Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
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| ClinicalTrials.gov Identifier: NCT03117751 |
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Recruitment Status :
Recruiting
First Posted : April 18, 2017
Last Update Posted : February 15, 2023
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Sponsor:
St. Jude Children's Research Hospital
Collaborators:
Incyte Corporation
Amgen
Servier
Information provided by (Responsible Party):
St. Jude Children's Research Hospital
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Acute Lymphoblastic Leukemia Acute Lymphoblastic Lymphoma | 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 | Phase 2 Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 1000 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Single (Outcomes Assessor) |
| Masking Description: | Only certain outcome measures as indicated will be blinded to the outcomes assessor. |
| Primary Purpose: | Treatment |
| Official Title: | Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma |
| Actual Study Start Date : | March 29, 2017 |
| Estimated Primary Completion Date : | September 30, 2026 |
| Estimated Study Completion Date : | March 31, 2028 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Experimental: B-ALL and B-LLy, Low-risk
Patients with low-risk B ALL and LLy will have Induction (6 weeks), Consolidation (8 weeks), and Continuation (120 weeks). During Remission Induction therapy, prednisone dose is 40mg/m^2 and 1-2 doses of daunorubicin (based on day 8 peripheral blood MRD in patients with ETV6-RUNX1 or hyperdiploid) are given. Dasatinib is given for patients with ABL-class fusion. Blinatumomab will be given to patients with certain genetic subtypes and those with Down syndrome. Interventions: Prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, thioguanine, methotrexate, dexamethasone, blinatumomab. |
Drug: Prednisone
Given orally (PO).
Other Names:
Drug: Vincristine Given intravenously (IV).
Other Names:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Pegaspargase Given IV or intramuscularly (IM) .
Other Names:
Drug: Erwinase® To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM).
Other Names:
Drug: Cyclophosphamide Given IV.
Other Name: Cytoxan® Drug: Cytarabine Given IV or by subcutaneous injection (SQ).
Other Names:
Drug: Mercaptopurine Given PO.
Other Names:
Drug: Dasatinib Given PO.
Other Name: Sprycel® Drug: Methotrexate Given IV.
Other Names:
Drug: Blinatumomab Given IV.
Other Name: Blincyto® Drug: Dexamethasone Given PO.
Other Names:
Drug: Thioguanine Participants with mercaptopurine-related pancreatitis. Given PO.
Other Names:
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM).
Other Names:
Drug: Calaspargase Pegol To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.
Other Name: ASPARLAS |
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Experimental: B-ALL and B-LLy, Standard-risk
Induction (6wks), Early Intensification (4wks), Consolidation (8wks) and Continuation (120 wks). Remission Induction: Prednisone dose is 40mg/m^2 and 2 doses daunorubicin are given. Dasatinib: given for patients with Ph+ and those with ABL-class fusion. Ruxolitinib: given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD ≥5%, LLy patients who don't qualify for complete response at end of Remission Induction and all patients with ETP and T/M MPAL. Bortezomib is given to patients without targetable lesions and Day 15 or Day 22 MRD >5%. Blinatumomab will be given to patients with residual disease at the end of induction (≥0.01% and <1%), certain genetic subtypes and Down syndrome. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, thioguanine, methotrexate, dexamethasone, doxorubicin |
Drug: Prednisone
Given orally (PO).
Other Names:
Drug: Vincristine Given intravenously (IV).
Other Names:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Pegaspargase Given IV or intramuscularly (IM) .
Other Names:
Drug: Erwinase® To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM).
Other Names:
Drug: Cyclophosphamide Given IV.
Other Name: Cytoxan® Drug: Cytarabine Given IV or by subcutaneous injection (SQ).
Other Names:
Drug: Mercaptopurine Given PO.
Other Names:
Drug: Dasatinib Given PO.
Other Name: Sprycel® Drug: Methotrexate Given IV.
Other Names:
Drug: Blinatumomab Given IV.
Other Name: Blincyto® Drug: Ruxolitinib Given PO.
Other Name: Jakafi® Drug: Bortezomib Given IV or subcutaneously (SQ).
Other Name: Velcade® Drug: Dexamethasone Given PO.
Other Names:
Drug: Doxorubicin Given IV.
Other Name: Adriamycin® Drug: Thioguanine Participants with mercaptopurine-related pancreatitis. Given PO.
Other Names:
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM).
Other Names:
Drug: Calaspargase Pegol To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.
Other Name: ASPARLAS |
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Experimental: B-ALL and B-LLy, High-risk
Induction (6 weeks), Early Intensification (4 weeks), Consolidation (8 weeks), and Immunotherapy (chimeric antigen receptor [CAR] T cells). Patients who do not respond to Immunotherapy will receive Reintensification therapy. During Remission Induction therapy, prednisone dose is 40mg/m^2 and 2 doses of daunorubicin are given. Dasatinib, ruxolitinib, and bortezomib are given as done for patients with standard-risk B-ALL but are discontinued in Immunotherapy and Reintensification therapy. Blinatumomab will be given to patients who are not able to receive CAR T cell therapy and patients with certain genetic subtypes and those with Down syndrome. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, blinatumomab, etoposide, dexamethasone, clofarabine, thioguanine, methotrexate. |
Drug: Prednisone
Given orally (PO).
Other Names:
Drug: Vincristine Given intravenously (IV).
Other Names:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Pegaspargase Given IV or intramuscularly (IM) .
Other Names:
Drug: Erwinase® To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM).
Other Names:
Drug: Cyclophosphamide Given IV.
Other Name: Cytoxan® Drug: Cytarabine Given IV or by subcutaneous injection (SQ).
Other Names:
Drug: Mercaptopurine Given PO.
Other Names:
Drug: Dasatinib Given PO.
Other Name: Sprycel® Drug: Methotrexate Given IV.
Other Names:
Drug: Blinatumomab Given IV.
Other Name: Blincyto® Drug: Ruxolitinib Given PO.
Other Name: Jakafi® Drug: Bortezomib Given IV or subcutaneously (SQ).
Other Name: Velcade® Drug: Dexamethasone Given PO.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Drug: Clofarabine Given IV.
Other Name: Clolar® Drug: Thioguanine Participants with mercaptopurine-related pancreatitis. Given PO.
Other Names:
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM).
Other Names:
Drug: Calaspargase Pegol To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.
Other Name: ASPARLAS |
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Experimental: T-ALL and T-LLy, Standard-risk
Induction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Continuation (120 wks). During Remission Induction therapy, prednisone dose is 60mg/m^2 and 3 doses daunorubicin are given. Dasatinib is given for patients with Ph+ and those with ABL-class fusion. Ruxolitinib is given for patients with activation of JAK-STAT signaling; ALL patients with Day 15 or Day 22 MRD ≥5% and all patients with ETP and T/M MPAL and LLy patients who don't qualify for complete response at end of Remission Induction. Bortezomib is given to patients without targetable lesions and Day 15 or Day 22 MRD ≥ 5%. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, dexamethasone, doxorubicin, nelarabine, thioguanine. |
Drug: Prednisone
Given orally (PO).
Other Names:
Drug: Vincristine Given intravenously (IV).
Other Names:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Pegaspargase Given IV or intramuscularly (IM) .
Other Names:
Drug: Erwinase® To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM).
Other Names:
Drug: Cyclophosphamide Given IV.
Other Name: Cytoxan® Drug: Cytarabine Given IV or by subcutaneous injection (SQ).
Other Names:
Drug: Mercaptopurine Given PO.
Other Names:
Drug: Dasatinib Given PO.
Other Name: Sprycel® Drug: Methotrexate Given IV.
Other Names:
Drug: Ruxolitinib Given PO.
Other Name: Jakafi® Drug: Bortezomib Given IV or subcutaneously (SQ).
Other Name: Velcade® Drug: Dexamethasone Given PO.
Other Names:
Drug: Doxorubicin Given IV.
Other Name: Adriamycin® Drug: Nelarabine Given IV.
Other Names:
Drug: Thioguanine Participants with mercaptopurine-related pancreatitis. Given PO.
Other Names:
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM).
Other Names:
Drug: Calaspargase Pegol To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.
Other Name: ASPARLAS |
|
Experimental: T-ALL and T-LLy, High-risk
Induction (6 wks), Early Intensification (4 wks), Consolidation (8 wks), and Reintensification. During Remission Induction therapy, prednisone dose is 60mg/m^2 and 3 doses daunorubicin are given. Dasatinib, ruxolitinib, and bortezomib given as done for patients with standard-risk T-ALL but are discontinued in Reintensification therapy. Interventions: prednisone, vincristine, daunorubicin, pegaspargase (or Erwinase®, Rylaze™ or Calaspargase pegol), cyclophosphamide, cytarabine, mercaptopurine, dasatinib, bortezomib, ruxolitinib, methotrexate, etoposide, dexamethasone, clofarabine, vorinostat, idarubicin, nelarabine, thioguanine.. |
Drug: Prednisone
Given orally (PO).
Other Names:
Drug: Vincristine Given intravenously (IV).
Other Names:
Drug: Daunorubicin Given IV.
Other Names:
Drug: Pegaspargase Given IV or intramuscularly (IM) .
Other Names:
Drug: Erwinase® To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV or intramuscularly (IM).
Other Names:
Drug: Cyclophosphamide Given IV.
Other Name: Cytoxan® Drug: Cytarabine Given IV or by subcutaneous injection (SQ).
Other Names:
Drug: Mercaptopurine Given PO.
Other Names:
Drug: Dasatinib Given PO.
Other Name: Sprycel® Drug: Methotrexate Given IV.
Other Names:
Drug: Ruxolitinib Given PO.
Other Name: Jakafi® Drug: Bortezomib Given IV or subcutaneously (SQ).
Other Name: Velcade® Drug: Dexamethasone Given PO.
Other Names:
Drug: Etoposide Given IV.
Other Names:
Drug: Clofarabine Given IV.
Other Name: Clolar® Drug: Vorinostat Given PO.
Other Names:
Drug: Idarubicin Given IV.
Other Names:
Drug: Nelarabine Given IV.
Other Names:
Drug: Thioguanine Participants with mercaptopurine-related pancreatitis. Given PO.
Other Names:
Drug: Asparaginase Erwinia chrysanthemi (recombinant)-rywn To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given intramuscularly (IM).
Other Names:
Drug: Calaspargase Pegol To be used in case of hypersensitivity or intolerance to Pegaspargase or if Pegaspargase is not available. Given IV.
Other Name: ASPARLAS |
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Experimental: ALL, CEP72 T/T, Vincristine
Patients with the CEP72 rs904627T/T genotype (~16% of patients) will be randomized (unblinded design, only those who evaluate neuropathy are blinded) to receive either 1.5 mg/m^2 or 1 mg/m^2 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. Intervention: vincristine. |
Drug: Vincristine
Given intravenously (IV).
Other Names:
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Experimental: ALL, CEP72 C/T or C/C, Vincristine
Patients with either a CEP72 rs904627 C/T or C/C genotype (~84% of patients) will be randomized (unblinded design, only those who evaluate neuropathy are blinded) to receive vincristine (2 mg/m^2 per dose except during Reinduction I and Reinduction II when 3 weekly doses of 1.5 mg/m^2 will be given) and dexamethasone pulses through Week 49 of Continuation Treatment or through Week 101 of Continuation Treatment. Patients at low-risk will complete vincristine in Week 49. Interventions: vincristine, dexamethasone, methotrexate, mercaptopurine. |
Drug: Vincristine
Given intravenously (IV).
Other Names:
Drug: Mercaptopurine Given PO.
Other Names:
Drug: Methotrexate Given IV.
Other Names:
Drug: Dexamethasone Given PO.
Other Names:
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Primary Outcome Measures :
- Event-free survival of ALL patients (EFS) [ Time Frame: At 3.5 years after enrollment of the last participant ]5-year EFS: Kaplan-Meier estimates of EFS curve of ALL patients will be computed and compared historically with those of the St. Jude Children's Research Hospital's (SJCRH) TOTXVI study (NCT00549848). All eligible patients entered on the current TOT17 study will be included in these comparisons. Comparisons by log-rank tests will be made both un-stratified and stratified by risk groups.
- Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation [ Time Frame: At 6 months after the last randomized patient completes Continuation Treatment (Week 120). ]This will be a single-blind, stratified block randomized experiment. Although the investigators who evaluate neuropathy and neuropathic pain and the patients are blinded for treatment assignment, treating clinicians and pharmacy staff are not. Patients will be randomized at a 1:1 ratio into two treatment groups: 1.5 mg/m^2 vs. 1 mg/m^2 vincristine (VCR) dose. Randomization will be stratified by two factors known to significantly affect neuropathy during the Continuation phase, namely, Grade 2 or higher neuropathy prior to Continuation (none, 1 episode, 2 or more episodes) and race (black, others). The proportion of patients who develop two or more episodes of Grade 2 or higher neuropathy during Continuation Treatment will be compared between the two VCR dose groups, using a Z-test for two sample proportions.
- Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype [ Time Frame: After the last randomized patient is followed for 1 year after Week 101 of Continuation therapy ]This will be a single blind stratified block randomized experiment. The investigators who evaluate neuropathy and neuropathic pain and the patients are blinded for treatment assignment. Treating clinicians and pharmacy staff will not be blinded. Standard/high-risk patients will be randomized at a 1:1 ratio into two treatment groups at Week 49 of Continuation therapy: to vincristine + dexamethasone (VCR+DEX) pulses or to 6-mercaptopurine + methotrexate (6MP+MTX). The primary analysis will compare the cumulative incidence of the first episode of Grade 2 or higher neuropathy or neuropathic pain (the end point) by stratified Gray's test. Adverse events other than the endpoint rendering a patient drop out after Continuation Week 49 are regarded as competing events.
Secondary Outcome Measures :
- 5-year overall survival (OS) of ALL patients compared to historical controls [ Time Frame: 3.5 years after enrollment of the last patient ]Kaplan-Meier estimates of OS curve of ALL patients will be computed and compared historically with those of the St. Jude Children's Research Hospital's (SJCRH) TOTXVI study (NCT00549848). All eligible patients entered on the current TOT17 study will be included in these comparisons. Comparisons by log-rank tests will be made both un-stratified and stratified by risk groups.
- EFS of LLy patients [ Time Frame: 3.5 years after enrollment of the last patient ]5-year EFS: Kaplan-Meier estimates of EFS curve in patients with LLy will be computed.
- 5-year OS of LLy patients [ Time Frame: 3.5 years after enrollment of the last patient ]Kaplan-Meier estimates of OS curve in patients with LLy will be computed.
- The efficacy of blinatumomab in B-ALL patients [ Time Frame: 3.5 years after enrollment of the last patient ]Comparison with historical control by log-rank tests will be performed.
- Comparison of MRD measurements between flow cytometry and sequencing [ Time Frame: From Day 8 through Day 42 after remission induction (At 6 months after enrollment of the 40^t^h evaluable patient) ]For this comparison, 40 patients will be accrued for Day 8, Day 15 and Day 42 MRD, and primarily assess the correlation and concordance between the two methods at these time points if sufficient cells are available, and secondarily analyze for Day 22 and MRD levels obtained after remission induction.
- Log hazard ratio of the association of low level of MRD and treatment outcome [ Time Frame: 3.5 years after enrollment of the last patient ]The investigators will analyze the association of next-generation sequencing-determined MRD level (as a continuous variable) with the risk of relapses in bone marrow and possibly other sites (bone marrow or combined relapses). Fine-Gray regression model will be applied to estimate the hazard ratio of relapse as a function of the increase in MRD level.
- Comparison of bone marrow and peripheral blood MRD [ Time Frame: From Day 15 through Day 42 of remission induction and end of therapy (At 6 months after enrollment of the last evaluable patient) ]Parametric (linear) or non-parametric (if necessary) regression models will be fitted to analyze the relationship between the MRD levels in peripheral blood by sequencing methods and MRD levels in bone marrow (by sequencing or flow cytometry). The peripheral blood MRD level corresponding to 0.01% in bone marrow is then obtained by solving the (regression) equation for the peripheral blood MRD level.
- Isolated CNS relapse in CNS1b patients [ Time Frame: 3.5 years after enrollment of the last patient ]Traditional CNS2 patients with negative TdT and negative next-generation sequencing results will receive CNS1 therapy on TOT17. Risk of isolated CNS relapse in this subset of patients will be compared to that in the CNS2 patients treated on TOTXV and TOTXVI, using stratified (by protocol) Gray's test.
- Level of clonal diversity and rise of leukemic clones during treatment [ Time Frame: From Day 1 through week 120 of continuation (at 6 months after the last enrolled patient completes Week 120) ]In this study the investigators will use single-cell, cell-free, and bulk population sequencing to monitor somatic mutations in peripheral blood as patients undergo treatment, which will be correlated with clonal diversity at diagnosis, in vitro chemotherapy resistance, MRD, and patient outcome.
- Number and type of germline or somatic genomic variants associated with drug resistance [ Time Frame: 3.5 years after enrollment of the last participant ]The number and type of 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 will be given.
- Comparison of drug sensitivity of ALL cells between diagnosis and relapse in vitro and in vivo [ Time Frame: 5 years after enrollment of the last participant ]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
- Change in bone mineral density (BMD) in the tibia [ Time Frame: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation) ]The primary outcome is BMD in the tibia, measured at baseline and the end of intervention. The changes from baseline to the end of the intervention between the treatment and control groups will be compared.
- Change in markers of bone turnover [ Time Frame: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation) ]Linear mixed models or other methods will be used to evaluate this outcome.
Other Outcome Measures:
- Log odds ratio of pharmacogenetic predictors of treatment outcome (host toxicity or in vivo efficacy) [ Time Frame: 5 years after enrollment of the last participant ]The log odds ratio of pharmacogenetics predictors of treatment outcome will be given.
- Log odds ratio of pharmacokinetic predictors of treatment outcome (host toxicity or in vivo efficacy) [ Time Frame: 5 years after enrollment of the last participant ]The log odds ratio of pharmacokinetic predictors of treatment outcome will be given.
- Log odds ratio of pharmacodynamic predictors of treatment outcome (host toxicity or in vivo efficacy) [ Time Frame: 5 years after enrollment of the last participant ]The log odds ratio of pharmacodynamic predictors of treatment outcome will be given.
- Thiopurine metabolism [ Time Frame: 3.5 years after enrollment of the last participant ]A detailed assessment of thiopurine metabolism will be done and correlated with 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome.
- Number of participants experiencing specific therapy-related infection events [ Time Frame: 1 year after completion of therapy for last enrolled patient (up to 3.5 years after enrollment) ]All enrolled participants will be eligible for this component. Descriptive statistics, such as frequency and proportion, will be summarized for breakthrough infections, antibiotic-resistant infections, febrile neutropenia episodes and adverse events. Cumulative incidence of breakthrough infection, febrile neutropenia and adverse events will also be explored, with competing risks and/or recurrent event appropriately adjusted.
- 5-year EFS of MPAL patients [ Time Frame: 3.5 years after enrollment of the last patient ]Kaplan-Meier estimates of EFS curve in patients with MPAL will be computed.
- 5-year OS of MPAL patients [ Time Frame: 3.5 years after enrollment of the last patient ]Kaplan-Meier estimates of OS curve in patients with MPAL will be computed.
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 1 Year to 18 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03117751
Contacts
| Contact: Hiroto Inaba, MD, PhD | 866-278-5833 | referralinfo@stjude.org |
Locations
| United States, California | |
| Lucile Packard Children's Hospital Stanford University | Recruiting |
| Palo Alto, California, United States, 94305 | |
| Contact: Norman J. Lacayo, MD 650-723-5535 mailto:lacayon@stanford.edu | |
| Principal Investigator: Norman J. Lacayo, MD | |
| Rady Children's Hospital San Diego | Recruiting |
| San Diego, California, United States, 92123 | |
| Contact: Deborah E. Schiff, MD 858-966-5811 dschiff@rchsd.org | |
| Principal Investigator: Deborah E. Schiff, MD | |
| United States, Illinois | |
| Children's Hospital of Illinois at OSF-Saint Francis Medical Center (St. Jude Midwest Affiliate - Peoria) | Recruiting |
| Peoria, Illinois, United States, 61637 | |
| Contact: Mary E. Ross, MD 309-624-4945 meross@uic.edu | |
| Principal Investigator: Mary E. Ross, MD | |
| United States, Michigan | |
| Children's Hospital of Michigan | Active, not recruiting |
| Detroit, Michigan, United States, 48201 | |
| United States, North Carolina | |
| St. Jude Affiliate Clinic - Novant Health Hemby Children's Hospital | Recruiting |
| Charlotte, North Carolina, United States, 28204 | |
| Contact: Jessica Bell, MD 704-384-1900 jbell@novanthealth.org | |
| Principal Investigator: Jessica Bell, MD | |
| United States, Oklahoma | |
| The Children's Hospital at Saint Francis | Recruiting |
| Tulsa, Oklahoma, United States, 74136 | |
| Contact: Gregory B. Kirkpatrick, MD 918-502-6720 gbkirkpatrick@saintfrancis.com | |
| Principal Investigator: Gregory B. Kirkpatrick, MD | |
| United States, Tennessee | |
| St. Jude Children's Research Hospital | Recruiting |
| Memphis, Tennessee, United States, 38105 | |
| Contact: Hiroto Inaba, MD, PhD 866-278-5833 referralinfo@stjude.org | |
| Principal Investigator: Hiroto Inaba, MD, PhD | |
| United States, Texas | |
| Cook Children's Medical Center | Recruiting |
| Fort Worth, Texas, United States, 76104 | |
| Contact: Kenneth M. Heym, MD 682-885-4007 kenneth.heym@cookchildrens.org | |
| Principal Investigator: Kenneth M. Heym, MD | |
| Australia, Victoria | |
| The Royal Children's Hospital Melbourne | Recruiting |
| Parkville, Victoria, Australia, 3052 | |
| Contact: Seong L Khaw, MD FRACP PhD + 61-393454893 SeongLin.Khaw@rch.org.au | |
| Principal Investigator: Seong L Khaw, MD FRACP PhD | |
Sponsors and Collaborators
St. Jude Children's Research Hospital
Incyte Corporation
Amgen
Servier
Investigators
| Principal Investigator: | Hiroto Inaba, MD, PhD | St. Jude Children's Research Hospital |
Additional Information:
| Responsible Party: | St. Jude Children's Research Hospital |
| ClinicalTrials.gov Identifier: | NCT03117751 |
| Other Study ID Numbers: |
TOT17 NCI-2017-00582 ( Registry Identifier: NCI Clinical Trial Registration Program ) |
| First Posted: | April 18, 2017 Key Record Dates |
| Last Update Posted: | February 15, 2023 |
| Last Verified: | February 2023 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by St. Jude Children's Research Hospital:
|
Leukemia Lymphoma Pediatric B-Cell T-Cell |
Additional relevant MeSH terms:
|
Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases Cytarabine Dexamethasone Prednisone Prednisolone Cyclophosphamide |
Doxorubicin Methotrexate Etoposide Etoposide phosphate Vincristine Bortezomib Daunorubicin Asparaginase Dasatinib Mercaptopurine Vorinostat Idarubicin Clofarabine Pegaspargase Thioguanine |