Dynamics of Resistance Emergence to Azacitidine-based Therapies in Acute Myeloid Leukemia

NCT ID: NCT06225128

Last Updated: 2024-05-29

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 120 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2024-01-16
• Study Completion Date: 2027-06-19

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 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.

By 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.

Conditions

Acute Myeloid Leukemia

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Patients with AML

Biobanking blood

Intervention Type: OTHER

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.

Bone marrow specimens

Intervention Type: OTHER

Additional volume of 2mL (EDTA)

• at screening for correlative studies,at Day 7 for smears and for correlative studies.
• Post-cycle 1 and post-cycle 6 evaluations for correlative studies.

Optionnal :

Trephine biopsy at screening and at post-cycle 1 and 6 evaluations (performed at the same time as aspiration)

Interventions

Biobanking blood

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.

Intervention Type: OTHER

Bone marrow specimens

Additional volume of 2mL (EDTA)

• at screening for correlative studies,at Day 7 for smears and for correlative studies.
• Post-cycle 1 and post-cycle 6 evaluations for correlative studies.

Optionnal :

Trephine biopsy at screening and at post-cycle 1 and 6 evaluations (performed at the same time as aspiration)

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• be ≥18 years old,
• have a newly diagnosed AML according to ICC 2022 criteria,

• patients with AML related to prior chemotherapy or radiotherapy for another cancer will be eligible,
• patients with MDS/AML per ICC 2022 criteria will be eligible,
• have signed the informed consent form of the eTHEMA observatory trial
• have ≥10% blasts on the bone marrow smear at screening,
• have not received any treatment for AML except for hydroxyurea and/or steroids,

• Patients having previously received hypomethylating agents for an antecedent myelodysplastic syndrome are ineligible,
• be eligible to AZA/VEN or AZA/IVO therapy, due to general health status,
• have an ECOG performance status ≤ 2,
• be planned to receive azacitidine and venetoclax (AZA/VEN) or azacitidine and ivosidenib (AZA/IVO) as frontline therapy,
• weigh ≥ 40 kg (compliance to Loi Jardé for PB sampling),
• have provided written informed consent obtained prior to any screening procedures

Exclusion Criteria

At screening, patients must NOT:

• have suspected or proven acute promyelocytic leukemia based on morphology, karyotype or molecular assay, including APL with non-PML::RARA rearrangements,
• have suspected or proven AML with t(9;22)(q34.1;q11.2)/BCR::ABL1 based on karyotype or molecular assay,
• have myeloid sarcoma,
• have failed to perform bone marrow aspiration at screening,
• be pregnant or breastfeeding (for women),
• present any of concurrent severe and/or uncontrolled medical condition, which could compromise participation in the study,
• be enrolled in a clinical trial which could compromise participation in the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Hôpital Saint Louis

Paris, , France

Site Status: RECRUITING

Countries

France

Central Contacts

Raphael Itzykson, Pr

Role: CONTACT

raphael.itzykson@aphp.fr

+33142499643

Jérôme Lambert, Pr

Role: CONTACT

jerome.lambert@u-paris.fr

+33142499742

Facility Contacts

Raphael Itzykson, Pr

Role: primary

raphael.itzykson@aphp.fr

142499643 ext. +33

Other Identifiers

APHP230805

Identifier Type: -

Identifier Source: org_study_id