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

Acute Myeloid Leukemia Clinical Trial

— DREAM  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06225128
• Other study ID #: APHP230805
• Status: Recruiting
• Start date: January 16, 2024
• Est. completion date: June 19, 2027

Study information

• Verified date: July 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Raphael Itzykson, Pr
• Phone: +33142499643
• Email: raphael.itzykson[@]aphp.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: June 19, 2027
• Est. primary completion date: June 19, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Other:
• 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.
• 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)

Locations

Country	Name	City	State
France	Hôpital Saint Louis	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Number of MRD-negative response (including CRMRD-, CRhMRD- and CRiMRD-)		Up to 6 months
Secondary	Best response after any number of AZA/VEN cycles	It is ranked as follow : CR > CRh > Cri	Up to 6 months
Secondary	MRD-negative response after any number of AZA/VEN cycles	including CRMRD-, CRhMRD- and CriMRD-	Up to 6 months
Secondary	Response duration	Defined as the interval between first response among CR, CRh and Cri	Up to 6 months
Secondary	Treatment failure per ELN22 criteria		Up to 6 months
Secondary	Overall survival		Up to 6 months
Secondary	Event-free survival		Up to 6 months
Secondary	Relapse-free survival		Up to 6 months
Secondary	Cumulative Incidence of Relapse (CIR) according to DST on the NEXT platform		Up to 6 months