Ignite Creation Date:
2025-12-26 @ 11:14 AM
Ignite Modification Date:
2025-12-29 @ 7:09 PM
Study NCT ID:
NCT06225128
Status:
RECRUITING
Last Update Posted:
2024-05-29
First Post:
2023-12-12
Is Gene Therapy:
True
Has Adverse Events:
False
Brief Title:
Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid Leukemia
Sponsor:
Organization:
Raw JSON
{'hasResults': False, 'derivedSection': {'miscInfoModule': {'versionHolder': '2025-12-24'}, 'conditionBrowseModule': {'meshes': [{'id': 'D015470', 'term': 'Leukemia, Myeloid, Acute'}], 'ancestors': [{'id': 'D007951', 'term': 'Leukemia, Myeloid'}, {'id': 'D007938', 'term': 'Leukemia'}, {'id': 'D009370', 'term': 'Neoplasms by Histologic Type'}, {'id': 'D009369', 'term': 'Neoplasms'}, {'id': 'D006402', 'term': 'Hematologic Diseases'}, {'id': 'D006425', 'term': 'Hemic and Lymphatic Diseases'}]}}, 'protocolSection': {'designModule': {'studyType': 'OBSERVATIONAL', 'designInfo': {'timePerspective': 'PROSPECTIVE', 'observationalModel': 'COHORT'}, 'enrollmentInfo': {'type': 'ESTIMATED', 'count': 120}, 'patientRegistry': False}, 'statusModule': {'overallStatus': 'RECRUITING', 'startDateStruct': {'date': '2024-01-16', 'type': 'ACTUAL'}, 'expandedAccessInfo': {'hasExpandedAccess': False}, 'statusVerifiedDate': '2023-07', 'completionDateStruct': {'date': '2027-06-19', 'type': 'ESTIMATED'}, 'lastUpdateSubmitDate': '2024-05-26', 'studyFirstSubmitDate': '2023-12-12', 'studyFirstSubmitQcDate': '2024-01-23', 'lastUpdatePostDateStruct': {'date': '2024-05-29', 'type': 'ACTUAL'}, 'studyFirstPostDateStruct': {'date': '2024-01-25', 'type': 'ACTUAL'}, 'primaryCompletionDateStruct': {'date': '2027-06-19', 'type': 'ESTIMATED'}}, 'outcomesModule': {'primaryOutcomes': [{'measure': 'Overall Response (CR+CRh+Cri)', 'timeFrame': 'Up to 6 months', 'description': 'Overall Response (CR+CRh+Cri) per European LeukemiaNet 2022 criteria (Döhner et al., Blood 2022), according to DST on the NEXT platform on the population treated per protocol (AZA/VEN).'}], 'secondaryOutcomes': [{'measure': 'Number of MRD-negative response (including CRMRD-, CRhMRD- and CRiMRD-)', 'timeFrame': 'Up to 6 months'}, {'measure': 'Best response after any number of AZA/VEN cycles', 'timeFrame': 'Up to 6 months', 'description': 'It is ranked as follow : CR \\> CRh \\> Cri'}, {'measure': 'MRD-negative response after any number of AZA/VEN cycles', 'timeFrame': 'Up to 6 months', 'description': 'including CRMRD-, CRhMRD- and CriMRD-'}, {'measure': 'Response duration', 'timeFrame': 'Up to 6 months', 'description': 'Defined as the interval between first response among CR, CRh and Cri'}, {'measure': 'Treatment failure per ELN22 criteria', 'timeFrame': 'Up to 6 months'}, {'measure': 'Overall survival', 'timeFrame': 'Up to 6 months'}, {'measure': 'Event-free survival', 'timeFrame': 'Up to 6 months'}, {'measure': 'Relapse-free survival', 'timeFrame': 'Up to 6 months'}, {'measure': 'Cumulative Incidence of Relapse (CIR) according to DST on the NEXT platform', 'timeFrame': 'Up to 6 months'}]}, 'oversightModule': {'oversightHasDmc': False, 'isFdaRegulatedDrug': False, 'isFdaRegulatedDevice': False}, 'conditionsModule': {'conditions': ['Acute Myeloid Leukemia']}, 'descriptionModule': {'briefSummary': '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 AZA/VEN. The primary objective is to prospectively validate an ex vivo drug sensitivity testing (DST) assay as predictor of primary resistance to first-line AZA/VEN in 100 unfit AML patients. The study will also explore whether newer DST assays with enhanced niche mimicry can improve on the standard assay.\n\nBy serially interrogating the short-term fate of both leukemic and immune cells upon AZA/VEN 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 AZA/VEN 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 AZA/VEN 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 AZA/VEN 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.'}, 'eligibilityModule': {'sex': 'ALL', 'stdAges': ['ADULT', 'OLDER_ADULT'], 'maximumAge': '100 Years', 'minimumAge': '18 Years', 'samplingMethod': 'NON_PROBABILITY_SAMPLE', 'studyPopulation': 'Patients already included in eTHEMA observationnal cohort', 'healthyVolunteers': False, 'eligibilityCriteria': 'Inclusion Criteria:\n\n* be ≥18 years old,\n* have a newly diagnosed AML according to ICC 2022 criteria,\n\n * patients with AML related to prior chemotherapy or radiotherapy for another cancer will be eligible,\n * patients with MDS/AML per ICC 2022 criteria will be eligible,\n* have signed the informed consent form of the eTHEMA observatory trial\n* have ≥10% blasts on the bone marrow smear at screening,\n* have not received any treatment for AML except for hydroxyurea and/or steroids,\n\n * Patients having previously received hypomethylating agents for an antecedent myelodysplastic syndrome are ineligible,\n* be eligible to AZA/VEN or AZA/IVO therapy, due to general health status,\n* have an ECOG performance status ≤ 2,\n* be planned to receive azacitidine and venetoclax (AZA/VEN) or azacitidine and ivosidenib (AZA/IVO) as frontline therapy,\n* weigh ≥ 40 kg (compliance to Loi Jardé for PB sampling),\n* have provided written informed consent obtained prior to any screening procedures\n\nExclusion Criteria:\n\nAt screening, patients must NOT:\n\n* have suspected or proven acute promyelocytic leukemia based on morphology, karyotype or molecular assay, including APL with non-PML::RARA rearrangements,\n* have suspected or proven AML with t(9;22)(q34.1;q11.2)/BCR::ABL1 based on karyotype or molecular assay,\n* have myeloid sarcoma,\n* have failed to perform bone marrow aspiration at screening,\n* have received previous therapy for AML with any investigational agent or cytotoxic drug, within 28 days before starting treatment. Only hydroxyurea is permitted for the control of blood counts. Aside from hypomethylating agents, other treatments for an antecedent myeloid neoplasm (MDS or MPN) are not considered as exclusion criteria,\n* be pregnant or breastfeeding (for women),\n* present any of concurrent severe and/or uncontrolled medical condition, which could compromise participation in the study,\n* be enrolled in a clinical trial which could compromise participation in the study.'}, 'identificationModule': {'nctId': 'NCT06225128', 'acronym': 'DREAM', 'briefTitle': 'Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid Leukemia', 'organization': {'class': 'OTHER', 'fullName': 'Assistance Publique - Hôpitaux de Paris'}, 'officialTitle': 'Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid', 'orgStudyIdInfo': {'id': 'APHP230805'}}, 'armsInterventionsModule': {'armGroups': [{'label': 'Patients with AML', 'interventionNames': ['Other: Biobanking blood', 'Other: Bone marrow specimens']}], 'interventions': [{'name': 'Biobanking blood', 'type': 'OTHER', 'description': 'Additional volume of 30mL (EDTA) At Screening, pre-Cycle 1 Day 1,Day 1 H8, Day 2, Day of post-cycle 1 and post-cycle 6 evaluation.', 'armGroupLabels': ['Patients with AML']}, {'name': 'Bone marrow specimens', 'type': 'OTHER', 'description': 'Additional volume of 2mL (EDTA)\n\n* at screening for correlative studies,at Day 7 for smears and for correlative studies.\n* Post-cycle 1 and post-cycle 6 evaluations for correlative studies.\n\nOptionnal :\n\nTrephine biopsy at screening and at post-cycle 1 and 6 evaluations (performed at the same time as aspiration)', 'armGroupLabels': ['Patients with AML']}]}, 'contactsLocationsModule': {'locations': [{'city': 'Paris', 'status': 'RECRUITING', 'country': 'France', 'contacts': [{'name': 'Raphael Itzykson, Pr', 'role': 'CONTACT', 'email': 'raphael.itzykson@aphp.fr', 'phone': '142499643', 'phoneExt': '+33'}], 'facility': 'Hôpital Saint Louis', 'geoPoint': {'lat': 48.85341, 'lon': 2.3488}}], 'centralContacts': [{'name': 'Raphael Itzykson, Pr', 'role': 'CONTACT', 'email': 'raphael.itzykson@aphp.fr', 'phone': '+33142499643'}, {'name': 'Jérôme Lambert, Pr', 'role': 'CONTACT', 'email': 'jerome.lambert@u-paris.fr', 'phone': '+33142499742'}]}, 'ipdSharingStatementModule': {'ipdSharing': 'UNDECIDED'}, 'sponsorCollaboratorsModule': {'leadSponsor': {'name': 'Assistance Publique - Hôpitaux de Paris', 'class': 'OTHER'}, 'responsibleParty': {'type': 'SPONSOR'}}}}