Ignite Creation Date:
2024-05-06 @ 9:56 AM
Last Modification Date:
2024-10-26 @ 12:22 PM
Study NCT ID:
NCT03117751
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-03-05
First Post:
2017-03-27
Brief Title:
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Sponsor:
St Jude Childrens Research Hospital
Organization:
St Jude Childrens Research Hospital
Study Overview
Official Title:
Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 eg activated tyrosine kinases or JAKSTAT 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 leukemialymphoma cells in cerebrospinal fluid at diagnosis or MRD 001 at the end of induction
To determine in a randomized study design whether the incidence andor 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 standardhigh-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 001 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 BCL2MYC 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 germlineremission 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
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 eg activated tyrosine kinases or JAKSTAT 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 leukemialymphoma cells in cerebrospinal fluid at diagnosis or MRD 001 at the end of induction
To determine in a randomized study design whether the incidence andor 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 standardhigh-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 001 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 BCL2MYC 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 germlineremission 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 countlymphoma 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 ALLLLy 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 ALLLLy 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 TM MPAL ruxolitinib will be used This includes but is not limited to CRLF2 JAK2 and EPOR rearrangements and sequencestructural changes in JAK12 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 TM 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 TCF3HLF or BCL2MYC or with Down syndrome regardless of MRD level andor 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 leukemialymphoma cells in cerebrospinal fluid at diagnosis or MRD 001 at the end of Induction will receive nelarabine ALLLLy Patients with the CEP72 rs904627TT genotype 16 of patients will be randomized unblinded design except those who evaluate neuropathies to receive either 15 mgm2 or 1 mgm2 of vincristine after Continuation Week 1 Patients in low- risk will complete vincristine in Week 49 and those in standardhigh-risk will complete in Week 101 Standardhigh-risk patients with either a CEP72 rs904627 CT or CC 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
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 ALLLLy 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 ALLLLy 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 TM MPAL ruxolitinib will be used This includes but is not limited to CRLF2 JAK2 and EPOR rearrangements and sequencestructural changes in JAK12 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 TM 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 TCF3HLF or BCL2MYC or with Down syndrome regardless of MRD level andor 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 leukemialymphoma cells in cerebrospinal fluid at diagnosis or MRD 001 at the end of Induction will receive nelarabine ALLLLy Patients with the CEP72 rs904627TT genotype 16 of patients will be randomized unblinded design except those who evaluate neuropathies to receive either 15 mgm2 or 1 mgm2 of vincristine after Continuation Week 1 Patients in low- risk will complete vincristine in Week 49 and those in standardhigh-risk will complete in Week 101 Standardhigh-risk patients with either a CEP72 rs904627 CT or CC 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| NCI-2017-00582 | REGISTRY | NCI Clinical Trial Registration Program | None |