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Report for SNP rs904627
Developed by Shray Alag, 2020.
SNP Clinical Trial Gene
There is one clinical trial.
Clinical Trials
1 Total Therapy XVII for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia and Lymphoma
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-AL or B-LLy, and the proteasome inhibitor bortezomib for those lacking targetable lesions. - To improve overall treatment outcome of T-ALL and 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 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 LLy. - 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 DNA and 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 o 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 and to evaluate the benefits of a computer-based cognitive intervention. - To evaluate the impact of low-magnitude high frequency mechanical stimulation on bone mineral density and markers of bone turnover. Exploratory Objectives: - To identify pharmacogenetic, pharmacokinetic and pharmacodynamic predictors of treatment outcome. - To perform a detailed assessment of thiopurine metabolism and 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome. - To establish xenografts of representative subtypes of ALL. - To prospectively determine the risk and epidemiology of breakthrough infection or febrile neutropenia and adverse effects of antibiotics. - To use cell phenotyping and genomic approaches to characterize the non-tumor microenvironment and correlate with responses to conventional and immunotherapeutic approaches.
NCT03117751 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 MeSH:Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Leukemia, Lymphoid
HPO:Leukemia Lymphoid leukemia Lymphoma
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 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.
Primary Outcomes
Description: 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.
Measure: Event-free survival of ALL patients (EFS) Time: At 3.5 years after enrollment of the last participantDescription: 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.
Measure: Proportion of patients with CEP72TT genotype who develop two or more episodes of Grade 2 or higher neuropathy during Continuation Time: At 6 months after the last randomized patient completes Continuation Treatment (Week 120).Description: 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. 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.
Measure: Cumulative incidence of Grade 2 or higher neuropathy in patients with CEP72 CC or CT genotype Time: After the last randomized patient is followed for 1 year after Week 101 of Continuation therapySecondary Outcomes
Description: 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.
Measure: 5-year overall survival (OS) of ALL patients compared to historical controls Time: 3.5 years after enrollment of the last patientDescription: 5-year EFS: Kaplan-Meier estimates of EFS curve in patients with LLy will be computed.
Measure: EFS of LLy patients Time: 3.5 years after enrollment of the last patientDescription: Kaplan-Meier estimates of OS curve in patients with LLy will be computed.
Measure: 5-year OS of LLy patients Time: 3.5 years after enrollment of the last patientDescription: 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.
Measure: Comparison of MRD measurements between flow cytometry and sequencing Time: From Day 8 through Day 42 after remission induction (At 6 months after enrollment of the 40^t^h evaluable patient)Description: 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.
Measure: Log hazard ratio of the association of low level of MRD and treatment outcome Time: 3.5 years after enrollment of the last patientDescription: 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.
Measure: Comparison of bone marrow and peripheral blood MRD Time: From Day 15 through Day 42 of remission induction and end of therapy (At 6 months after enrollment of the last evaluable patient)Description: 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.
Measure: Isolated CNS relapse in CNS1b patients Time: 3.5 years after enrollment of the last patientDescription: 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.
Measure: Level of clonal diversity and rise of leukemic clones during treatment Time: From Day 1 through week 120 of continuation (at 6 months after the last enrolled patient completes Week 120)Description: 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.
Measure: Number and type of germline or somatic genomic variants associated with drug resistance Time: 3.5 years after enrollment of the last participantDescription: 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
Measure: Comparison of drug sensitivity of ALL cells between diagnosis and relapse in vitro and in vivo Time: 5 years after enrollment of the last participantDescription: A single-blind (psychological examiner), randomized, controlled, group sequential design will be used to evaluate the impact of computer-based cognitive intervention (Cogmed) administered during therapy, relative to the end of therapy, on neurocognitive outcomes. Patients will be randomized according to the procedure outlined in the protocol. Randomization will be stratified based on age (4-8; >9 years old) and treatment risk arm (low; standard/high) in order to roughly balance the groups on these factors. Patients will be randomized according to a 2:2:1 allocation (2 - On Therapy, 2 - End of Therapy, 1 - Control). The investigators will use a block-randomization scheme proposed by Zelen with a block size of 4. The change from pre to post intervention will be given.
Measure: Magnitude change in spatial span backward standard score (SSB) Time: From continuation week 73 to 3-4 months after end of therapy (continuation week 120)Description: 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 using a two-sample t-test, or Wilcoxon rank sum test if normality does not hold. Furthermore, the linear mixed model will be used to analyze the time effect, group effect and their interaction, adjusting for the factors used for stratification (gender, pubertal status, and risk group) and possible confounders (i.e., hormonal function and vitamin D metabolism, physical activity, etc.).
Measure: Change in bone mineral density (BMD) in the tibia Time: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)Description: Linear mixed models will be used to evaluate this outcome. If normality does not hold, the investigators will consider transforming the outcome measures for analysis. A linear mixed effects approach will also be used to allow for potential random missingness to make use of all available data in analysis
Measure: Change in markers of bone turnover Time: From baseline to week 49 Continuation treatment (up to 6 months after last patient completes week 49 Continuation)Other Outcomes
Description: The log odds ratio of pharmacogenetics predictors of treatment outcome will be given.
Measure: Log odds ratio of pharmacogenetic predictors of treatment outcome (host toxicity or in vivo efficacy) Time: 5 years after enrollment of the last participantDescription: The log odds ratio of pharmacokinetic predictors of treatment outcome will be given.
Measure: Log odds ratio of pharmacokinetic predictors of treatment outcome (host toxicity or in vivo efficacy) Time: 5 years after enrollment of the last participantDescription: The log odds ratio of pharmacodynamic predictors of treatment outcome will be given.
Measure: Log odds ratio of pharmacodynamic predictors of treatment outcome (host toxicity or in vivo efficacy) Time: 5 years after enrollment of the last participantDescription: A detailed assessment of thiopurine metabolism will be done and correlated with 6-mercaptopurine (6MP) tolerance, toxicity, and treatment outcome.
Measure: Thiopurine metabolism Time: 3.5 years after enrollment of the last participantDescription: 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.
Measure: Number of participants experiencing specific therapy-related infection events Time: 1 year after completion of therapy for last enrolled patient (up to 3.5 years after enrollment)