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NCT Number: NCT06225128

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

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.

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Key information

Conditions

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

Age range

18 year–100 year

Sex eligibility

All sexes

Study type

Observational

Primary location

Hôpital Saint Louis

Paris, France

Location status: Recruiting

Location contact

Raphael Itzykson, Pr

CONTACT

[email protected]

142499643 ext. +33

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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,
  • 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,
  • 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.

Treatment and study plan

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.

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)

Primary outcomes

  1. Overall Response (CR+CRh+Cri)

    Time frame: Up to 6 months

    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).

Secondary outcomes

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

    Time frame: Up to 6 months

  2. Best response after any number of AZA/VEN cycles

    Time frame: Up to 6 months

    It is ranked as follow : CR > CRh > Cri

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

    Time frame: Up to 6 months

    including CRMRD-, CRhMRD- and CriMRD-

  4. Response duration

    Time frame: Up to 6 months

    Defined as the interval between first response among CR, CRh and Cri

  5. Treatment failure per ELN22 criteria

    Time frame: Up to 6 months

  6. Overall survival

    Time frame: Up to 6 months

  7. Event-free survival

    Time frame: Up to 6 months

  8. Relapse-free survival

    Time frame: Up to 6 months

  9. Cumulative Incidence of Relapse (CIR) according to DST on the NEXT platform

    Time frame: Up to 6 months

Study contacts

Contact information is provided by the study sponsor or research team.

Jérôme Lambert, Pr

CONTACT

[email protected]

+33142499742

Raphael Itzykson, Pr

CONTACT

[email protected]

+33142499643

Sponsors and collaborators

Lead sponsor

Assistance Publique - Hôpitaux de Paris

Other

Registry information

Official study title

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

Acronym: DREAM

Important dates

Study start
2024
Primary completion
2027
Study completion
2027
First posted
Jan 25, 2024
Registry last updated
May 29, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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