Clinical trial NCT03117751: Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Official title: Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Acute Lymphoblastic Leukemia
Acute Lymphoblastic Lymphoma
Keywords: Leukemia
Lymphoma
Pediatric
B-Cell
T-Cell
Lead sponsor: St. Jude Children's Research Hospital
Sponsor class: OTHER
Collaborators: name: Incyte Corporation
name: Amgen
name: Servier
First posted: 2017-04-18
Enrollment: 790
Sex: ALL
Minimum age (years): 1
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Event-free survival of ALL patients (EFS)
timeFrame: At 3.5 years after enrollment of the last participant
measure: Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation
timeFrame: At 6 months after the last randomized patient completes Continuation Treatment (Week 120).
measure: Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype
timeFrame: After the last randomized patient is followed for 1 year after Week 101 of Continuation therapy
Secondary outcomes:
measure: 5-year overall survival (OS) of ALL patients compared to historical controls
timeFrame: 3.5 years after enrollment of the last patient
measure: EFS of LLy patients
timeFrame: 3.5 years after enrollment of the last patient
measure: 5-year OS of LLy patients
timeFrame: 3.5 years after enrollment of the last patient
measure: The efficacy of blinatumomab in B-ALL patients
timeFrame: 3.5 years after enrollment of the last patient
measure: Comparison of MRD measurements between flow cytometry and sequencing
timeFrame: From Day 8 through Day 42 after remission induction (At 6 months after enrollment of the 40^t^h evaluable patient)
measure: Log hazard ratio of the association of low level of MRD and treatment outcome
timeFrame: 3.5 years after enrollment of the last patient
measure: Comparison of bone marrow and peripheral blood MRD
timeFrame: From Day 15 through Day 42 of remission induction and end of therapy (At 6 months after enrollment of the last evaluable patient)
measure: Isolated CNS relapse in CNS1b patients
timeFrame: 3.5 years after enrollment of the last patient
measure: Level of clonal diversity and rise of leukemic clones during treatment
timeFrame: From Day 1 through week 120 of continuation (at 6 months after the last enrolled patient completes Week 120)
measure: Number and type of germline or somatic genomic variants associated with drug resistance
timeFrame: 3.5 years after enrollment of the last participant
measure: Comparison of drug sensitivity of ALL cells between diagnosis and relapse in vitro and in vivo
timeFrame: 5 years after enrollment of the last participant
measure: Change in bone mineral density (BMD) in the tibia
timeFrame: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
measure: Change in markers of bone turnover
timeFrame: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)
Other outcomes:
measure: Log odds ratio of pharmacogenetic predictors of treatment outcome (host toxicity or in vivo efficacy)
timeFrame: 5 years after enrollment of the last participant
measure: Log odds ratio of pharmacokinetic predictors of treatment outcome (host toxicity or in vivo efficacy)
timeFrame: 5 years after enrollment of the last participant
measure: Log odds ratio of pharmacodynamic predictors of treatment outcome (host toxicity or in vivo efficacy)
timeFrame: 5 years after enrollment of the last participant
measure: Thiopurine metabolism
timeFrame: 3.5 years after enrollment of the last participant
measure: Number of participants experiencing specific therapy-related infection events
timeFrame: 1 year after completion of therapy for last enrolled patient (up to 3.5 years after enrollment)
measure: 5-year EFS of MPAL patients
timeFrame: 3.5 years after enrollment of the last patient
measure: 5-year OS of MPAL patients
timeFrame: 3.5 years after enrollment of the last patient
Locations:
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital San Diego
state: California
city: Peoria
country: United States
facility: Children's Hospital of Illinois at OSF-Saint Francis Medical Center (St. Jude Midwest Affiliate - Peoria)
state: Illinois
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Charlotte
country: United States
facility: St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital
state: North Carolina
city: Memphis
country: United States
facility: St. Jude Children's Research Hospital
state: Tennessee
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: Parkville
country: Australia
facility: The Royal Children's Hospital Melbourne
state: Victoria
Study officials:
affiliation: St. Jude Children's Research Hospital
name: Hiroto Inaba, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: