Official Title
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Brief Title
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Protocol ID
NCT03117751
Lead Sponsor
St. Jude Children's Research Hospital
Brief Summary
The overarching objective of this study is to use novel precision medicine strategies
based on inherited and 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 Period
-
Enrollment Count
790 participants
Eligibility Criteria
Inclusion Criteria:
- Diagnosis of B- or T-ALL or LLy by immunophenotyping:
- LLy participants must have < 25% tumor cells in bone marrow and peripheral blood by
morphology and flow cytometry. If any of these show ≥25% blasts, patient will be
considered to have leukemia. 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.
Filters
Acute Lymphoblastic Leukemia
Acute Lymphoblastic Lymphoma
PHASE2
PHASE3
ACTIVE_NOT_RECRUITING
CHILD
ADULT