
will be added for patients with no targetable lesions and Day 15 MRD >5% or Day 42 MRD >1%
and LLy patients without targetable lesions whose responses do not qualify complete response
at the end of Remission Induction.
Consolidation Therapy will consist of high dose methotrexate (HDMTX) (every other week for 4
doses); daily mercaptopurine and IT chemotherapy on the same dates of HDMTX. Standard and
high-risk patients will also receive pegaspargase. Dasatinib will continue for patients with
ABL1-class fusions. Ruxolitinib will continue for patients with activation of JAK-STAT
signaling and Day 15 MRD ≥5% or Day 42 MRD ≥1% (or for LLy patients who do not qualify
complete response at the end of Remission Induction) and all cases with ETP ALL.
Immunotherapy: CAR T-cell therapy will be considered for High-risk B-ALL and B-LLy patients.
Blinatumomab will be given to patients with Standard risk B-ALL and B-LLy with residual
disease at the end of induction and High Risk B-ALL and B-LLy patients who are not able to
receive CAR T-cell therapy.
Reintensification therapy will be offered to certain High Risk patients with persistent MRD
after Immunotherapy (B-ALL and B-LLy) or Early Intensification (T-ALL and T-LLy), or those
who cannot receive Immunotherapy.
Continuation Treatment will consist of 120 weeks of risk-directed therapy. Dasatinib will
continue in patients with ABL1-class fusion. Ruxolitinib will continue in patients with
activation of JAK-STAT signaling and Day 15 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 patients with leukemia cells in cerebrospinal fluid at diagnosis or MRD ≥0.01%
at the end of Induction will receive nelarabine (LLy patients will not receive nelarabine).
ALL 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/m^2 or 1
mg/m^2 of vincristine after Continuation Week 1. Patients with either a CEP72 rs904627 C/T or
C/C genotype (84% of patients) will be randomized to receive vincristine and dexamethasone
pulses through Week 49 of Continuation Treatment or through Week 101 of Continuation
Treatment.
Inclusion Criteria:
- Diagnosis of B- or T-ALL or LLy by immunophenotyping:
- LLy participants must have < 25% tumor cells in bone marrow and peripheral blood by
morphology and flow cytometry. If any of these show >25% blasts, patient will be
considered to have leukemia.
- Age 1-18 years (inclusive).
- No prior therapy, or limited prior therapy, including systemic glucocorticoids for one
week or less, one dose of vincristine, emergency radiation therapy (e.g., to the
mediastinum, head and neck, orbit, etc.) and one dose of intrathecal chemotherapy.
- Written, informed consent and assent following Institutional Review Board (IRB),
National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office of
Human Research Protections (OHRP) Guidelines.
Exclusion Criteria:
- Participants who are pregnant or lactating. Males or females of reproductive potential
must agree to use effective contraception for the duration of study participation.
- Inability or unwillingness of research participant or legal guardian/representative to
give written informed consent.
We found this trial at
1
site
262 Danny Thomas Pl
Memphis, Tennessee 38105
Memphis, Tennessee 38105
(901) 495-3300
Principal Investigator: Hiroto Inaba, MD, PhD
Phone: 866-278-5833
St. Jude Children's Research Hospital St. Jude is unlike any other pediatric treatment and research...
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