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Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Recruiting
I'm InterestedTrial ID: NCT03117751
Purpose
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.
Official Title
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Stanford Investigator(s)
Eligibility
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.
Intervention(s):
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: Etoposide
drug: Clofarabine
drug: Vorinostat
drug: Idarubicin
drug: Nelarabine
drug: Thioguanine
drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn
drug: Calaspargase Pegol
Recruiting
I'm InterestedContact Information
Stanford University
School of Medicine
300 Pasteur Drive
Stanford,
CA
94305
Norman J. Lacayo, MD
650-723-5535