Ignite Creation Date:
2024-10-26 @ 3:42 PM
Last Modification Date:
2024-10-26 @ 3:42 PM
Study NCT ID:
NCT06630221
Status:
NOT_YET_RECRUITING
Last Update Posted:
None
First Post:
2024-10-04
Brief Title:
Eltrombopag as a Novel Therapeutic Approach for Low-risk MDS and CMML With TET2 Mutations
Sponsor:
None
Organization:
None
Study Overview
Official Title:
A Phase II Study of Eltrombopag as a Novel Therapeutic Approach for Patients With Low-risk Myelodysplastic Syndromes MDS and Chronic Myelomonocytic Leukemia CMML With TET2 Mutations
Status:
NOT_YET_RECRUITING
Status Verified Date:
2024-10
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 purpose of this study is to evaluate if a study drug called eltrombopag can improve the blood cell counts in patients with low-risk Myelodysplastic Syndromes MDS and Chronic Myelomonocytic Leukemia CMML with mutations in TET2 gene observe changes in the TET2 gene over time and evaluate the effectiveness of the treatment TET2 gene is one of the most frequently mutated genes altered parts of the DNA in MDS and CMML
Eltrombopag is a Food and Drug Administration FDA approved drug for the treatment of severe aplastic anemia and low levels of platelets in patients with persistent or chronic immune thrombocytopenia ITP and chronic hepatitis C Eltrombopag is considered investigational experimental in this study because the FDA has not approved its use in the treatment of low-risk MDS or CMML Eltrombopag is a drug that helps stimulate the bodys process of making more platelets small components of blood that help with clotting by interacting with specific parts of cells This interaction starts a series of signals that encourage the growth and development of the cells that produce platelets It was found that this drug could stop the growth of TET2 mutated cells
Eltrombopag is a Food and Drug Administration FDA approved drug for the treatment of severe aplastic anemia and low levels of platelets in patients with persistent or chronic immune thrombocytopenia ITP and chronic hepatitis C Eltrombopag is considered investigational experimental in this study because the FDA has not approved its use in the treatment of low-risk MDS or CMML Eltrombopag is a drug that helps stimulate the bodys process of making more platelets small components of blood that help with clotting by interacting with specific parts of cells This interaction starts a series of signals that encourage the growth and development of the cells that produce platelets It was found that this drug could stop the growth of TET2 mutated cells
Detailed Description:
Epigenetic changes such as alterations in DNA methylation and histone modification play an important role in the pathophysiology of myelodysplastic syndromes MDS With the development of next-generation sequencing NGS platforms it has become possible to identify genomic aberrations involved in the MDS epigenetics Additionally with the advances in therapeutic methods in MDS several novel genomic aberrations have been reported to predict the effectiveness of specific treatment It is becoming clear that genomic aberrations may offer more precise cancer phenotypes and help predict precise therapies for MDS patients eg IDH1 and IDH2 inhibitors TET2 gene is a member of the DNA methylation machinery and one of the most frequently mutated genes in MDS and chronic myelomonocytic leukemia CMML a disease entity similar to MDS with similar bone marrow dysplasia and accompanying cytopenias TET DNA dioxygenases hydroxylate 5-methylcytosine 5mC to 5-hydroxy-mC 5hmC a process that leads to passive demethylation and thereby initiation of differentiation programs of hematopoietic stem cells HSCs TET2 mutations TET2MT often act as founder lesions for clonal hematopoiesis of indeterminate potential CHIP Our group has demonstrated that mutational exclusivity of TET2 and isocitrate dehydrogenases 1 and 2 IDH12 result from production of a neomorphic natural TET2 inhibitor α-hydroxyglutarate 2HG 2HG is selectively and synthetically lethal to TET2-deficient HSCs reliant for their survival on minimal residual dioxygenase activity supplied by less abundant TET1 and TET3 This observation inspired the idea of generating TET inhibitors as drugs selective for TET2 mutant TET2MT leukemia cells Based on the structure of 2HG investigator generated a more potent TETi76 and showed that this drug is indeed synthetically lethal to TET2MT and TET2 proficient cells In search for alternative agents with suitable activity investigator next performed a high throughput drug screen using an in vitro DNA dioxygenase assay Among several hits eltrombopag EPAG was unique as it is already used in clinical practice as a thrombopoietin receptor TPOR agonist Investigator showed that this agent inhibited growth of TET2MT cells in murine TET2MT models independent of its TPOR activity and have determined its binding site and mode of action on TET dioxygenases1 Since EPAG is an FDA approved drug with known toxicities and good tolerability repurposing this agent as a TET inhibitor would greatly shorten the development time and thus rapidly provide a selective and well-tolerated drug for the therapy of patients with TET2MT MDS Investigators have obtained granular molecular and response data from historical trials of EPAG5Azacytidine in unselected MDS and aplastic anemia AA and were able to retrospectively assert that indeed those with TET2MT disease responded to EPAG therapy resulting in decreased TET2MT clonal burden
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None