Ignite Creation Date:
2024-05-06 @ 8:01 PM
Last Modification Date:
2024-10-26 @ 3:19 PM
Study NCT ID:
NCT06225128
Status:
RECRUITING
Last Update Posted:
2024-05-29
First Post:
2023-12-12
Brief Title:
Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid Leukemia
Sponsor:
Assistance Publique - Hôpitaux de Paris
Organization:
Assistance Publique - Hôpitaux de Paris
Study Overview
Official Title:
Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid
Status:
RECRUITING
Status Verified Date:
2023-07
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:
DREAM
Brief Summary:
Acute myeloid leukemia AML is a malignancy of aging endowed with poor prognosis The combination of the hypomethylating agent azacitidine AZA with the BCL-2 inhibitor venetoclax VEN is the first-line treatment of older AML patients but is endowed with substantial resistance The project leverages functional precision oncology single-cell studies and mouse experiments to dissect the mechanisms of primary and adaptive resistance to AZAVEN The primary objective is to prospectively validate an ex vivo drug sensitivity testing DST assay as predictor of primary resistance to first-line AZAVEN in 100 unfit AML patients The study will also explore whether newer DST assays with enhanced niche mimicry can improve on the standard assay
By serially interrogating the short-term fate of both leukemic and immune cells upon AZAVEN exposure in patients primed towards refractoriness transient or prolonged remission the aim is to dissect the cell-intrinsic and immune-mediated mechanisms of primary versus adaptive resistance A parallel flow cytometry study will interrogate the role of senescence in AZAVEN activity These translational studies will be mirrored by experiments in a transplantable AML model derived from syngeneic mice harboring the age-related Tet2-- leukemia-predisposing genotype Lineage tracing single-cell experiments will backtrack AZAVEN resistance to determine whether it is driven by selection or adaptation The actionable stress sensor Pml will be invalidated in the same model to determine whether Pml-driven senescence contributes to AZAVEN anti-leukemic activity in vivo The project will pave the way to the clinical implementation of functional precision oncology in a high-risk malignancy By simultaneously interrogating cell-intrinsic and immune-mediated drug resistance in vivo in a prospective patient cohort mirrored by controlled mice experiments the project will provide a framework for the integrative analysis of drug resistance in cancers
By serially interrogating the short-term fate of both leukemic and immune cells upon AZAVEN exposure in patients primed towards refractoriness transient or prolonged remission the aim is to dissect the cell-intrinsic and immune-mediated mechanisms of primary versus adaptive resistance A parallel flow cytometry study will interrogate the role of senescence in AZAVEN activity These translational studies will be mirrored by experiments in a transplantable AML model derived from syngeneic mice harboring the age-related Tet2-- leukemia-predisposing genotype Lineage tracing single-cell experiments will backtrack AZAVEN resistance to determine whether it is driven by selection or adaptation The actionable stress sensor Pml will be invalidated in the same model to determine whether Pml-driven senescence contributes to AZAVEN anti-leukemic activity in vivo The project will pave the way to the clinical implementation of functional precision oncology in a high-risk malignancy By simultaneously interrogating cell-intrinsic and immune-mediated drug resistance in vivo in a prospective patient cohort mirrored by controlled mice experiments the project will provide a framework for the integrative analysis of drug resistance in cancers
Detailed Description:
None
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