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

NCT06225128 | Recruiting

• 1 other identifier: APHP230805
• Study Type: observational
• Target: 120
• Locations: 1 country
• Sites: 1

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

Outcome Measures

Primary Outcomes (1)

• Overall Response (CR+CRh+Cri)

  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).

  Up to 6 months

Secondary Outcomes (9)

• Number of MRD-negative response (including CRMRD-, CRhMRD- and CRiMRD-)

  Up to 6 months

• Best response after any number of AZA/VEN cycles

  Up to 6 months

• MRD-negative response after any number of AZA/VEN cycles

  Up to 6 months

• Response duration

  Up to 6 months

• Treatment failure per ELN22 criteria

  Up to 6 months

Study Arms (1)

Patients with AML

Other: Biobanking blood; Other: Bone marrow specimens

Interventions

Biobanking blood 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.

Patients with AML

Bone marrow specimens 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)

Patients with AML

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Patients already included in eTHEMA observationnal cohort

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hôpital Saint Louis

Paris, France

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Central Study Contacts

Raphael Itzykson, Pr

CONTACT

+33142499643; raphael.itzykson@aphp.fr

Jérôme Lambert, Pr

CONTACT

+33142499742; jerome.lambert@u-paris.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 12, 2023
• First Posted: January 25, 2024
• Study Start: January 16, 2024
• Primary Completion (Estimated): June 19, 2027
• Study Completion (Estimated): June 19, 2027
• Last Updated: May 29, 2024

Record last verified: 2023-07

Locations

FR (1)