Involvement of CDA and/or dCK Metabolizing Enzymes in the Response to Azacytidine Treatment of Patients With Hematologic Malignancies

NCT06886425 | Recruiting

• 2 other identifiers: RCAPHM19_03332020-A02042-37
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

Until now, the development of personalized medicine in oncology has relied on the use of somatic biomarkers to help therapists choose the right molecule(s) to administer, based on the genetic and molecular profile of each hematological disease. In this project, investigators propose to extend the strategy of therapeutic individualization to the field of dosage targeting. Today, azacytidine is a standard treatment for patients with acute myeloid leukemia (AML) and/or myelodysplastic syndromes (MDS), usually as monotherapy. According to the treatment regimen, azacytidine is prescribed at a standard dose (DS=75mg/m²/d), administered subcutaneously every day for 7 days. The treatment cycle is repeated every 28 days. No study has evaluated the relevance of "a priori" dose adjustment on an individual basis, according to each patient's pharmacogenetic data. In current practice, doses are adapted a posteriori, and reduced empirically, following the occurrence of observed toxicity (6 to 71% of patients) (Schuck A et al. 2017). This ex-post adjustment in the face of grade 3-4 toxicity is a loss of chance for the patient. Similarly, under-dosing patients for fear of toxicity is another loss of chance. Investigator's hypothesis is that the optimal dose of azacytidine depends not only on the characteristics of the patient's pathology (risk groups including cytogenetic and molecular biology data), but also on the patient's individual characteristics (genetic status of metabolic enzymes and transporters). A mathematical model of the PK/PD type could, on the basis of early observations of circulating levels, be capable of rapidly predicting the pharmacodynamic repercussions in each patient, thus enabling rapid individualization of dosages. In the future, such a tool could make it possible to propose dosage adjustments rapidly after treatment initiation, before toxicity occurs, by predicting azacytidine exposure levels, themselves correlated with the patient's clinical condition. Study design: In this open-label, paucicentric, non-randomized study, patients with AML and/or MDS, all of whom are receiving azacytidine-based chemotherapy as part of their standard treatment regimen, will be included. Each patient will be monitored for toxicities (EORTC), treatment response and progression-free survival. In addition to the standard care described above, each patient will undergo a series of constitutional genetic investigations conducted by NGS on markers linked to azacytidine pharmacokinetics (CDA, dCK). Another series of blood samples will be taken to calculate individual azacytidine pharmacokinetic parameters using a Bayesian approach. Expected results: This study should make it possible to correlate pharmacogenetics with patient plasma exposure, and ultimately improve the molecule's efficacy/toxicity balance by personalizing dosage regimens, which until now have been carried out on an empirical basis. Prospects: If the data are validated, a pre-therapeutic ADC assay could predict azacytidine pharmacodynamics and enable individual dose and/or dosage adjustment, as is the case with 5-FU and DPD.

Conditions

Myelodysplastic Syndromes (MDS); Leukemia Acute Myeloid - AML

Outcome Measures

Primary Outcomes (1)

• Plasma dosage of azacytidine

  assessment of the relationship between azacytidine pharmacokinetic profile and cytidine deaminase status

  Through study completion, an average of 2 years

Secondary Outcomes (2)

• phenotypic activity of CDA

  Through study completion, an average of 2 years

• Determination of ADC genotype

  Through study completion, an average of 2 years

Study Arms (1)

Blood sampling

EXPERIMENTAL

Blood sampling through the differents cures of the patients

Other: genetic study; Other: Pharmacokinetic study; Other: Study of phenotypic activity of cytidine deaminase

Interventions

genetic study OTHER

Blood sampling : Cure 1 before starting treatment Cure 3 before starting treatment Cure 6 after completion of treatment

Blood sampling

Pharmacokinetic study OTHER

Cure 1: after completion of subcutaneous administration of azacytidine A total of 5 samples in the induction phase. Cure 3: after completion of subcutaneous administration of azacytidine A total of 5 samples in the induction phase. Cure 6: after completion of subcutaneous administration of azacytidine A total of 5 samples in the induction phase.

Blood sampling

Study of phenotypic activity of cytidine deaminase OTHER

Blood sampling : Cure 1 before starting treatment Cure 3 before starting treatment Cure 6 after completion of treatment

Blood sampling

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients over 18 years of age
• Patients with acute myeloid leukemia
• Patient with myelodysplastic syndrome
• Person who has given non-opposition
• Patient who has signed an authorization to perform a constitutional genetic analysis (in the context of care)
• Need for effective contraception in patients of childbearing age

You may not qualify if:

• Failure to obtain non-opposition
• Adults under guardianship or safeguard of justice
• Persons deprived of their liberty
• Patient participating in another research project
• Pregnancy in progress

Sponsors & Collaborators

• Assistance Publique Hopitaux De Marseille: lead

Study Sites (1)

Hôpital de la Conception

Marseille, 13005, France

RECRUITING

MeSH Terms

Conditions

Myelodysplastic Syndromes

Interventions

Genetic Association Studies

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Genetic Techniques; Investigative Techniques

Central Study Contacts

Geoffroy Venton

CONTACT

0491435817; promotion.interne@ap-hm.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 7, 2025
• First Posted: March 20, 2025
• Study Start: June 14, 2021
• Primary Completion (Estimated): June 14, 2026
• Study Completion (Estimated): June 14, 2028
• Last Updated: March 20, 2025

Record last verified: 2025-03

Locations

FR (1)