Ignite Creation Date:
2024-05-06 @ 6:52 PM
Last Modification Date:
2024-10-26 @ 2:56 PM
Study NCT ID:
NCT05811910
Status:
RECRUITING
Last Update Posted:
2023-04-13
First Post:
2023-03-31
Brief Title:
Genetic Polymorphisms in Drug Induced Neuropathy in Children With ALL
Sponsor:
IRCCS Burlo Garofolo
Organization:
IRCCS Burlo Garofolo
Study Overview
Official Title:
Role of Genetic Polymorphisms in Drug Induced Neuropathy in Children With Acute Lymphoblastic Leukemia
Status:
RECRUITING
Status Verified Date:
2023-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Therapeutic success in childhood ALL reaches an outstanding success that currently relies upon risk stratification of patients with appropriate modulation of chemotherapy intensity based on underlying blasts biological and molecular characteristics and depth of initial treatment response ALL polychemotherapeutic approaches share similar therapeutic scheme with more intensive and toxic earlier phases about 6 months followed by a prolonged immunosuppressive regimen for maintenance about 18 months Protocols comprise glucocorticoids antimetabolites asparaginase alkylating agents antimitotic drugs antibiotics and in case of Philadelphia positive ALL anti-tyrosine kinase inhibitors combined together at different dosages and timing according to the patients class of risk ALL chemotherapeutic agents can damage nearly all organs Some adverse reactions are extensions of the drugs desired pharmacological effects on bone marrow and affect almost all children Other adverse effects occur unpredictably in a smaller fraction of patients who for unknown reasons are more susceptible Concerns about chemotherapy-related toxicities generated a significant need of finding predictive markers for the a priori identification of at-risk patients Pharmacogenomics markers can be useful tools in clinics for tailoring therapy intensity on patients genetic profile and in basic research for better understanding mechanistic and regulatory pathways of the biological functions associated with ALL treatment toxicities Several genome wide association studies explored the landscape of ALL treatment-associated toxicities discovering the contribution of important variants Among these TPMT single nucleotide polymorphisms SNPs have a well-recognized role in thiopurine-induced myelotoxicity SNP rs924607 CT in the promoter region of the gene encoding for the centrosomal protein 72 CEP72 was associated with increased risk and severity of vincristine-related peripheral neuropathy The aim of this study is to perform a GWAS in ALL children to provide insight into genetic loci affecting the occurrence of severe grade III-V vincristine-related peripheral neuropathy during induction therapy in the AIEOP protocols
Detailed Description:
Acute lymphoblastic leukemia ALL is the most common haematological cancer in children Therapeutic success in childhood ALL reaches an outstanding success 5-years survival of about 85-90 that currently relies upon risk stratification of patients with appropriate modulation of chemotherapy intensity based on underlying blasts biological and molecular characteristics and depth of initial treatment response Although with some difference worldwide ALL polychemotherapeutic approaches share the same therapeutic scheme with more intensive and toxic earlier phases to induce and consolidate remission about 6 months followed by a prolonged immunosuppressive regimen for maintenance about 18 months In particular protocols comprise mostly glucocorticoids antimetabolites asparaginase alkylating agents antimitotic drugs antibiotics and in case of Philadelphia positive ALL anti-tyrosine kinase inhibitors combined together at different dosages and timing according to the patients class of risk ALL chemotherapeutic agents can damage nearly all organs Some adverse reactions such as the hematological toxicities and their consequences such as infections are extensions of the drugs desired pharmacological effects on bone marrow and affect almost all children Other adverse effects occur unpredictably in a smaller fraction of patients who for unknown reasons are more susceptible High dose antimetabolites and DNA damaging drugs may cause a direct injury in healthy proliferating tissues resulting in mucositis about 40 of ALL patients Corticosteroids may cause bone toxicities such as osteoporosis 5-70 endocrinopathies such as insulin resistance hyperglycemia and prediabetes 10-20 and central nervous system toxicities 10-15 Vincristine treatment is associated to peripheral motor or sensory neuropathy development 5-158 Methotrexate crystals can precipitate in kidneys inducing nephrotoxicity about 39 Asparaginase can lead to hypersensitivity reactions 30-70 and pancreatitis 2-18 Additional acute toxicities such as venous thromboembolism are rarer but still might contribute to the incidence of treatment related deaths Concerns about chemotherapy-related toxicities have generated a significant need of finding predictive markers for the a priori identification of at-risk patients In particular pharmacogenomics markers can be useful tools both in clinics for tailoring therapy intensity on patients genetic profile and in basic research for better understanding the mechanistic and regulatory pathways of the biological functions associated with ALL treatment toxicities Several genome wide association studies GWAS -performed mainly by USCanadian Childrens Oncology Group COG ALL protocols- had explored and investigated the landscape of ALL treatment-associated toxicities discovering the contribution of important variants Among these TPMT single nucleotide polymorphisms SNPs have a well-recognized role in thiopurine-induced myelotoxicity ad genotype-based guidelines are already available SNP rs924607 CT in the promoter region of the gene encoding for the centrosomal protein 72 CEP72 was found to be associated with increased risk and severity of vincristine-related peripheral neuropathy To authors knowledge this is the only variant whose clinical validation is currently ongoing in a perspective clinical trial Saint Jude Children Research Hospital SJCRH Total Therapy XVII NCT03117751 The aim of this study is to perform a GWAS in ALL children to provide insight into genetic loci affecting the occurrence of severe grade III-V vincristine-related peripheral neuropathy during induction therapy in the AIEOP protocols
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
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